Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a ...reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56
-like cytotoxic transcriptomic states. In experimental models, NF-κB and mTOR orchestrated radiation-induced CXCL8 secretion from tumor cells with senescence features causing directional migration of CD56
NK cells, thus linking senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined high-dose radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice, suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy.
Various computational approaches have been developed for estimating the relative abundance of different cell types in the tumor microenvironment (TME) using bulk tumor RNA data. However, a ...comprehensive comparison across diverse datasets that objectively evaluates the performance of these approaches has not been conducted. Here, we benchmarked seven widely used tools and gene sets and introduced Consensus
, a method that integrates gene sets from all the other methods for relative TME cell estimation of 18 cell types. We collected a comprehensive benchmark dataset consisting of pan-cancer data (DNA-derived purity, leukocyte methylation, and hematoxylin and eosin-derived lymphocyte counts) and cell-specific benchmark datasets (peripheral blood cells and tumor tissues). Although none of the methods outperformed others in every benchmark, Consensus
ranked top three in all cancer-related benchmarks and was the best performing tool overall. We provide a Web resource to interactively explore the benchmark results and an objective evaluation to help researchers select the most robust and accurate method to further investigate the role of the TME in cancer (www.consensusTME.org). SIGNIFICANCE: This work shows an independent and comprehensive benchmarking of recently developed and widely used tumor microenvironment cell estimation methods based on bulk expression data and integrates the tools into a consensus approach.
Babesiosis is considered an emerging disease because its incidence has significantly increased in the last 30 years, providing evidence of the expanding range of this rare but potentially ...life-threatening zoonotic disease. Babesia divergens is a causative agent of babesiosis in humans and cattle in Europe. The recently sequenced genome of B. divergens revealed over 3,741 protein coding-genes and the 10.7-Mb high-quality draft become the first reference tool to study the genome structure of B. divergens. Now, by exploiting this sequence data and using new computational tools and assembly strategies, we have significantly improved the quality of the B. divergens genome. The new assembly shows better continuity and has a higher correspondence to B. bovis chromosomes. Moreover, we present a differential expression analysis using RNA sequencing of the two different stages of the asexual lifecycle of B. divergens: the free merozoite capable of invading erythrocytes and the intraerythrocytic parasite stage that remains within the erythrocyte until egress. Comparison of mRNA levels of both stages identified 1,441 differentially expressed genes. From these, around half were upregulated and the other half downregulated in the intraerythrocytic stage. Orthogonal validation by real-time quantitative reverse transcription PCR confirmed the differential expression. A moderately increased expression level of genes, putatively involved in the invasion and egress processes, were revealed in the intraerythrocytic stage compared with the free merozoite. On the basis of these results and in the absence of molecular models of invasion and egress for B. divergens, we have proposed the identified genes as putative molecular players in the invasion and egress processes. Our results contribute to an understanding of key parasitic strategies and pathogenesis and could be a valuable genomic resource to exploit for the design of diagnostic methods, drugs and vaccines to improve the control of babesiosis.
Post-transcriptional gene silencing (PTGS) is an evolutionarily conserved plant defense mechanism against viruses. This paper aimed to evaluate a dsDNA construct (77 bp) as a template for in vitro ...production of virus-derived artificial small hairpin RNAs (shRNAs) and test for their potential to trigger the RNAi mechanism in
plants against CMV after their foliar infiltration. This approach allowed for the production of significant amounts of shRNAs (60-mers) quickly and easily. The gene silencing was confirmed using polymerase chain reaction (PCR), immunological-based assays, and real-time PCR (qPCR). The highest levels of gene silencing were recorded for mRNAs coding for replication protein (ORF1a), the viral suppressor of RNA silencing (ORF2b), and the capsid protein (ORF3b), with 98, 94, and 70% of total transcript silencing, respectively. This protocol provides an alternative to producing significant shRNAs that can effectively trigger the RNAi mechanism against CMV.
The synthetic atypical cannabinoid Abn-CBD, a cannabidiol (CBD) derivative, has been recently shown to modulate the immune system in different organs, but its impact in obesity-related ...meta-inflammation remains unstudied. We investigated the effects of Abn-CBD on metabolic and inflammatory parameters utilizing a diet-induced obese (DIO) mouse model of prediabetes and non-alcoholic fatty liver disease (NAFLD).
Ten-week-old C57Bl/6J mice were fed a high-fat diet for 15 weeks, following a 2-week treatment of daily intraperitoneal injections with Abn-CBD or vehicle. At week 15 mice were obese, prediabetic and developed NAFLD. Body weight and glucose homeostasis were monitored. Mice were euthanized and blood, liver, adipose tissue and pancreas were collected and processed for metabolic and inflammatory analysis.
Body weight and triglycerides profiles in blood and liver were comparable between vehicle- and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicle-treated DIO mice.
These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders.
The high-throughput proteomics data generated by increasingly more sensible mass spectrometers greatly contribute to our better understanding of molecular and cellular mechanisms operating in live ...beings. Nevertheless, proteomics analyses are based on accurate genomic and protein annotations, and some information may be lost if these resources are incomplete. Here, we show that most proteomics data may be recovered by interconnecting genomics and proteomics approaches (i.e., following a proteogenomic strategy), resulting, in turn, in an improvement of gene/protein models. In this study, we generated proteomics data from Leishmania donovani (HU3 strain) promastigotes that allowed us to detect 1908 proteins in this developmental stage on the basis of the currently annotated proteins available in public databases. However, when the proteomics data were searched against all possible open reading frames existing in the L. donovani genome, twenty new protein-coding genes could be annotated. Additionally, 43 previously annotated proteins were extended at their N-terminal ends to accommodate peptides detected in the proteomics data. Also, different post-translational modifications (phosphorylation, acetylation, methylation, among others) were found to occur in a large number of Leishmania proteins. Finally, a detailed comparative analysis of the L. donovani and Leishmania major experimental proteomes served to illustrate how inaccurate conclusions can be raised if proteomes are compared solely on the basis of the listed proteins identified in each proteome. Finally, we have created data entries (based on freely available repositories) to provide and maintain updated gene/protein models. Raw data are available via ProteomeXchange with the identifier PXD051920.
Night shift work, exposure to light at night (ALAN) and circadian disruption may increase the risk of hormone-dependent cancers.
We evaluated the association of exposure to ALAN during sleeping time ...with breast and prostate cancer in a population based multicase-control study (MCC-Spain), among subjects who had never worked at night. We evaluated chronotype, a characteristic that may relate to adaptation to light at night.
We enrolled 1,219 breast cancer cases, 1,385 female controls, 623 prostate cancer cases, and 879 male controls from 11 Spanish regions in 2008-2013. Indoor ALAN information was obtained through questionnaires. Outdoor ALAN was analyzed using images from the International Space Station (ISS) available for Barcelona and Madrid for 2012-2013, including data of remotely sensed upward light intensity and blue light spectrum information for each geocoded longest residence of each MCC-Spain subject.
Among Barcelona and Madrid participants with information on both indoor and outdoor ALAN, exposure to outdoor ALAN in the blue light spectrum was associated with breast cancer adjusted odds ratio (OR) for highest vs. lowest tertile, OR=1.47; 95% CI: 1.00, 2.17 and prostate cancer (OR=2.05; 95% CI: 1.38, 3.03). In contrast, those exposed to the highest versus lowest intensity of outdoor ALAN were more likely to be controls than cases, particularly for prostate cancer. Compared with those who reported sleeping in total darkness, men who slept in "quite illuminated" bedrooms had a higher risk of prostate cancer (OR=2.79; 95% CI: 1.55, 5.04), whereas women had a slightly lower risk of breast cancer (OR=0.77; 95% CI: 0.39, 1.51).
Both prostate and breast cancer were associated with high estimated exposure to outdoor ALAN in the blue-enriched light spectrum. https://doi.org/10.1289/EHP1837.
The atypical cannabinoid Abn-CBD improves the inflammatory status in preclinical models of several pathologies, including autoimmune diseases. However, its potential for modulating inflammation in ...autoimmune type 1 diabetes (T1D) is unknown. Herein we investigate whether Abn-CBD can modulate the inflammatory response during T1D onset using a mouse model of T1D (non-obese diabetic- (NOD)-mice) and of beta cell damage (streptozotocin (STZ)-injected mice). Six-week-old female NOD mice were treated with Abn-CBD (0.1–1 mg/kg) or vehicle during 12 weeks and then euthanized. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1 mg/kg of body weight) or vehicle for 1 week, following STZ challenge, and euthanized 1 week later. Blood, pancreas, pancreatic lymph nodes (PLNs) and T cells were collected and processed for analysis. Glycemia was also monitored. In NOD mice, treatment with Abn-CBD significantly reduced the severity of insulitis and reduced the pro-inflammatory profile of CD4+ T cells compared to vehicle. Concomitantly, Abn-CBD significantly reduced islet cell apoptosis and improved glucose tolerance. In STZ-injected mice, Abn-CBD decreased circulating proinflammatory cytokines and ameliorated islet inflammation reducing intra-islet phospho-NF-κB and TXNIP. Abn-CBD significantly reduced 2 folds intra-islet CD8+ T cells and reduced Th1/non-Th1 ratio in PLNs of STZ-injected mice. Islet cell apoptosis and intra-islet fibrosis were also significantly reduced in Abn-CBD pre-treated mice compared to vehicle. Altogether, Abn-CBD reduces circulating and intra-islet inflammation, preserving islets, thus delaying the progression of insulitis. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat the early stages of T1D.
Abnormal cannabidiol (Abn-CBD) ameliorates inflammation preserving pancreatic beta cells in type 1 diabetes. CTL: Cytotoxic T lymphocytes; Th1: T helper type 1 cells; Th2: T helper type 2 cells; Th17: T helper type 17 cells. This figure was created using Servier Medical Art (Servier; https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License. Display omitted
•Abn-CBD reduces circulating and intra-islet inflammation in hyperglycemic mice.•Abn-CBD protects islet beta cells from acute (STZ) and chronic (NOD mice) damage.•Abn-CBD reduces the severity of insulitis in NOD mice.•Abn-CBD-related compounds are potential therapies for early stages of T1D.
Patients with hematologic malignancies have greater risk-factors for primary bloodstream infections (BSI).
From 2004-2009, we analyzed bacteremia caused by extended-spectrum beta-lactamase ...Escherichia coli (ESBL-EC) (n = 100) and we compared with bacteremia caused by cephalosporin-susceptible E. coli (n = 100) in patients with hematologic malignancies.
To assess the clinical features, risk factors, and outcome of ESBL-EC BSI in patients with hematologic malignancies, and to study the molecular epidemiology of ESBL-EC isolates.
The main diagnosis was acute leukemia in 115 patients (57.5%). Death-related E. coli infection was significantly increased with ESBL-EC (34% vs. control group, 19%; p = 0.03). Treatment for BSI was considered appropriate in 64 patients with ESBL-EC (mean survival, 245 ± 345 days), and in 45 control patients this was 443 ± 613 (p = 0.03). In patients not receiving appropriate antimicrobial treatment, survival was significantly decreased in cases compared with controls (26 ± 122 vs. 276 ± 442; p = 0.001). Fifty six of the ESBL-EC isolates were characterized by molecular analysis: 47 (84%) expressed CTX-M-15, two (3.6%) SHV, and seven (12.5%) did not correspond to either of these two ESBL enzymes. No TLA-1 enzyme was detected.
Patients who had been previously hospitalized and who received cephalosporins during the previous month, have an increased risk of ESBL-EC bacteremia. Mortality was significantly increased in patients with ESBL-EC BSI. A polyclonal trend was detected, which reflects non-cross transmission of multiresistant E.coli isolates.
Los discursos políticos en campañas electorales están orientados a movilizar y atraer con mensajes persuasivos al electorado y principalmente se argumenta apelando a las emociones incurriendo en ...falacias. Este artículo presenta un corpus de falacias en discursos políticos elaborados por candidatos a la presidencia de México, con el objetivo de obtener un recurso lingüístico en español que permita desarrollar sistemas computacionales para su minería. Hasta ahora no se conoce un corpus de falacias para el idioma español y los corpus de argumentos elaborados en el área de Minería de Argumentos se limitan a un etiquetado de la estructura argumentativa y no están elaborados a partir de discursos políticos. El corpus se elaboró con argumentos extraídos de los discursos y se realizó una anotación manual de premisas y conclusiones. Se obtuvo un acuerdo entre anotadores de 0.692 utilizando el índice kappa de Cohen. Posteriormente, se identificaron los argumentos válidos y las falacias, y como resultado se obtuvo un acuerdo de 0.442 con el mismo índice. Como contribución adicional, se presenta una línea base para la identificación de falacias utilizando los métodos de similitud coseno, support vector machine, logistic regression y decision trees, y la extracción de términos afectivos en los argumentos. En esta línea base se obtuvo un F1-score de 0.62 y es un resultado de comparación para futuras investigaciones.
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