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In the advanced renal cell carcinoma (RCC) scenario, there are no consistent biomarkers to predict the clinical benefit patients derived from immune checkpoint blockade (ICB). Taking this into consideration, herein, we conducted a retrospective study in order to develop and validate a gene expression score for predicting clinical benefit to the anti-PD-1 antibody nivolumab in the context of patients diagnosed with advanced clear cell RCC enrolled in the CheckMate-009, CheckMate-010, and CheckMate-025 clinical trials. First, a three-gene expression score (3GES) with prognostic value for overall survival integrating HMGA1, NUP62, and ARHGAP42 transcripts was developed in a cohort of patients treated with nivolumab. Its prognostic value was then validated in the TCGA-KIRC cohort. Second, the predictive value for nivolumab was confirmed in a set of patients from the CheckMate-025 phase 3 clinical trial. Lastly, we explored the correlation of our 3GES with different clinical, molecular, and immune tumor characteristics. If the results of this study are definitively validated in other retrospective and large-scale, prospective studies, the 3GES will represent a valuable tool for guiding the design of ICB-based clinical trials in the aRCC scenario in the near future.

ABSTRACT: Salmonella spp. is a prevalent pathogen that causes great public health concern worldwide. Bacteriophage-based cocktails have arisen as an alternative to antibiotics to inhibit the growth of Salmonella. However, the bactericidal effect of bacteriophage cocktails in vivo largely differs from their observed effect in vitro. This is partly because in vitro developments of cocktails do not always consider the bacterial diversity nor the environmental conditions where bacteriophages will have to replicate. Here, we isolated and sequenced 47 bacteriophages that showed variable degrees of lytic activity against 258 Salmonella isolates from a commercial broiler company in Brazil. Three of these bacteriophages were characterized and selected to assemble a cocktail. In vitro quantitative assays determined the cocktail to be highly effective against multiple serovars of Salmonella, including Minnesota and Heidelberg. Remarkably, the in vitro lytic activity of the cocktail was retained or improved in conditions that more closely resembled the chicken gut, such as anaerobiosis, 42°C, and Salmonella mono-strain biofilms. Analysis of bacterial cross-resistance between the 3 bacteriophages composing the cocktail revealed limited or no generation of cross-resistance. Our results highlight the relevance of an optimized flux of work to develop bacteriophage cocktails against Salmonella with high lytic efficacy and strong potential to be applied in vivo in commercial broiler farms.

Mosses have been widely used as biomonitors of a variety of atmospheric pollutants, including radionuclides. Here we determine the radionuclide activity concentration of 210Pb, 137Cs, 7Be, and 40K in moss tissue (Hylocomium splendens) collected from 24 sites across Ireland and assess the influence of precipitation on radionuclide spatial distribution. Lead-210 was the most abundant radionuclide (range: 226–968 Bq kg–1), followed by 7Be (range: –1), 40K (range: –1), and 137Cs (range: –1). Albeit nearly thirty years since the Chernobyl disaster, 137Cs activity concentration was detected at 67% of the study sites; however, the spatial distribution was not fully consistent with the 1986 Chernobyl deposition pattern. Rather, 137Cs was weakly correlated with rainfall, with higher concentrations along the west coast, suggesting that the 2011 Fukushima Dai-ichi nuclear accident was also a potential source. Average annual rainfall was a significant predictor of 210Pb activity (linear regression, R2 = 0.63, p < 0.001). As such, the highest radionuclide activity was observed for 210Pb (average: 541 Bq kg–1), owing to the high levels of precipitation across the study sites (average: 1585 mm). In contrast, 7Be or 40K were not correlated with precipitation; rather, 40K and 7Be were significantly correlated to each other (rs = 0.7), suggesting that both radionuclides were transferred from the substrate or through soil re-suspension. Precipitation is widely reported as an important factor in the spatial distribution of radionuclides; however, only 210Pb activity concentrations in moss were strongly influenced by precipitation in the current study.

Background and purpose: Hypo-fractionated lung Stereotactic Ablative Body Radiotherapy (SABR) has often been avoided when tumours are close to the chest wall. Our strategic objective was the reduction of fraction number, while maintaining target biological effective dose coverage without increasing chest wall toxicity (CWT) predictors. Materials and methods: Twenty previously treated lung SABR patients were stratified into four cohorts according to distance from PTV to the chest wall,

Immune checkpoint inhibitors, such as pembrolizumab, are revolutionizing therapeutic strategies for different cancer types, including non‐small‐cell lung cancer (NSCLC). However, only a subset of patients benefits from this therapy, and new biomarkers are needed to select better candidates. In this study, we explored the value of liquid biopsy analyses, including circulating free DNA (cfDNA) and circulating tumour cells (CTCs), as a prognostic or predictive tool to guide pembrolizumab therapy. For this purpose, a total of 109 blood samples were collected from 50 patients with advanced NSCLC prior to treatment onset and at 6 and 12 weeks after the initiation of pembrolizumab. Plasma cfDNA was measured using hTERT quantitative PCR assay. The CTC levels at baseline were also analysed using two enrichment technologies (CellSearch® and Parsortix systems) to evaluate the efficacy of both approaches at detecting the presence of programmed cell death ligand 1 on CTCs. Notably, patients with high baseline hTERT cfDNA levels had significantly shorter progression‐free survival (PFS) and overall survival (OS) than those with low baseline levels. Moreover, patients with unfavourable changes in the hTERT cfDNA levels from baseline to 12 weeks showed a higher risk of disease progression. Additionally, patients in whom CTCs were detected using the CellSearch® system had significantly shorter PFS and OS than patients who had no CTCs. Finally, multivariate regression analyses confirmed the value of the combination of CTCs and cfDNA levels as an early independent predictor of disease progression, identifying a subgroup of patients who were negative for CTCs, who presented low levels of cfDNA and who particularly benefited from the treatment.

The two most developed biomarkers in liquid biopsy (LB)—circulating tumor cells and circulating tumor DNA—have been joined by the analysis of extracellular vesicles (EVs). EVs are lipid-bilayer enclosed structures released by all cell types containing a variety of molecules, including DNA, mRNA and miRNA. However, fast, efficient and a high degree of purity isolation technologies are necessary for their clinical routine implementation. In this work, the use of ExoGAG, a new easy-to-use EV isolation technology, was validated for the isolation of EVs from plasma and urine samples. After demonstrating its efficiency, an analysis of the genetic material contained in the EVs was carried out. Firstly, the sensitivity of the detection of point mutations in DNA from plasma EVs isolated by ExoGAG was analyzed. Then, a pilot study of mRNA expression using the nCounter NanoString platform in EV-mRNA from a healthy donor, a benign prostate hyperplasia patient and metastatic prostate cancer patient plasma and urine samples was performed, identifying the prostate cancer pathway as one of the main ones. This work provides evidence for the value of using ExoGAG for the isolation of EVs from plasma and urine samples, enabling downstream applications of the analysis of their genetic cargo.

Abstract Background Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50–60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power. Results Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (ORAB v/s AC-AD: 0.654 [0.408–1.046]; OR AD v/s AB-AC: 1.291 [0.860–1.939]) or palate anomalies (ORAB v/s AC-AD: 1.731 [0.708–4.234]; OR AD v/s AB-AC: 0.628 [0.286–1.382]). Conclusions The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.

MORGANE MERTEUIL Liberad el feminismo Barcelona: Edicions Bellaterra, 2017 100 páginas

Allelic imbalance (AI) indicates the presence of functional variation in cis regulatory regions. Detecting cis regulatory differences using AI is widespread, yet there is no formal statistical methodology that tests whether AI differs between conditions. Here, we present a novel model and formally test differences in AI across conditions using Bayesian credible intervals. The approach tests AI by environment (G×E) interactions, and can be used to test AI between environments, genotypes, sex, and any other condition. We incorporate bias into the modeling process. Bias is allowed to vary between conditions, making the formulation of the model general. As gene expression affects power for detection of AI, and, as expression may vary between conditions, the model explicitly takes coverage into account. The proposed model has low type I and II error under several scenarios, and is robust to large differences in coverage between conditions. We reanalyze RNA-seq data from a Drosophila melanogaster population panel, with F1 genotypes, to compare levels of AI between mated and virgin female flies, and we show that AI × genotype interactions can also be tested. To demonstrate the use of the model to test genetic differences and interactions, a formal test between two F1s was performed, showing the expected 20% difference in AI. The proposed model allows a formal test of G×E and G×G, and reaffirms a previous finding that cis regulation is robust between environments.

Resumen El objetivo de este texto es el de analizar las representaciones bisexuales que existen en Sex, de Beatriz Gimeno, y Gut Symmetries, de Jeanette Winterson, exponiendo los mitos y estereotipos asociados a esta realidad, y mediante una serie de referencias críticas que abordan las teorías queer, el feminismo lésbico y temas como la pornografía o los símbolos fálicos, con figuras como Butler, Wittig, Rich o Preciado, para concluir si estas obras reflejan y en qué modo esta materia. Abstract The aim of this paper is to analyze the representations about bisexuality that are included in Sex, by Beatriz Gimeno, and Gut Symmetries, by Jeanette Winterson, exposing the myths and stereotypes associated with this reality, and through a series of critical references that address the queer theories, lesbian feminism and issues such us pornography or phallic symbols, with figures such as Butler, Wittig, Rich or Preciado, to conclude if this works reflect this matter.

Approximately 19% of all cancer-related deaths are due to lung cancer, which is the leading cause of mortality worldwide. Small cell lung cancer (SCLC) affects approximately 15% of patients diagnosed with lung cancer. SCLC is characterized by aggressiveness; the majority of SCLC patients present with metastatic disease, and less than 5% of patients are alive at 5 years. The gold standard of SCLC treatment is platinum and etoposide-based chemotherapy; however, its effects are short. In recent years, treatment for SCLC has changed; new drugs have been approved, and new biomarkers are needed for treatment selection. Liquid biopsy is a non-invasive, rapid, repeated and alternative tool to the traditional tumor biopsy that could allow the most personalized medicine into the management of SCLC patients. Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) are the most commonly used liquid biopsy biomarkers. Some studies have reported the prognostic factors of CTCs and cfDNA in SCLC patients, independent of the stage. In this review, we summarize the recent SCLC studies of CTCs, cfDNA and other liquid biopsy biomarkers, and we discuss the future utility of liquid biopsy in the clinical management of SCLC.

MET alterations may provide a potential biomarker to evaluate patients who will benefit from treatment with MET inhibitors. Therefore, the purpose of the present study is to investigate the utility of a liquid biopsy-based strategy to assess MET alterations in cancer patients. We analyzed MET amplification in circulating free DNA (cfDNA) from 174 patients with cancer and 49 healthy controls and demonstrated the accuracy of the analysis to detect its alteration in patients. Importantly, a significant correlation between cfDNA concentration and MET copy number (CN) in cancer patients (r = 0.57, p −10) was determined. Furthermore, we evaluated two approaches to detect the presence of MET on circulating tumor cells (CTCs), using the CellSearch® and Parsortix systems and monitored patients under anti-EGFR treatment (n = 30) combining both cfDNA and CTCs analyses. This follow-up provides evidence for the potential of MET CN assessment when patients develop resistance to anti-EGFR therapy and a significant association between the presence of CTCs MET+ and the Overall Survival (OS) in head and neck cancer patients (P = 0.05; HR = 6.66). In conclusion, we develop specific and noninvasive assays to monitor MET status in cfDNA/CTCs and demonstrate the utility of plasma MET CN determination as a biomarker for monitoring the appearance of resistance to anti-EGFR therapy.

The Iberian wolf (Canis lupus) is the top predator in the Iberian environments in which it lives, feeding on a wide range of species, thus encountering a wide range of disease agents. Therefore, the wolf can serve as sentinel of environmental contamination with pathogens. We investigated the exposure of free-living wolves to 14 serovars of Leptospira interrogans sensu lato. Kidney samples from 49 wolves collected from 2010-2013 in northwestern Spain were analysed by culture, direct immunofluorescence and polymerase chain reaction. Tissue fluids were analysed for antibodies by a microscopic agglutination test. Ten wolves (observed prevalence: 20%, 95% confidence interval = 11-33%) showed evidence of contact with leptospires, eight through direct detection and nine through serology (7 wolves were positive according to both techniques). Titres below the cut-off level were also detected in seven cases. Serovars confirmed were Canicola (n = 4), Icterohaemorrhagiae (n = 3) and Sejroë, Ballum and Grippotyphosa (n = 1 each), indicating that wolves were infected with serovars for which dogs, rodents and ungulates, are the natural hosts and supporting the utility of the wolf and other large predators as environmental sentinels for pathogens.

Background: Research efforts have focused on the evaluation of the bioactive quality of animal products (milk, cheese, meat, and other by-products) contrasting various feeding strategies coming from different ecological zones. The study aimed to describe the fatty acids (FA), polyphenols (P), bioactive compounds (BC), and antioxidant activity (AA) of goat’s milk. Methods: Dairy goats were fed with five systems: (1) Grazing; (2) conventional diet (CD); (3) CD + 10% of Acacia farnesiana (AF) pods; (4) CD + 20% AF; and (5) CD + 30% AF. The fatty acid profile, health promoting and thrombogenic indexes were calculated. Milk extracts were evaluated by HPLC to determent phenolic compounds (gallic, caffeic, chlorogenic, and ferulic acids, catechin, epicatechin, and quercetin). Antioxidant activity of goat’s milk extract was evaluated using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•), oxygen radical absorbance capacity (ORAC), and the ferric reducing antioxidant power (FRAP) assays. Results: Conventional diet showed the highest content of polyunsaturated fatty acids while grazing showed the best n-6:n-3 and the linoleic:alpha linolenic acid ratio. Similarly, grazing and AF boosted the polyphenol content. Conclusions: Acacia farnesiana inclusion in the goats’ diets increased the presence of bioactive compounds and the antioxidant activity while diminishing the cholesterol content of goat’s milk.

We present the first record of the weakly electric fish Gymnotus henni in Panama, which also represents the first record of Gymnotus in the Pacific slope of the country. One specimen was collected in a tributary of the Chucunaque River in the Tuira basin. The species showed a monophasic electric organ discharge. Molecular analyses indicated that G. henni from Panama and Colombia are closely related and represent an independent and basal lineage to the Central American G. cylindricus and South American G. carapo groups. Evolutionary and biogeographic implications are discussed.

Se presentan variantes de laboreo mínimo para la plantación de la caña de azúcar en los suelos arcillosos pesados del norte de la provincia de Villa Clara. Los aspectos considerados para la conformación de las mismas fueron: equipos e implementos disponibles, condición del terreno y el consumo de combustible. Los principales resultados mostraron aumento en la productividad de 3,51 h/ha, disminución en el consumo de combustibles alrededor de 60 L/ha con el laboreo mínimo total, lográndose población y rendimiento agrícola similares a los alcanzados en la tecnología tradicional.

En dietas para rumiantes, los aminoácidos son rápidamente degradados por los microorganismos del rumen, por lo que se han protegido análogos de metionina (RPMet) a la degradación ruminal para incrementar el flujo del aminoácido al duodeno. Con el propósito de estimar la degradabilidad ruminal de un RPMet (Mepron.M85, Degussa-Hülls) se realizaron dos experimentos. En el Exp 1 se determinó la degradabilidad in situ del RPMet a 12 18 y 24 h incubando el sustrato en el rumen de dos vacas con cánula ruminal. En el Exp 2, se realizaron cuatro determinaciones secuenciadas de degradabilidad in vitro a 12 y 18 h de incubación, utilizando como inóculo una mezcla de líquido ruminal de dos vacas adultas canuladas ruminalmente. Se encontraron diferencias en la degradabilidad del RPMet entre periodos de incubación (P

Con el objetivo de evaluar el efecto del banco de energía de Urochloa humidicola sobre la utilización y ganancia de peso de bovinos en sabanas de baja fertilidad natural, se llevó a cabo un estudio en una finca ubicada en el municipio Tinaco del estado Cojedes, Venezuela (9°42”™ N y 68°26”™ O) en suelos de textura franco arcillo arenosa con bajo contenido de fósforo (3 ppm), potasio (28 a 33 ppm) y calcio (71 a 77 ppm). Se evaluaron dos tratamientos: T1: Sabana más banco de energía (S + BE) y T2: Sabana sola (S), con una carga animal promedio de 0,92 y 0,42 UA/ha/año, respectivamente. La superficie del banco de energía fue el 20% de la superficie del potrero. La utilización fue estimada previamente en función de la materia seca disponible, usando tres transectas/tratamiento de 1 km de largo, donde cada transecta representó una repetición. Los animales utilizados fueron mautes y toretes, mientras que un grupo de vacas gestantes se usaron para ajustar cargas animales. El diseño utilizado fue de bloques al azar y las medias se compararon mediante la prueba de Tukey. Los resultados mostraron una mayor eficiencia de utilización de materia seca en T1 con 55%. La ganancia de peso por individuo fue similar (P>0,05), pero la ganancia por superficie fue el doble en comparación al testigo (69 vs 36 kg/ha/año). Se concluye que el uso de bancos de energía en sabanas incrementa la productividad de la misma.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)–engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease. [ABSTRACT FROM AUTHOR]