Deciphering radiological stable disease to immune checkpoint inhibitors.

BACKGROUND: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. PATIENTS AND METHODS: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. RESULTS: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. CONCLUSIONS: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.

Analysis of outcomes of emergency general and gastrointestinal surgery during the COVID-19 pandemic.

BACKGROUND: Few surgical studies have provided adjusted comparative postoperative outcome data among contemporary patients with and without COVID-19 infection and patients treated before the pandemic. The aim of this study was to determine the impact of performing emergency surgery in patients with concomitant COVID-19 infection. METHODS: Patients who underwent emergency general and gastrointestinal surgery from March to June 2020, and from March to June 2019 in 25 Spanish hospitals were included in a retrospective study (COVID-CIR). The main outcome was 30-day mortality. Secondary outcomes included postoperative complications and failure to rescue (mortality among patients who developed complications). Propensity score-matched comparisons were performed between patients who were positive and those who were negative for COVID-19; and between COVID-19-negative cohorts before and during the pandemic. RESULTS: Some 5307 patients were included in the study (183 COVID-19-positive and 2132 COVID-19-negative during pandemic; 2992 treated before pandemic). During the pandemic, patients with COVID-19 infection had greater 30-day mortality than those without (12.6 versus 4.6 per cent), but this difference was not statistically significant after propensity score matching (odds ratio (OR) 1.58, 95 per cent c.i. 0.88 to 2.74). Those positive for COVID-19 had more complications (41.5 versus 23.9 per cent; OR 1.61, 1.11 to 2.33) and a higher likelihood of failure to rescue (30.3 versus 19.3 per cent; OR 1.10, 0.57 to 2.12). Patients who were negative for COVID-19 during the pandemic had similar rates of 30-day mortality (4.6 versus 3.2 per cent; OR 1.35, 0.98 to 1.86) and complications (23.9 versus 25.2 per cent; OR 0.89, 0.77 to 1.02), but a greater likelihood of failure to rescue (19.3 versus 12.9 per cent; OR 1.56, 95 per cent 1.10 to 2.19) than prepandemic controls. CONCLUSION: Patients with COVID-19 infection undergoing emergency general and gastrointestinal surgery had worse postoperative outcomes than contemporary patients without COVID-19. COVID-19-negative patients operated on during the COVID-19 pandemic had a likelihood of greater failure-to-rescue than prepandemic controls.

Effects of yeast culture supplementation on lactation performance and rumen fermentation profile and microbial abundance in mid-lactation Holstein dairy cows.

The continuous trend for a narrowing margin between feed cost and milk prices across dairy farms in the United States highlights the need to improve and maintain feed efficiency. Yeast culture products are alternative supplements that have been evaluated in terms of milk performance and feed efficiency; however, less is known about their potential effects on altering rumen microbial populations and consequently rumen fermentation. Therefore, the objective of this study was to evaluate the effect of yeast culture supplementation on lactation performance, rumen fermentation profile, and abundance of major species of ruminal bacteria in lactating dairy cows. Forty mid-lactation Holstein dairy cows (121 ± 43 days in milk; mean ± standard deviation; 32 multiparous and 8 primiparous) were used in a randomized complete block design with a 7-d adaptation period followed by a 60-d treatment period. Cows were blocked by parity, days in milk, and previous lactation milk yield and assigned to a basal total mixed ration (TMR; 1.6 Mcal/kg of dry matter, 14.6% crude protein, 21.5% starch, and 38.4% neutral detergent fiber) plus 114 g/d of ground corn (CON; n = 20) or basal TMR plus 100 g/d of ground corn and 14 g/d of yeast culture (YC; n = 20; Culture Classic HD, Cellerate Yeast Solutions, Phibro Animal Health Corp.). Treatments were top-dressed over the TMR once a day. Cows were individually fed 1 × /d throughout the trial. Blood and rumen fluid samples were collected in a subset of cows (n = 10/treatment) at 0, 30, and 60 d of the treatment period. Rumen fluid sampled via esophageal tubing was analyzed for ammonia-N, volatile fatty acids (VFA), and ruminal bacteria populations via quantitative PCR amplification of 16S ribosomal DNA genes. Milk yield was not affected by treatment effects. Energy balance was lower in YC cows than CON, which was partially explain by the trend for lower dry matter intake as % body weight in YC cows than CON. Cows fed YC had greater overall ruminal pH and greater total VFA (mM) at 60 d of treatment period. There was a contrasting greater molar proportion of isovalerate and lower acetate proportion in YC-fed cows compared with CON cows. Although the ruminal abundance of specific fiber-digesting bacteria, including Eubacterium ruminantium and Ruminococcus flavefaciens, was increased in YC cows, others such as Fibrobacter succinogenes were decreased. The abundance of amylolytic bacteria such as Ruminobacter amylophilus and Succinimonas amylolytica were decreased in YC cows than CON. Our results indicate that the yeast culture supplementation seems to promote some specific fiber-digesting bacteria while decreasing amylolytic bacteria, which might have partially promoted more neutral rumen pH, greater total VFA, and isovalerate.

Enzymatic effects of Pleurotus ostreatus spent substrate on whole-plant corn silage and performance of lactating goats.

Pleurotus ostreatus (oyster mushroom) synthesizes enzymes that degrade lignin, cellulose, and hemicellulose. The objectives of this study were to evaluate the effect of Pleurotus ostreatus spent substrate (POSS) on whole-plant corn silage (WPCS) chemical composition, antioxidant capacity, lignin monomers, and in vitro digestibility, as well as the performance of lactating goats fed corn silage treated with different levels of POSS. In experiment 1, 4 levels of lignocellulolytic enzymes were tested in a complete randomized design: 0, 10, 20, and 30 mg of lignocellulosic enzymes per kilogram of fresh matter, 4 replicates per treatment (vacuum-sealed bags). The bags were opened 60 d after ensiling. In experiment 2, corn silage treated with 3 enzyme levels (0, 10, or 30 mg/kg of fresh matter) was fed to lactating goats as part of the total mixed ration. Nine lactating Saanen goats (62.68 ± 7.62 kg BW; 44 ± 8 d in milk; 2.91 ± 0.81 kg of milk/day, mean ± SD) were assigned to three 3 × 3 Latin squares. Data were analyzed using the GLIMMIX procedure of SAS (version 9.4, SAS Institute Inc.), and means were compared by linear and quadratic orthogonal contrast. In experiment 1, neutral detergent fiber (NDF), acid detergent fiber (ADF), lignin, and cellulose quadratically decreased in the WPCS treated with POSS. At the nadir point, POSS decreased NDF by 14.1%, ADF by 19.5%, lignin by 9.07%, and cellulose by 22.1% compared with the untreated silage. Therefore, POSS led to a quadratic increase in in vitro dry matter digestibility of WPCS (+8.88% at the vertex) compared with the untreated silage. In experiment 2, POSS quadratically increased the in vivo total-tract ADF digestibility. Also, the concentration of polyphenols in the milk of goats linearly increased with the addition of POSS, and no differences were observed among treatments for milk yield and composition. In summary, adding 10 mg of lignocellulolytic enzymes from POSS per kilogram of fresh matter of whole-plant corn at ensiling had a more evident reduction in lignin and cellulose concentration, leading to greater in vitro digestibility, as well as greater in vivo ADF digestibility; however, milk yield was not different among treatments.

Glutathione and IGF-1 in bovine seminal cryopreservation: oxidative stress response and pregnancy rate / [Glutationa e IGF-1 na criopreservação seminal bovina: resposta do estresse oxidativo e taxa de gestação]

The objective of this study was to evaluate the rate of conception, metabolic, and structural conditions of cryopreserved bovine sperm cells, plus extender with IGF-1 and glutathione (GSH). 12 ejaculations of Nelore bulls were used, submitted to treatments: control, gSH (2mM/mL), IGF-1 (100ng/mL) and gSH (1mM/mL) + IGF-1 (50ng/mL). After cryopreservation and thawing the semen passed the fast thermo resistance test (TTR), plasma membrane and acrosomal integrity (PIAI), mitochondrial membrane potential (AP), oxidative stress, and conception rate. Tukey test was used for the statistical analysis of the parametric variables and the Friedman test for nonparametric. The gestation percentage was compared by the Chi-square test. There was no statistical difference (P<0.05) between treatments for the TTRr variable. Otherwise in the oxidative stress evaluated with the CellROX probe was noted that the IGF-1 showed the highest number of reactive cells (P<0.05). The PIAI, AP and gestation rate showed no difference among treatments (P>0.05), with an average of conceptions of 36.58%. It is concluded that IGF-1, gSH and their association did not cause changes in sperm motility, mitochondrial potential, plasma and acrosomal membrane integrity. IGF-1 increased oxidative stress, however, there was no difference in the gestation rate among the treatments.(AU)

Objetivou-se avaliar a taxa de concepção, as condições metabólicas e estrutural das células espermáticas bovinas criopreservadas, acrescidas de diluidores com fator de crescimento semelhante à insulina do tipo 1(IGF-1) e glutationa (GSH). Foram utilizados 12 ejaculados de touros da raça Nelore, submetidos aos tratamentos: controle, gSH (2mM/mL), IGF-1 (100ng/mL) e gSH (1mM/mL) + IGF-1 (50ng/mL). Após a criopreservação e descongelação, o sêmen passou pelos testes de termorresistência rápida (TTRr), integridade de membrana plasmática e acrossomal (PIAI), alto potencial mitocondrial (AP), estresse oxidativo e taxa de concepção. Utilizou-se o teste de Tukey para as análises estatísticas das variáveis paramétricas e o teste de Friedman para as não paramétricas, com significância de 5%. A percentagem de gestação foi comparada pelo teste do qui-quadrado. Não hove diferença estatística (P<0,05) entre os tratamentos para a variável TTRr. Já no estresse oxidativo avaliado com a sonda CellROX, observou-se que o IGF-1 apresentou maior quantidade de células reativas (P<0,05), 36,38± 24,10. A PIAI, o AP e a taxa de gestação não apresentaram diferença entre tratamentos (P>0,05), com média de concepções de 36,58%. Conclui-se que o IGF-1, a gSH e a sua associação não causaram mudanças na motilidade espermática, no potencial mitocondrial, na integridade da membrana plasmática e acrossomal. O IGF-1 aumentou o estresse oxidativo, porém sem diferença na taxa de gestação entre os tratamentos.(AU)

Short communication: Molecular markers for epithelial cells across gastrointestinal tissues and fecal RNA in preweaning dairy calves.

The objective of this study was to compare the transcription of gene markers for gastrointestinal (GI) epithelial cells, including fatty acid binding protein 2 (FABP2) and cytokeratin 8 (KRT8), and tight junction complex genes (TJP1, CLDN1, CLDN4) in fecal RNA against several GI tract tissue sections in dairy calves. Eight healthy Jersey calves were euthanized at 5 wk of age, and postmortem samples were collected from rumen, duodenum, jejunum, ileum, large intestine, cecum, and feces for total RNA isolation. Tissues and fecal samples were immediately frozen in liquid nitrogen until RNA isolation. A real-time quantitative PCR analysis was performed using a single standard curve composited of equal amounts of all samples, including cDNA from fecal and GI tract tissues. The mRNA expression of the tight junctions TJP1, CLDN1, and CLDN4 was greater in fecal RNA compared with lower GI tract tissues (i.e., duodenum, jejunum, ileum, large intestine, and cecum). Similar to fecal RNA, rumen tissue had greater expression of tight junctions CLDN1 and CLDN4 than lower GI tract tissues. Similarly, rumen tissue had greater expression of TPJ1 than all lower GI tract tissues except duodenum. The expression of TJP1 and CLDN4 was greater in fecal RNA than in rumen tissue; in contrast, CLDN1 mRNA expression was greater in rumen tissue than in the fecal RNA. The expression of FABP2 was greater in duodenum in comparison to all tissue except ileum. The mRNA expression of FABP2 in fecal samples was similar to jejunum and ileum. The expression of KRT8 in fecal samples was similar to duodenum, large intestine, and cecum. The fecal RNA had a greater expression of KRT8 in comparison to jejunum and ileum. The rumen tissue had the lowest mRNA expression of KRT8. The expression levels of FABP2, KRT8, and tight junction genes observed in fecal transcripts suggest that a considerable amount of RNA derived from GI tract epithelial cells can be detected in fecal RNA, which is in agreement with previous data in neonatal dairy calves and other biological models including humans, rodents, and primates. The greater expression of tight junctions in fecal RNA in comparison to sections of the low GI remains to be understood, and due to the importance of tight junctions in GI physiology, further clarification of this effect is warranted. The similarities in mRNA expression of FABP2 and KRT8 between fecal RNA and intestinal sections add up to the accumulating evidence that fecal RNA can be used to investigate molecular alterations in the GI tract of neonatal dairy calves. Further research in this area should include high-throughput transcriptomic analysis via RNA-seq to uncover novel molecular markers for specific sections of the GI tract of neonates.

Comparación de perfil lipídico por sexo y edad en una población de equinos en Caldas (Colombia) / Comparison of lipid profile by sex and age in an equine population in Caldas (Colombia)

RESUMEN Objetivo: comparar el perfil lipídico en equinos y analizar la correlación entre las cantidades lipídicas del suero de cuatro grupos. Materiales y Métodos: se obtuvieron muestras de sangre de 160 equinos en estado de ayuno, los cuales se diferenciaron por sexo y edad sin discriminar la raza así: machos jóvenes (40) y adultos (40), y hembras jóvenes (40) y adultas (40), las hembras no estaban preñadas; se determinaron los niveles de triglicéridos (TG), colesterol total (CT) y el colesterol de las lipoproteínas de alta densidad (C-HDL) mediante el método enzimático colorimétrico. El colesterol de las lipoproteínas de muy baja densidad (C-VLDL) y de baja densidad (C-LDL) se determinó usando las fórmulas de Friedewald. Los resultados se compararon mediante un análisis estadístico de Anova simple con el programa estadístico IBM SPSS Statistics 23®, donde se aceptaba diferencia estadísticamente significativa cuando p < 0,05. Resultados: las variables de CT, TG, C-HDL, C-LDL y C-VLDL del total de la población de acuerdo a la media y desviación estándar mostraron valores expresados en mg/dl de 100,3 ± 12,89; 45,59 ± 11,95; 62,03 ± 10,88; 27,91 ± 6,48; 9,11 ± 2. Al comparar los 4 grupos se encontró diferencia significativa en el C-HDL en los adultos (p-valor: 0,031), siendo mayor en las hembras adultas. Conclusiones: se presenta una diferencia estadísticamente significativa entre género para C-HDL siendo más alto en hembras adultas, mientras que para el resto de los elementos analizados (TG, CT, C-LDL, C-VLDL) no se encontró diferencia significativa entre género y edad.

ABSTRACT Objective: to compare the lipid profile in equines and to analyze the correlation bet-ween serum lipid amounts of four groups. Materials and Methods: Blood samples were obtained from 160 horses in the fasting state, they were differentiated by sex and age without discriminating race as follows: young (40) and adult males (40) and young (40) and adult females (40), the females were not pregnant; the levels of triglycerides (TG), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) were determined by the enzymatic colorimetric method. Very low density (C-VLDL) and low density (LDL-C) lipoprotein cholesterol was determined using the Friedewald formula. The results were compared using a statistical analysis of SIMPLE ANOVA with the statistical program IBM SPSS Statistics 23®, where a statistically significant difference was accepted when P < 0.05. Results: The variables of CT, TG, C-HDL, C-LDL and C-VLDL of the total population according to mean and standard deviation showed values expressed in mg/dl of100.3 ± 12.89; 45.59 ± 11.95; 62.03 ± 10.88; 27.91 ± 6.48; 9.11 ± 2. When comparing the 4 groups we found a significant difference in HDL-C in adults (p-value: 0.031), being higher in adult females. Conclusions: a statistically significant difference between genotype for HDL-C was found to be higher in adult females, whereas for the rest of the analyzed elements (TG, CT, C-LDL, C-VLDL) no significant difference between gender and age was found.

Media preferences, micro-morphometric analysis, and cardinal growth temperature determination for Phytophthora infestans sensu lato isolated from different hosts in Colombia / Preferências de mídia, análise micro-morfométricos e determinação da temperature cardeal de crescimento para Phytophthora infestans sensu lato isolada de diferentes hospedeiros na Colômbia

Abstract During the last years Phytophthora infestans sensu lato (Mont. De Bary) has caused epidemics in Colombia in Andean fruit crops such as Solanum quitoense and Solanum betaceum. Establishment of new or modified experimental procedures to study this pathogen is a mandatory subject for scientists. Twelve isolates of Phytophthora spp. obtained from six different Solanum hosts in Colombia were used to evaluate the effect of five different solid media for growth and ability to produce sporangia and liberate zoospores. Determination of the best media culture and optimal growth temperature were necessary to perform measurements and correlate the provenance of isolates with phenotypic traits. Modifications were made to use ingredients available in local markets on the following media: lime bean agar (LBA), Tree tomato or tree tomato agar (TA), carrot agar (AZ), Rye A modified agar and 32% non-clarified V8 agar. Cardinal temperature determination was performed at 10, 15, 20, and 25 °C. Morphometric traits were measured once the optimal media culture and temperature were defined. Correlation analysis showed that there is a relationship between the host and isolate's preferences for media culture and optimal growth temperature. In addition, the production of characteristic sporangia, sporangiophore and mycelia was related with the media type used and host from which the isolate was collected. In this work useful information was provided to make studies about the biology and development of isolates gathered from cultivated and wild non-traditional hosts.

Resumo Durante os últimos anos Phytophthora infestans sensu lato causou epidemias na Colômbia em lavouras de frutos andinos, como Solanum quitoense e Solanum betaceum. Estabelecimento de procedimentos experimentais novos ou modificados para estudar este patógeno é um assunto obrigatório para os cientistas. Doze isolados de Phytophthora spp. obtidos de seis diferentes hosts Solanum na Colômbia foram usados para avaliar o efeito de cinco diferentes mídias sólidas para o crescimento e a capacidade de produzir esporângios e libertar zoósporos. Determinação da melhor cultura de mídia e temperatura de crescimento ideal foram necessárias para realizar medições e correlacionar a proveniência de isolados com traços fenotípica. Foram feitas modificações para usar os ingredientes disponíveis nos mercados locais nos seguintes meios: ágar do feijão de cal (LBA), tomate da árvore ou ágar do tomate da árvore (TA), ágar da cenoura (AZ), centeio um ágar modificado e 32% de ágar-V8 não-esclarecido. A determinação da temperatura Cardeal foi realizada em 10, 15, 20 e 25 °C. Traços morfométricos foram medidos uma vez que a cultura de mídia ideal e temperatura foram definidos. Análise de correlação mostrou que há uma relação entre o hospedeiro e isolar as preferências para a cultura de mídia e temperatura de crescimento ideal. Além disso, a produção de esporângios característica, esporangióforo e mycelia foi relacionada com o tipo de mídia utilizado e hospedeiros a partir do qual o isolado foi coletado. Neste trabalho foram fornecidas informações úteis para fazer estudos sobre a biologia e o desenvolvimento de isolados recolhidos de hospedeiros não-tradicionais cultivados e selvagens.

A real-life analysis on the indications and prognostic relevance of perioperative chemotherapy in locally advanced resectable gastric adenocarcinoma.

BACKGROUND AND PURPOSE: Perioperative chemotherapy (periCTX) based on the "MAGIC" scheme has become a standard treatment in Europe for locally advanced oesophagogastric cancer. We assessed implementation and long-term oncological outcomes of MAGIC periCTX for locally advanced gastric cancer. METHODS: Population-based cohort study of all patients with locally advanced gastric cancer undergoing surgical resection with curative intent in Catalonia and Navarra (the first two autonomous communities included in the EURECCA Upper GI Spanish Working Group) between January 2011 and December 2013. The main variable was the percentage of patients treated with MAGIC periCTX. Kaplan-Meier analysis and Cox proportional hazards model were used to assess the survival benefit of periCTX. RESULTS: Among 814 patients, 217 (26.6%) received periCTX (especially patients more likely to receive it: aged < 70 years, with proximal tumors, low anesthetic risk, and cT3-4/cN+ clinical stage). 35% did not complete perioperative chemotherapy, with no relationship with age. PeriCTX showed no effect on postoperative morbimortality. Histological tumor regression was more often absent or poor (38.2%) than total or almost total (27.8%), although clinico-pathological lymph-node downstaging was higher than expected by staging inaccuracy (38.7% vs. 24.2%). PeriCTX was associated with a better survival only in cT3-4 and cN+ patients, showing less prognostic relevance than optimal oncological surgery with D2 lymphadenectomy. CONCLUSIONS: Only 26.6% of locally advanced resectable gastric cancer patients received PeriCTX. Pathological response was poor, although some degree of nodal downstaging was observed. Survival benefit of periCTX was limited to cT3-4 and cN+ patients, being less relevant than D2 lymphadenectomy.

Prevalence of peripheral neuropathy associated with chemotherapy in four oncology centers of Colombia. / Prevalencia de neuropatia periferica asociada a quimioterapia en cuatro centros oncologicos de Colombia.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy is a common adverse reaction in a variety of medications frequently used for a great number of cancer treatments. This condition consists of mainly sensory-type symptoms, motor components and autonomic changes. Reported prevalence ranges from 30-68%, after the completion of chemotherapy in non-Latin American people with different populations and socioeconomic levels. AIM: To determine the prevalence of chemotherapy-induced peripheral neuropathy in a Colombian population. PATIENTS AND METHODS: A real-world evidence cross-sectional retrospective study was performed in all patients from oncological clinical centers in Colombia, which received pharmacological therapy for any cancer between January 2015 and December 2016, with taxanes (paclitaxel, docetaxel), alkylators (oxaliplatin), proteasome inhibitors (bortezomib), and epothilone B analogs (ixabepilone). RESULTS: A total of 1,551 patients in four cities were included, and 11,280 doses were applied; predominantly females (n = 1,094; 70.5%), with a mean age of 57 ± 13 years old. Paclitaxel was the most commonly prescribed drug (n = 788; 50.8%). Chemotherapy-induced peripheral neuropathy was developed in 48.9% of paclitaxel, 58.5% of oxaliplatin, 50.5% of docetaxel, 43.7% of bortezomib and 95.2% of ixabepilone patients. Thirty-three patients were treated with two of these medications simultaneously. CONCLUSIONS: Chemotherapy-induced peripheral neuropathy is a frequent adverse reaction to daily cancer therapy in Colombian patients managed with taxanes, alkylators, proteasome inhibitors, and epothilone B analogs. Hence, it is necessary to establish more successful diagnostic methods and incorporate validated scales in the routine evaluation of all patients receiving these medications in our environment.

TITLE: Prevalencia de neuropatia periferica asociada a quimioterapia en cuatro centros oncologicos de Colombia.Introduccion. La neuropatia periferica inducida por quimioterapia es una reaccion comun a una variedad de medicamentos usados en el tratamiento del cancer, que consiste principalmente en sintomas sensitivos, con componentes motores y cambios autonomicos. La prevalencia es del 30-68% despues de terminar la quimioterapia en paises no latinoamericanos. Objetivo. Determinar la prevalencia de la neuropatia periferica inducida por quimioterapia en la poblacion colombiana. Pacientes y metodos. Estudio retrospectivo con evidencia del mundo real en la totalidad de pacientes atendidos en cuatro centros oncologicos de Colombia, quienes recibieron terapia farmacologica para algun tipo de cancer entre enero de 2015 y diciembre de 2016 con taxanos (paclitaxel, docetaxel), agentes alquilantes (oxaliplatino), inhibidores de proteasoma (bortezomib) y analogos de epotilona B (ixabepilona). Resultados. Se siguio a un total de 1.551 pacientes en cuatro ciudades a quienes se les aplicaron 11.280 dosis, con predominio femenino (n = 1.094; 70,5%) y una edad media de 57 ± 13 años. El paclitaxel fue el farmaco mas prescrito (n = 788; 50,8%). La neuropatia inducida por quimioterapia se presento en el 48,9% de los pacientes con paclitaxel, el 58,5% de los pacientes con oxaliplatino, el 50,5% de los pacientes con docetaxel, el 43,7% de los pacientes con bortezomib y el 95,2% de los pacientes con ixabepilona. Se trato a 33 pacientes con dos de estos medicamentos simultaneamente. Conclusiones. La neuropatia periferica inducida por quimioterapia es una reaccion adversa frecuente en pacientes con cancer en Colombia tratados con taxanos, alquilantes, inhibidores de proteasoma e ixabepilona. Es necesario establecer metodos diagnosticos efectivos e incorporar escalas validadas en la evaluacion rutinaria de los pacientes que reciben estas medicaciones.

Commissioning of pencil beam and Monte Carlo dose engines for non-isocentric treatments in scanned proton beam therapy.

This work describes the dosimetric commissioning of the treatment planning system (TPS) RayStation v6.1 from RaySearch Laboratories (Stockholm, Sweden) for a synchrotron-based scanned proton beam delivery with isocentric and non-isocentric setups at MedAustron. Focus was on the comparison of the pencil beam (PBv4.1) and Monte Carlo (MCv4.0) calculation algorithms. Commissioning of dose calculations was done first for 1D/2D dose delivery where the performance of the beam model in reproducing dosimetric properties for the delivery of single static pencil beams and mono-energetic layers with multiple spots was evaluated. The commissioning for 3D beam delivery employed test cases with increasing complexity: from box-shaped fields in homogeneous phantoms to the introduction of oblique incidences and inhomogeneities. Dose calculations were compared to the measured data for different air gaps and using beams with and without range shifter (RaShi). Depth-dose curves and spot shape comparisons showed good agreement of the results obtained with PBv4.1 and MCv4.0 algorithms at isocentric setup for open beam configurations (without RaShi). Comparison of transverse dose profiles for lateral heterogeneities at different depths showed better performance of the MCv4.0 algorithm in comparison to the PBv4.1 algorithm. In the case of 3D delivery comparisons of measured and TPS-calculated dose with MCv4.0 algorithm in box-shaped fields in water showed an average agreement within 2%. The results for dose calculations with the PBv4.1 algorithm showed larger deviations for beams with RaShi at all evaluated air gaps (from 64.8 cm to 14.8 cm). Our results suggest that the MCv4.0 algorithm shall be used in clinics for final dose calculation when beams with RaShi are used especially in the presence of large air gaps, inclined patient surface and lateral inhomogeneities. The detailed stepwise methodology implemented for the RayStation commissioning in this work could serve as further guidance for other facilities introducing a new TPS for proton beam therapy.

Characterization of PTW-31015 PinPoint ionization chambers in photon and proton beams.

The increased use of complex forms of radiotherapy using small-field photon and proton beams has invoked a growing interest in the use of micro-ionization chambers. In this study, 48 PTW-TM31015 PinPoint-type micro-ionization chambers that are used in the commissioning and patient specific QA of a proton pencil beam scanning (PBS) delivery system have been characterized in proton and high-energy photon beams. In both beam modalities, the entire set of PinPoint chambers was characterized by imaging them, by evaluating their stability using check source measurements, by experimentally determining the ion recombination, polarity effect and by cross calibrating them in terms of absorbed dose to water against Farmer-type ionization chambers. Beam quality correction factors were theoretically derived for both beam modalities. None of the chambers' check source readings drifted by more than 0.5% over a one year period. Beam quality correction factors for the 6 MV photon with reference to 60Co were on average 1.0 ± 0.5% lower than the theoretical values calculated according to the data and procedures outlined in IAEA TRS-398. While this difference is within the overall dosimetric uncertainty, it is significant considering only uncorrelated uncertainties indicating inconsistencies in the theoretical data. Beam quality correction factors for the 179.2 MeV proton beam with reference to 60Co were in good agreement with the theoretical data. Ion recombination and polarity correction factors were very consistent for all chambers with standard deviations of 0.2% or below show that findings from more comprehensive investigations in the literature can be considered as representative for all the chambers of this type. The characterization of 48 PinPoint-type micro-ionization chambers performed in this study provided a unique opportunity to investigate chamber-to-chamber variations of calibration, beam quality correction factors, ion recombination and polarity correction factors for an unprecedented sample size of chambers for both high-energy photon and proton beams.

Phosphorylation of nuclear factor erythroid 2-like 2 (NFE2L2) in mammary tissue of Holstein cows during the periparturient period is associated with mRNA abundance of antioxidant gene networks.

Changes in the production of reactive oxygen species in the mammary gland of dairy cows during the periparturient period could lead to oxidative stress and potentially impair mammary function. Phosphorylation of the transcription factor nuclear factor erythroid 2-like 2 (NFE2L2), also known as nuclear factor-E2-related factor 2, controls mRNA abundance of genes encoding antioxidant proteins and enzymes. The hypothesis was that NFE2L2 phosphorylation status and target gene mRNA abundance in the mammary gland of dairy cows is altered around parturition. Total NFE2L2 protein, phosphorylated protein (p-NFE2L2), and ratio of p-NFE2L2 to NFE2L2 along with mRNA abundance of 24 genes related to the NFE2L2 signaling pathway, apoptosis, and cell proliferation were measured in mammary tissue samples from Holstein cows at -30, 1, 15, and 30 d relative to parturition. Although total NFE2L2 protein abundance did not differ, p-NFE2L2 and p-NFE2L2-to-NFE2L2 ratio were greater after parturition. The upregulation of DNA damage inducible transcript 3 (DDIT3) postpartum indicated a localized oxidative stress state. Among genes evaluated, thioredoxin (TXN), glutathione peroxidase 1 (GPX1), and glutathione S-transferase mu 1 (GSTM1) had the highest (37.1, 15.1, and 4.8% of total mRNA measured, respectively) abundance. The mRNA abundance of various target genes with detoxifying enzymatic functions and free radical scavenging activities [glutamate-cysteine ligase catalytic subunit (GCLC); glutathione reductase (GSR); ferrochelatase (FECH); TXN; thioredoxin reductase 1 (TXNRD1); and NAD(P)H quinone dehydrogenase 1 (NQO1)] were consistently upregulated (linear effect of time) as parturition approached and lactation began. Among the transcription regulators, NFE2L2 had the highest mRNA abundance (7.3% of total mRNA measured). Abundance of NFE2L2 and other transcription factors [nuclear factor kappa B subunit 1 (NFKB1), retinoid X receptor α (RXRA), and mitogen-activated protein kinase 14 (MAPK14)] were upregulated (linear effect of time) from -30 d to 30 d relative to parturition. Overall, NFE2L2 phosphorylation and downstream signaling leading to postpartal upregulation of genes associated with oxidative stress and inflammation in the mammary gland seem to be key components of normal cellular function to maintain proper redox homeostasis. However, if the longitudinal increases in mRNA and protein abundance of these antioxidant mechanisms are a reflection of cellular oxidative stress, then the likelihood of protein and DNA damage would be greater and might be one factor compromising cell viability and potentially lactation persistency. The actual cues coordinating these molecular responses remain to be determined.

Comparación de lípidos sanguíneos entre pollos de engorde y gallinas ponedoras / Blood lipid comparison between broilers and laying hens

RESUMEN El objetivo del presente estudio fue comparar los niveles séricos del colesterol total, triglicéridos, colesterol de la lipoproteína de alta densidad y colesterol de la lipoproteína de baja densidad entre pollos de engorde y gallinas ponedoras. Se recolectó sangre después de ayuno de 30 pollos de engorde de la línea Cobb 500 de 35 días de edad y de 40 gallinas ponedoras de la línea Hy-Line W-36 de 26 semanas. Se midieron los niveles séricos de triglicéridos y colesterol total mediante métodos enzimáticos colorimétricos, mientras que para determinar el colesterol de las lipoproteínas de alta y de baja densidad se usó el método directo [detergente + N,Nbis(4-sulfobutil)-m-toluidina]. Los datos se analizaron medieante ANOVA simple usando el paquete estadístico Statgraphics® Plus 5.1. Se presentaron diferencias significativas (P < 0.05) entre los pollos de engorde y las gallinas ponedoras en los niveles séricos de los triglicéridos (21.4 vs. 759.6 mg/dL, respectivamente) y en los niveles de colesterol de la lipoproteína de alta densidad (93.1 vs. 64.6 mg/dL, respectivamente). No se encontraron diferencias significativas (P > 0,05) para el colesterol total (125.1 and 137.0 mg/dL, respectivamente) ni para los niveles de colesterol de la lipoproteína de baja densidad (52.2 and 48.2 mg/dL, respectivamente). Los resultados del presente estudio muestran que aunque hubo diferencias de sexo, edad, madurez sexual y sistemas de producción, no se encontraron diferencias en los niveles séricos de colesterol total o en los niveles de colesterol de la lipoproteína de baja densidad entre pollos de engorde y gallinas ponedoras. La diferencia en la concentración de triglicéridos, es debida al transporte de lípidos hacia el ovario en las gallinas ponedoras.

ABSTRACT The aim of the present study was to compare total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol serum levels between broiler chickens and laying hens. Whole blood was collected after fasting from 30, 35-day-old broiler chickens (Cobb 500 line) and 40, 26-week-old laying hens (Hy-Line line W-36). The serum triglyceride and total cholesterol levels were measured by enzymatic colorimetric methods, while a direct method [detergent + N,N-Bis(4- sulfobutyl)-m-toluidine] was used to determine the low density lipoprotein cholesterol and high density lipoprotein cholesterol levels. Data were analyzed by simple ANOVA using the statistics package Statgraphics® Plus 5.1. Significant differences (P < 0.05) were found between broiler chickens and laying hens in serum triglycerides (21.4 vs. 759.6 mg/dL, respectively) and high-density lipoprotein cholesterol levels (93.1 vs.64.6 mg/dL, respectively). No significant differences were found for total cholesterol (125.1 and 137.0 mg/dL, respectively) or low-density liprotein cholesterol levels (52.2 and 48.2 mg/dL, respectively). The results of the present study show that even though there are differences in gender, age, sexual maturity and production systems, there are no differences in serum total cholesterol or low-density lipoprotein cholesterol levels between broiler chickens and laying hens. The 35-fold difference in serum triglycerides is related to the transport of lipids to the ovary in a laying hen.

[Barriers impeding access to epilepsy surgery: a review of the literature]. / Barreras de acceso a la cirugia de la epilepsia: revision de la bibliografia.

Drug-resistant epilepsy, a chronic condition with long-term consequences can be treated with surgery. The efficacy and safety of surgery for temporal lobe epilepsy have been established through a large number of retrospective and prospective cohort studies and two randomized controlled clinical trials. Despite the excellent outcomes reported after surgery, the literature suggests that this procedure is an underutilized treatment. While evidence is lacking as to why epilepsy surgery is underused, cited reasons include: failure of primary care physicians and neurologists to provide information and identify patients who could be referred for surgery; different levels of technology at various centers, resulting in different candidate selection strategies; the belief that epilepsy surgery is a risky procedure and that it should be only viewed as the last option; patient preference to avoid surgery; parents wanting to wait until their child is old enough to participate in the decision-making process regarding surgery; unwillingness of insurers to cover the expenses associated with presurgical evaluations or lack of insurance; racial and social disparities, among others. In this paper we review the available epidemiological data about lack of utilization of epilepsy surgery.

TITLE: Barreras de acceso a la cirugia de la epilepsia: revision de la bibliografia.La epilepsia farmacorresistente es una condicion cronica con consecuencias a largo plazo que puede ser tratada quirurgicamente. La eficacia y la seguridad de la cirugia de la epilepsia del lobulo temporal se han establecido a traves de un gran numero de estudios de cohorte retrospectivos y prospectivos y dos ensayos clinicos controlados aleatorizados. A pesar de los excelentes resultados comunicados con la cirugia, la bibliografia sugiere que este procedimiento es un tratamiento subutilizado. Aunque no existe evidencia de esto, entre algunos de los motivos descritos se apuntan el fallo de los medicos de atencion primaria y los neurologos en proveer informacion, identificar y remitir a los pacientes a un centro de cirugia; los diferentes niveles de tecnologia en los centros, lo que provoca distintas estrategias de seleccion de los candidatos; la creencia de que la cirugia de la epilepsia es un procedimiento arriesgado que deberia contemplarse solo como ultima opcion; la preferencia del paciente por evitar la cirugia; el deseo de los padres de esperar hasta que sus hijos sean lo suficientemente mayores para participar en el proceso de toma de decisiones; el hecho de que las aseguradoras no cubran los gastos asociados con las evaluaciones prequirurgicas o la carencia de un seguro medico, y la desigualdad racial y social, entre otros. En este articulo se revisan los datos epidemiologicos disponibles en relacion con la falta de acceso a la cirugia de la epilepsia.

Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.

Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

Media preferences, micro-morphometric analysis, and cardinal growth temperature determination for Phytophthora infestans sensu lato isolated from different hosts in Colombia

Abstract During the last years Phytophthora infestans sensu lato (Mont. De Bary) has caused epidemics in Colombia in Andean fruit crops such as Solanum quitoense and Solanum betaceum. Establishment of new or modified experimental procedures to study this pathogen is a mandatory subject for scientists. Twelve isolates of Phytophthora spp. obtained from six different Solanum hosts in Colombia were used to evaluate the effect of five different solid media for growth and ability to produce sporangia and liberate zoospores. Determination of the best media culture and optimal growth temperature were necessary to perform measurements and correlate the provenance of isolates with phenotypic traits. Modifications were made to use ingredients available in local markets on the following media: lime bean agar (LBA), Tree tomato or tree tomato agar (TA), carrot agar (AZ), Rye A modified agar and 32% non-clarified V8 agar. Cardinal temperature determination was performed at 10, 15, 20, and 25 °C. Morphometric traits were measured once the optimal media culture and temperature were defined. Correlation analysis showed that there is a relationship between the host and isolates preferences for media culture and optimal growth temperature. In addition, the production of characteristic sporangia, sporangiophore and mycelia was related with the media type used and host from which the isolate was collected. In this work useful information was provided to make studies about the biology and development of isolates gathered from cultivated and wild non-traditional hosts.

Resumo Durante os últimos anos Phytophthora infestans sensu lato causou epidemias na Colômbia em lavouras de frutos andinos, como Solanum quitoense e Solanum betaceum. Estabelecimento de procedimentos experimentais novos ou modificados para estudar este patógeno é um assunto obrigatório para os cientistas. Doze isolados de Phytophthora spp. obtidos de seis diferentes hosts Solanum na Colômbia foram usados para avaliar o efeito de cinco diferentes mídias sólidas para o crescimento e a capacidade de produzir esporângios e libertar zoósporos. Determinação da melhor cultura de mídia e temperatura de crescimento ideal foram necessárias para realizar medições e correlacionar a proveniência de isolados com traços fenotípica. Foram feitas modificações para usar os ingredientes disponíveis nos mercados locais nos seguintes meios: ágar do feijão de cal (LBA), tomate da árvore ou ágar do tomate da árvore (TA), ágar da cenoura (AZ), centeio um ágar modificado e 32% de ágar-V8 não-esclarecido. A determinação da temperatura Cardeal foi realizada em 10, 15, 20 e 25 °C. Traços morfométricos foram medidos uma vez que a cultura de mídia ideal e temperatura foram definidos. Análise de correlação mostrou que há uma relação entre o hospedeiro e isolar as preferências para a cultura de mídia e temperatura de crescimento ideal. Além disso, a produção de esporângios característica, esporangióforo e mycelia foi relacionada com o tipo de mídia utilizado e hospedeiros a partir do qual o isolado foi coletado. Neste trabalho foram fornecidas informações úteis para fazer estudos sobre a biologia e o desenvolvimento de isolados recolhidos de hospedeiros não-tradicionais cultivados e selvagens.

Corium molecular biomarkers reveal a beneficial effect on hoof transcriptomics in peripartal dairy cows supplemented with zinc, manganese, and copper from amino acid complexes and cobalt from cobalt glucoheptonate.

Supplying trace minerals in more bioavailable forms such as amino acid complexes (AAC) could help ameliorate the incidence of hoof disorders in peripartal dairy cows. The aim of this study was to evaluate the effects of supplementing metal AAC during the peripartal period on expression of 28 genes in corium tissue related to claw composition, oxidative stress, inflammation, chemotaxis, and transcriptional regulation. Forty-four multiparous Holstein cows received a common diet from -30 to 30 d relative to parturition and were assigned to receive an oral bolus containing either inorganic trace minerals (INO) or AAC (i.e., organic) Zn, Mn, Cu, and Co to achieve supplemental levels of 75, 65, 11, and 1 ppm, respectively, in the total diet dry matter. Inorganic trace minerals were provided in sulfate form, and AAC were supplied via Availa Zn, Availa Mn, Availa Cu, and COPRO (Zinpro Corp., Eden Prairie, MN). Locomotion score was recorded before enrollment and weekly throughout the experiment. Incidence of hoof health problems at 30 d in milk was evaluated before a hoof biopsy in a subset of cows (INO=10; AAC=9). Locomotion score did not differ between treatments in the prepartum or postpartum period. The incidence of heel horn erosion was lower in AAC cows, but the incidence of sole ulcers did not differ. Downregulation of KRT5, CTH, CALML5, and CYBB, and upregulation of BTD in AAC cows indicated a decrease in the need for activation of cellular pathways to regenerate corium tissue and increase biotin availability in the sole claw. These molecular changes in the sole could have been triggered by the lower incidence of heel erosion in response to AAC. Among the genes associated with oxidative stress, the AAC cows had greater expression of NFE2L2, a transcription factor that regulates the antioxidant response, and the antioxidant enzyme SOD1. Among genes associated with inflammation, AAC cows had greater expression of TLR4, and lower expression of TLR2, IL1B, and TNF compared with INO cows. Supplementation with metal AAC during the peripartal period affected the expression of genes involved in composition, oxidative stress, and inflammation status in the corium. The hoof biopsy procedure used in the present study should be further perfected and implemented in future lameness research to expand our understanding of hoof biology in dairy cows.