One of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells ...escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel vascular-targeting agent targeting semaphorin 4D (Sema4D) demonstrated impaired tumor growth and extended survival in the RIP1-Tag2 model. Surprisingly, although there was no induction of intratumor hypoxia by anti-Sema4D therapy, the increase in local invasion and distant metastases was comparable with the one produced by VEGFR inhibition. Mechanistically, the antitumor effect was due to an alteration in vascular function by modification of pericyte coverage involving platelet-derived growth factor B. On the other hand, the aggressive phenotype involved a macrophage-derived Sema4D signaling engagement, which induced their recruitment to the tumor invasive fronts and secretion of stromal cell-derived factor 1 (SDF1) that triggered tumor cell invasive behavior via CXCR4. A comprehensive clinical validation of the targets in different stages of PanNETs demonstrated the implication of both Sema4D and CXCR4 in tumor progression. Taken together, we demonstrate beneficial antitumor and prosurvival effects of anti-Sema4D antibody but also unravel a novel mechanism of tumor aggressivity. This mechanism implicates recruitment of Sema4D-positive macrophages to invasive fronts and their secretion of proinvasive molecules that ultimately induce local tumor invasion and distant metastasis in PanNETs. SIGNIFICANCE: An anti-semaphorin-4D vascular targeting agent demonstrates antitumor and prosurvival effects but also unravels a novel promalignant effect involving macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients.
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Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and ...resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs.
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•Resistance to antiangiogenic therapy involves metabolic symbiosis patterning in RCC•mTOR pathway mediates this resistance and mTOR inhibition blocks metabolic symbiosis•In patients, antiangiogenics induce symbiotic patterning mostly in resistant tumors•mTOR pathway implication is also suggested in patients treated with antiangiogenics
Jimenez-Valerio et al. describe a mechanism of resistance to antiangiogenics in RCC that involves metabolic symbiosis patterning between tumor cells that can be blocked with mTOR inhibitors. Validation in patients demonstrates that antiangiogenics produce the same metabolic symbiosis pattern, mostly in resistant tumors, with mTOR pathway involvement.
The study of perceived economic differences in everyday life is relevant to deepening knowledge of how inequality shapes psychological processes. In the current research, Spanish undergraduates (N = ...547) were asked what their friends with the most and least money could do with their resources. Using a qualitative and quantitative approach, we performed a content analysis of the 1,085 open‐ended responses given, ran latent class analyses with the coded material to identify groups of participants, and explored whether class membership was associated with their awareness of inequality and support for redistribution. Participants perceived inequality among their friends through daily indicators such as consumption, opportunities, leisure, and mental health; some participants used compensatory strategies to mitigate perceived inequality. Latent class analyses suggested that participants differed mostly in the attention paid to consumption and in the use of compensatory strategies. Exploratory analyses suggested that perceiving inequality in everyday life in terms of consumption, negative attributes towards the wealthy, or positive attributes towards low socioeconomic groups was related to acknowledging economic differences among individuals and support for redistribution. The study of perceived economic inequality in everyday life continues a new line of research with the potential to obtain results more consistent with people's experiences.
An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as ...renal cell carcinoma patients. To address, this we developed an extensive series of 27 patient biopsy‐derived orthotopic xenograft models (Ren‐PDOX) that represent inter‐patient heterogeneity. In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species‐discriminative RNA sequencing identified a tumor cell‐specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion‐annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro‐invasive subtype of Ren‐PDOXs. Validation in an independent series of 15 antiangiogenic‐treated patients confirmed that pre‐treatment ALDH1A3 can significantly discriminate patients with pro‐aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment.
Renal cell carcinoma (RCC) biopsy‐derived orthotopic xenograft models (PDOX) reveal patient‐specific induction of invasion and metastasis after antiangiogenics. Molecular characterization identifies ALDH1A3 as a pre‐treatment discriminator of pro‐malignant tumors that predicts response to therapy.
Patient's original histomorphologic and molecular characteristics were maintained in an extensive series of 27 patient biopsy‐derived orthotopic xenograft models (Ren‐PDOX).
Antiangiogenic treatment produced patient‐specific responses of increased invasiveness and metastatic dissemination in approximately half of the models studied.
By a novel technique of species‐discriminative RNA‐sequencing and subsequent filtering using patient data, the key molecular traits of pro‐invasive type of tumors was unraveled.
ALDH1A3 was clinically validated as a possible predictive factor of pro‐aggressiveness in 15 antiangiogenic‐treated RCC patients.
Renal cell carcinoma (RCC) biopsy‐derived orthotopic xenograft models (PDOX) reveal patient‐specific induction of invasion and metastasis after antiangiogenics. Molecular characterization identifies ALDH1A3 as a pre‐treatment discriminator of pro‐malignant tumors that predicts response to therapy.
Nanomedicine has emerged as a promising strategy to address some of the limitations of traditional biomedical sensing, imaging and therapy modalities. Its applicability and efficacy are, in part, ...hindered by the difficulty in both controllably delivering nanoparticles to specific regions and accurately monitoring them in tissue. Gold nanoparticles are among the most extensively used inorganic nanoparticles which benefit from high biocompatibility, flexible functionalization, strong and tunable resonant absorption, and production scalability. Moreover, their capability to enhance optical fields at their plasmon resonance enables local boosting of non-linear optical processes, which are otherwise very inefficient. In particular, two-photon induced luminescence (TPL) in gold offers high signal specificity for monitoring gold nanoparticles in a biological environment. In this article, we demonstrate that TPL microscopy provides a robust sub-micron-resolution technique able to quantify accumulated gold nanorods (GNRs) both in cells and in tissues. First, the temporal accumulation of GNRs with two different surface chemistries was measured in 786-O cells during the first 24 hours of incubation, and at different nanoparticle concentrations. Subsequently, GNR accumulation in mice, 6 h and 24 hours after tail vein injection, was quantified by TPL microscopy in biopsied tissue from kidney, spleen, liver and clear cell renal cell carcinoma (ccRCC) tumors, in good agreement with inductively coupled mass spectroscopy. Our data suggest that TPL microscopy stands as a powerful tool to understand and quantify the delivery mechanisms of gold nanoparticles, highly relevant to the development of future theranostic medicines.
TPL microscopy is able to study and quantify the delivery mechanisms of nanoparticles, highly relevant to the development of nanomedicines.
Parental feeding practices, such as the use of food to soothe, can be shaped by various factors, including the family environment and parents' psychological characteristics and capacities. To our ...knowledge, the combined effect of these factors has not been studied. Furthermore, parental feeding practices have mainly been studied in women, resulting in a gender gap in the research. This study aims to investigate the combined effect of family environment and parental characteristics on the likelihood of using food to soothe children, taking the gender of both parents into account. This cross‐sectional study included a sample of 846 parents (36.3% men) of 1‐year‐old children from different regions of Spain. Participants completed an online survey that included questionnaires to measure whether parents used food to soothe children, the family environment, parents' characteristics, and their psychological capacities. Binary logistic regression analyses were performed to identify associations between the variables. The final model showed that, within the family environment, higher levels of dyadic adjustment between couples (OR = 0.965; p = .026) were associated with a reduced likelihood of using food to soothe children, whereas the psychological characteristic of parental fatigue (OR = 1.053; p = .007) appeared to be associated with an increased likelihood. Also associated with an increased likelihood of this practice were higher parental sense of competence (OR = 1.028; p = .029) and the attention dimension of emotional intelligence (OR = 1.043; p = .007). Our study suggests that using food to soothe children may be influenced by factors at different levels, from the quality and adjustment of the couple's relationship to parental fatigue, self‐competence, and emotional intelligence. For future research, it may be worthwhile contextualizing parental practices to gain a better understanding of children's behavior.
Our results suggested that having good quality and adjustment in the relationship between partners reduced the risk of using food to calm children, whereas the highest levels of fatigue, parent sense of competence, and attention to the emotions increased it. A positive family environment, parents' mental well‐being, and self‐capacities have an effect on parents' feeding practices on their children. Expanding our knowledge about which factors could be associated with different feeding practices is relevant to prevent children obesity and other non‐communicable diseases.
La verificación de noticias falsas es una herramienta importante para mejorar la calidad de la información que circula en redes virtuales. Aunque existen distintas agencias de verificación de ...noticias, también encontramos algunas estrategias más informales como el uso del hashtag #Stopbulos. Así, la presente investigación pretende realizar una caracterización del hashtag #StopBulos en Twitter como forma de verificación de la información y de control de la difusión de fake news. Los resultados mostraron que existía diversidad entre los usuarios y las temáticas de los tuits que incluían dicho hashtag, mientras que la principal función era desmentir fake news. No obstante, se encontró que aquellos que conseguían una mayor difusión eran los usuarios con mayor número de seguidores y carácter institucional. Se discuten las implicaciones del uso del hashtag #StopBulos como una herramienta que permite identificar información falsa en redes sociales.
Background: In any sport, it is of the utmost importance to identify variables capable of positively influencing scores. Futsal is a sport of intermittent high-intensity intervals that requires the ...athletes’ physical, technical, and tactical skills. There are no specific recommendations on anthropometry–body composition for this sport. The aim of this study was to describe the somatotype and the anthropometric characteristics, body composition, and somatotype of a group of Spanish elite female futsal players of the first-division league. Methods: Eighty-eight players (24 ± 4.94 years) from 14 teams of the first women’s division of the Spanish Futsal League were evaluated. Measurements were taken according to the anthropometric protocol of the International Society for the Advancement of Kinanthropometry (ISAK). Body composition (BC) and somatotype were calculated according to the 4-component model and Heath-Carter, respectively. Results: Pivot and goalkeeper positions were most different from the rest. Both were the heaviest positions and presented the largest mesomorphic data (4.13 ± 1.29 and 3.67 ± 0.95), kg of bone mass (10.60 ± 1.00 and 10.37 ± 1.08), and kg of lean mass (29.80 ± 1.25 and 29.12 ± 2.12), for the pivot and goalkeeper, respectively. Conclusion: The evaluation and evolution of the somatotype and BC is an assessment tool that could be a useful guide for technical and medical staff.
Owing to their unique combination of chemical and physical properties, inorganic nanoparticles show a great deal of potential as suitable agents for early diagnostics and less invasive therapies. ...Yet, their translation to the clinic has been hindered, in part, by the lack of non-invasive methods to quantify their concentration in vivo while also assessing their effect on the tissue physiology. In this work, we demonstrate that diffuse optical techniques, employing near-infrared light, have the potential to address this need in the case of gold nanoparticles which support localized surface plasmons. An orthoxenograft mouse model of clear cell renal cell carcinoma was non-invasively assessed by diffuse reflectance and correlation spectroscopies before and over several days following a single intravenous tail vein injection of polyethylene glycol-coated gold nanorods (AuNRs-PEG). Our platform enables to resolve the kinetics of the AuNR-PEG uptake by the tumor in quantitative agreement with ex vivo inductively coupled plasma mass spectroscopy. Furthermore, it allows for the simultaneous monitoring of local tissue hemodynamics, enabling us to conclude that AuNRs-PEG do not significantly alter the animal physiology. We note that the penetration depth of this current probe was a few millimeters but can readily be extended to centimeters, hence gaining clinical relevance. This study and the methodology presented here complement the nanomedicine toolbox by providing a flexible platform, extendable to other absorbing agents that can potentially be translated to human trials.
Introduction: Globally, 31% of deaths are attributed to cardiovascular disease (CVD). There are many factors that can influence CVD that can be useful for determining if a population is at risk; ...these factors include stress, occupation, and lifestyle. Objective: to identify and compare the prevalence of CVD risk factors among those attending a university clinic for nutritional advice.
Methodology: the sample of this cross-sectional study included the teaching and research staff (Faculty), people working in administration and services (ASS) and students. The risk factors of obesity/overweight, hypertension, hypercholesterolemia, diabetes type 2, sedentary lifestyle, and smoking were quantified for 98 university students, faculty and staff.
Results: It was found that 80% of the sample had one or more of the CVD risks, furthermore, more than 50% had over three of the risk factors. Those particularly at risk were the individuals within the Faculty group with a (p<0.05) prevalence of having three of the risk components compared to the rest of the population. However, those within the ASS group were identified to live a more sedentary lifestyle compared to the Faculty (p<0.05). Within this sample population differences could be found for the prevalence of CVD risk factors.
Conclusions: To be able to provide preventative measures and protect those who are most vulnerable it is crucial to be able to pinpoint these differences within a population.
Funding. M. Lozano-Casanova are supported by a FPU grant number: FPU21/04232 by the Ministerio de Universidades.
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