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OAd-MSC WT and OAd-MSC TLR4−/− show similar expression of cell membrane receptors in vitro

OAd-MSC MyD88−/−

Cancer immunotherapy aims to activate the immune system. Some immunotherapeutic agents can be loaded in carrier cells for delivering to the tumors. However, a challenge with cell-based therapies is the selection of the appropriate cells to produce effective clinical outcomes. We hypothesize that therapies based on cells presenting a natural low proinflammatory profile (“silent cells”) in the peripheral blood would result in better antitumor responses by increasing their homing to the tumor site. We studied our hypothesis in an immunotherapy model consisting of mesenchymal stromal cells (MSCs) carrying oncolytic adenoviruses for the treatment of immunocompetent mice. Toll-like receptor signaling–deficient cells (TLR4, TLR9, or MyD88 knockout) were used as “silent cells,” while regular MSCs were used as control. Although in vitro migration was similar in regular and knockout carrier cells, in vivo tumor homing of silent cells was significantly higher after systemic administration. This better homing to the tumor site was highly related to the mild immune response triggered by these silent cells in peripheral blood. As a result, the use of silent cells significantly improved the antitumor efficacy of the treatment in comparison with the use of regular MSCs. While cancer immunotherapies generally aim to boost local immune responses in the tumor microenvironment, low systemic inflammation after systemic administration of the treatment may indeed enhance their tumor homing and improve the overall antitumor effect. These findings highlight the importance of selecting appropriate donor cells as therapeutic carriers in cell-based therapies for cancer treatment.Significance:Cells carrying drugs, virus, or other antitumor agents are commonly used for the treatment of cancer. This research shows that silent cells are excellent carriers for immunotherapies, improving tumor homing and enhancing the antitumor effect.

Several studies have evaluated the efficacy of using human oncolytic adenovirus (OAdv)–loaded mesenchymal stem cells (MSC) for cancer treatment. For example, we have described the antitumor efficacy of CELYVIR, autologous bone marrow–mesenchymal stem cells infected with the OAdv ICOVIR-5, for treatment of patients with neuroblastoma. Results from this clinical trial point out the role of the immune system in the clinical outcome. In this context, a better understanding of the immunophenotypic changes of human MSCs upon adenoviral infection and how these changes affect human autologous or allogeneic peripheral blood mononuclear cells (PBMC) could guide strategies to improve the antitumor efficacy of infected MSCs. In this work, we show how infection by an OAdv induces toll-like receptor 9 overexpression and activation of the NFĸB pathway in menstrual blood–derived MSCs, leading to a specific cytokine secretion profile. Moreover, a proinflammatory environment, mainly mediated by monocyte activation that leads to the activation of both T cells and natural killer cells (NK cell), is generated when OAdv-loaded MSCs are cocultured with allogeneic PBMCs. This combination of allogeneic PBMCs and OAdv-loaded MSCs enhances antitumor efficacy both in vitro and in vivo, an effect partially mediated by monocytes and NK cells. Altogether our results demonstrate not only the importance of the immune system for the OAdv-loaded MSCs antitumor efficacy, but in particular the benefits of using allogeneic MSCs for this therapy.

Supplementary Material and Methods

Supplementary Figure 1. Cytokine array; Supplementary Figure 2. Effect of TLR-9 knock-down on OAd-infected MenSCs properties.

Canine quality of life evaluation

Characterization of canine mesenchymal stem cells and their susceptibility to canine adenoviral infection and replication

Dogs with spontaneous tumors treated in veterinary hospitals offer an excellent opportunity for studying immunotherapies, including oncolytic viruses. Oncolytic viruses have advanced into the clinic as an intratumorally administered therapeutic; however, intravenous delivery has been hindered by neutralization in the blood. To circumvent this hurdle, mesenchymal stem cells have been used as a "Trojan horse." Here, we present the treatment of 27 canine patients with cancer with canine mesenchymal stem cells infected with ICOCAV17, a canine oncolytic adenovirus. No significant adverse effects were found. The response rate was 74%, with 14.8% showing complete responses, including total remissions of lung metastasis. We detected virus infection, stromal degeneration, and immune cell infiltration in tumor biopsies after 4 weeks of treatment. The increased presence of antiadenoviral antibodies in the peripheral blood of treated dogs did not appear to prevent the clinical benefit of this therapy. These data indicate that oncolytic viruses loaded in mesenchymal stem cells represent an effective cancer immunotherapy.Significance: The classical clinical limitations of antitumoral viroimmunotherapy can be overcome by use of mesenchymal stem cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4891/F1.large.jpg. Cancer Res; 78(17); 4891–901. ©2018 AACR.

Supplementary Figure Legends

Sarcomas have been modeled in mice by the expression of specific fusion genes in mesenchymal stem cells (MSC), supporting the concept that MSCs might be the target initiating cell in sarcoma. In this study, we evaluated the potential oncogenic effects of p53 and/or retinoblastoma (Rb) deficiency in MSC transformation and sarcomagenesis. We derived wild-type, p53−/−, Rb−/−, and p53−/−Rb−/− MSC cultures and fully characterized their in vitro growth properties and in vivo tumorigenesis capabilities. In contrast with wild-type MSCs, Rb−/−, p53−/−, and p53−/−Rb−/− MSCs underwent in vitro transformation and showed severe alterations in culture homeostasis. More importantly, p53−/− and p53−/−Rb−/− MSCs, but not Rb−/− MSCs, were capable of tumor development in vivo after injection into immunodeficient mice. p53−/− or p53−/−Rb−/− MSCs originated leiomyosarcoma-like tumors, linking this type of smooth muscle sarcoma to p53 deficiency in fat tissue–derived MSCs. Sca1+ and Sca1 low/− cell populations isolated from ex vivo–established, transformed MSC lines from p53−/−Rb−/− tumors showed identical sarcomagenesis potential, with 100% tumor penetrance and identical latency, tumor weight, and histologic profile. Our findings define the differential roles of p53 and Rb in MSC transformation and offer proof-of-principle that MSCs could provide useful tools to dissect the sarcoma pathogenesis. Cancer Res; 70(10); 4185–94. ©2010 AACR.

Supplementary Figure 2 from Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo

Supplementary Figure 1 from Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo

Supplementary Figure 3 from Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo

The study of brain changes in response to mindfulness (MF) practice could serve as a way to expand our understanding of key cognitive processes such as consciousness, attention, or executive functions. The aim of this work is to offer an updated review of the studies that have investigated the effects of MF on cognition; specifically, the processes of consciousness, attention, and executive functioning, measured by evoked potentials (EP). The main studies on this topic from 2006 to the present are reviewed and the principal findings are grouped according to the EP measured, mainly N1, N2, and P3. The convergent evidence derived from the updated research allows us to propose a hypothetical model of the existing correlations between the influences of MF on cognitive processes and the associated EP components. However, the methodological limitations found mean that we should take these results with caution and advise a methodological refinement for future research.

Problem gambling has recently been reclassified as a non-substance-associated behavioral addiction. To the associated vital impact (family, social, labor, and economic), we must add its increasing incidence in recent years, which has led to prioritizing the problem from the point of view of public health. Although the effects of advertising on gambling behavior have been explored since the second half of the twentieth century, there is a lack of research regarding its underlying mechanisms. Thus, the objective of this review is to present an update on the effects of advertisements on gambling attitudes and behavioral intentions, as well as to present the neurobiological correlates of gambling-related cues as a possible hypothesis for this effect. Advertisements in various formats may act both as a precipitating factor and as a maintenance factor for the gambling disorder, changing both attitudes and beliefs about gambling. Activation of brain areas related to reward, such as accumbens nucleus, to memory, such as hippocampus or amygdala, and to executive functions could be the underlying mechanism of this effect. Also, ads promoting responsible gambling do not appear to be effective in reducing behavior or encouraging self-control, but the available evidence is scarce. Therefore, the number of studies on this topic needs to increase. In addition, the available evidence questions the effectiveness of responsible gambling policies to promote self-control in this population, as well as to reduce the negative impact of this disorder, so future research on neural-cue reactivity to gambling-related stimuli may serve to improve the design of advertising strategies that increase the impact of these messages.

Increasing incidence of problem gambling has led to prioritizing the problem from the point of view of public health. Additionally, gambling disorder has been recently classified as a behavioral addiction, with implications for both its diagnosis and treatment. However, the shared neural substrate of addictions, to substances and behavioral, is still discussed. Thus, this systematic review aims to provide up-to-date knowledge from the past five years (2017-2022) concerning the neural correlates of gambling related stimuli (cue-reactivity) on the basis of a previous review (Brevers et al., Cognitive, Affective and Behavioral Neuroscience 18:718-729, 2019). A total of five studies were included in the review. Activation of brain areas related to memory, reward and executive functions could be the underlying mechanism of this behavioral addiction. Specifically, nucleus accumbens and striatum (ventral and dorsal), parahippocampal regions, the right amygdala and several prefrontal cortex regions have systematically been found more active in those subjects exposed to gambling-related cues. Also, the insula could play a pivotal role connecting these three systems in a highly integrated neural network with several implications for reward processing modulation, associative learning and top-down attentional regulation to improve saliency of addiction-related cues. These results are consistent with previous findings on other substance addictions, such as alcohol, tobacco, marijuana or cocaine. The study of neural reactivity to stimuli related to addiction could be useful as a biomarker of the severity of the disorder, the efficacy of the treatment, the risk of relapse, in addition to being an objective criterion to measure the effectiveness of prevention campaigns.

Factor de impacto: 5,987 Q1 There is increasing evidence about the use of oncolytic adenoviruses (Ads) as promising immunotherapy agents. We have previously demonstrated the clinical efficiency of mesenchymal stem cells (MSCs) infected with oncolytic Ads as an antitumoral immunotherapy (called Celyvir) in human and canine patients, using ICOVIR-5 or ICOCAV17 as human and canine oncolytic Ads, respectively. Considering the better clinical outcomes of canine patients, in this study we searched for differences in cellular responses of human and canine MSCs to Ad infection that may help understand the mechanisms leading to higher antitumor immune response. We found that infection of human and canine MSCs with ICOVIR-5 or ICOCAV17 did not activate the NF-κB pathway or the interferon regulatory factors IRF3 and IRF7. However, we observed differences in the profile of cytokines secretion, as infection of canine MSCs with ICOCAV17 resulted in lower secretion of several cytokines. Moreover, we showed that infection of human MSCs with ICOVIR-5 increased the phosphorylation of a number of proteins, including AKT and c-JUN. Finally, we demonstrated that differences in regulation of AKT and c-JUN in human and canine MSCs by ICOVIR-5 or ICOCAV17 are intrinsic to each virus. Our findings suggest that ICOCAV17 induces a more limited host response in canine MSCs, which may be related to a better clinical outcome. This result opens the possibility to develop new human oncolytic Ads with these specific properties. In addition, this improvement could be imitated by selecting specific human MSC on the basis of a limited host response after Ad infection. This study was funded by Instituto de Salud Carlos III (PI14CIII/00005 and PI17CIII/00013 grants), Consejería de Educación, Juventud y Deporte of Comunidad de Madrid (P2017/BMD-3692 grant), Fundación Oncohematología Infantil, AFANION, and Asociación Pablo Ugarte, whose support we gratefully acknowledge. Sí

Melancolía y espiritualidad han sido relacionadas en fechas tan tempranas como la Grecia clásica. Desde entonces, en cada época histórica, algunos de los autores más destacados en los campos de las humanidades, la filosofía, la medicina o las artes han realizado observaciones y comentarios acerca de la posible relación entre las personas con tendencias melancólicas y la inclinación espiritual. Para alcanzar el objetivo de esta investigación, que es hacer una revisión bibliográfica sobre la posible relación entre melancolía y espiritualidad, se han revisado documentos y obras originales sobre este tema de autores desde la Grecia clásica hasta el presente. De manera sistemática se encuentra una relación entre las personas melancólicas y la predisposición hacia la vida mística y espiritual, además de encontrar personas excepcionales, especialmente en el campo de las artes. Más concretamente, se señala que la angustia podría actuar como un mecanismo que impulsaría a la persona melancólica, desde el sufrimiento, a iniciar una profundización introspectiva y existencial, facilitando así el contacto con la vía mística y espiritual. Estas indagaciones previas deben ser complementadas y ampliadas con más investigaciones realizadas desde otros abordajes metodológicos que permitan corroborar las hipótesis planteadas. Asimismo, se recomienda tener en cuenta las limitaciones encontradas, como la falta de claridad conceptual acerca del significado de “melancolía” o la ausencia de metodologías cuantitativas. Melancholy and spirituality have been related as early as classical Greece. Since then, in every historical epoch, some of the most relevant authors in the fields of humanities, philosophy, medicine and the arts have made observations and comments about the possible relationship between melancholic people and spirituality tendency. For the purpose of this research, documents and original works about this topic have been reviewed since classical Grece to present. As a result of this review, a relationship between melancholic people and spirituality tendency is systematically found, also related to exceptional authors, especially in the arts. More specifically, anguish and suffering could act as mechanisms that would drive the melancholic person to initiate into introspection and existentialism, thus facilitating contact with the mystical and spiritual path. However, these preliminary inquiries should be complemented and expanded with more research carried out from other methodological approaches, allowing the corroboration of the hypothesis raised. Likewise, it is recommended to consider the limitations found, such as the lack of conceptual clarity about the meaning of "melancholy" or the absence of quantitative methodologies applied to this topic. Psicología y Ciencias de la Salud

Phubbing is defined as ignoring other individuals by using a mobile phone during a face-to-face conversation. The Phubbing Scale (PS) was developed to assess this practice. In this study, we analyze the psychometric properties of the 8-item version of the PS (PS-8) in the Portuguese population, providing validity evidence based on internal structure and on relationships with other variables, and examining item properties, reliability, and measurement invariance across gender. Participants were 391 Portuguese adults (132 men, 259 women) who completed a battery of questionnaires. Confirmatory factor analysis yielded satisfactory goodness-of-fit indices for the two-factor structure (communication disturbance and phone obsession), which was invariant across gender. Item homogeneity and reliability of factor scores (McDonald’s omega) were satisfactory. Validity evidence based on relationships with other variables was provided by positive associations with time spent on the Internet on weekdays and at the weekend, time spent on social networking sites, number of social networks used, Internet addiction, problematic mobile phone use, Facebook intrusion, fear of missing out, and depression. These associations show the addictive component of phubbing and its relationship with mental health. The PS-8 is a short and easy-to-administer scale with adequate psychometric properties for measuring phubbing in the Portuguese population.

Background: Oncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade gliomas. Companion dogs present malignant gliomas with biological, genetic, phenotypic, immunological, and clinical similarities to human gliomas. These features favor comparative approaches, leading to the treatment of canine oncological patients to achieve translational applications to the human clinic. The systemic administration of oncolytic viruses presents a challenge due to their limitations in effectively targeting tumors and metastases. Therefore, the aim of this study is to evaluate the safety and antitumor activity of a virotherapy used in spontaneous canine tumors. Methods: Ten dogs with high-grade rostrotentorial gliomas underwent weekly systemic endovenous cellular virotherapy with dCelyvir (canine mesenchymal stem cells infected with the canine oncolytic adenovirus ICOCAV17) for 8 weeks. Efficacy was determined in seven dogs according to the Response Assessment in Veterinary Neuro-Oncology criteria considering clinical status and MRI measurements. Medical history, physical and neurological examinations, and vaccination status were evaluated prior to and during follow-up. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. Immune populations were analyzed by flow cytometry in peripheral blood and by gene expression and immunohistochemistry in the tumor microenvironment. Results: The treatment was well tolerated and major adverse effects were not observed. Two dogs had partial responses (76% and 86% reduction in tumor size), and 3/7 showed stable disease. ICOCAV17 was detected in peripheral blood in nine dogs, and a correlation between the ICOCAV17 particles and anti-canine adenovirus (CAV) antibodies was observed. ICOCAV17 was detected in 3/9 tumor tissues after necropsies. Regarding tumor-infiltrating lymphocytes, the dogs with disease stabilization and partial response tended to have reduced memory B-cell infiltration and increased monocyte/macrophage lineage cells. Conclusions: These findings indicate that dCelyvir is safe and presents efficacy in canine rostrotentorial high-grade gliomas. These data are relevant to the ongoing phase Ib regulated human clinical trial that is administering this virotherapy to children, adolescents, and young adults with diffuse pontine glioma. Celyvir should be further explored as a treatment in veterinary and human neuro-oncology. This work was funded by Instituto de Salud Carlos III (PI14CIII/00005 and PI17CIII/00013 grants to JG-C), Consejeria de Educación, Juventud y Deporte of Comunidad de Madrid (P2017/BMD-3692 grant to JG-C), the Madrid Regional Government (CellCAM; P2010/BMD-2420 to JG-C), the Asociación Pablo Ugarte, and the Asociación AFANION. This work was also supported by Universidad Alfonso X el Sabio and Santander Universidades-Fundación Universidad Alfonso X el Sabio (1010909 grant to AJP-B) Sí

Caregiver burden is the negative impact that caregivers perceive as a result of their caregiving tasks. According to the stress process model, contextual variables and primary and secondary stressors produce negative mental health outcomes in caregivers. However, this relationship may be buffered by psychological resources which act as mediators/moderators. Although there is research on the mediating/moderating effect of mastery, coping strategies, and social support, the effect of psychological values remains unexplored. This study aimed to explore, after controlling for contextual variables and stressors, which character strengths are associated with caregiver burden. We also sought to analyze the mediating/moderating effect of character strengths on the relationship between burden and the significant contextual variables and stressors. To this end, a sample of 115 caregivers of people diagnosed with dementia completed a questionnaire battery. Correlational analysis, multiple regression modeling, and mediation and moderation analysis were performed. The results revealed that the caregivers who experience the greatest burden are those who live with the care recipient, who score higher on perceived stress, who feel their leisure time is limited, and who perceive more financial strain. Higher scores on caregiver burden were associated with lower scores on hope, zest, social intelligence, and love. Regression modeling indicated that hope was the strength which best predicted burden and that hope mediated the relationship between perceived stress and burden. No moderation effect was found. The results suggest that hope-based programs could enhance positive emotions and reduce the perceived negative impact of caregiving.

espanolEl objetivo de este estudio es analizar la relacion, en cuidadores informales de personas con demencia, entre las fortalezas psicologicas y la salud mental, incluyendo depresion, ansiedad, estres, sobrecarga del cuidador y problemas de salud mental. Para analizar esta relacion se llevo a cabo diversos analisis de correlacion canonica, incluyendo en el primer conjunto las variables las fortalezas psicologicas, agrupadas por virtudes, y en el segundo las variables de salud psicologica. Los resultados sugieren la existencia de intercorrelaciones significativas entre estas variables. Aquellos cuidadores informales que tienden a mostrar puntuaciones mas elevadas en las fortalezas psicologicas correspondientes a las virtudes de Coraje, Humanidad, y Trascendencia tienden a mostrar menores puntuaciones en depresion, estres, sobrecarga del cuidador, y problemas de salud mental. En concreto, fueron significativas las relaciones con las fortalezas de valor, vitalidad, amor, inteligencia social, belleza, gratitud, esperanza y humor. Los hallazgos de este estudio sugieren que programas de intervencion basados en la promocion y desarrollo de estas fortalezas psicologicas podria mejorar la salud mental de los cuidadores. EnglishThe aim of this study was to analyze the relationship between character strengths and mental health in informal dementia caregivers. Variables included depression, anxiety, stress, caregiver burden, and mental health problems. We conducted a series of canonical-correlation analyses. The first set of variables comprised character strengths, classified into virtues, and the second set comprised the mental health variables. Results show significant intercorrelations between character strengths and informal caregivers’ mental health. Informal caregivers who tended to have higher scores in character strengths from the virtues of courage, humanity, and transcendence, also tended to have lower scores in depression, stress, caregiver burden, and mental health problems. Specifically, significant relationships were found between bravery, zest, love, social intelligence, appreciation of beauty, gratitude, hope, and humor. The findings from this study suggest that intervention programs based on the promotion and development of these character strengths might improve the psychological health of caregivers.

The aim was to analyze the psychometric properties of the Spanish version of the Gain in Alzheimer Care Instrument (GAIN), providing validity evidence based on its internal structure, reliability, item analysis, and relationships with other variables. A sample of 113 informal caregivers of people with dementia completed the GAIN, along with questionnaires assessing burden, general mental health, stress, anxiety, depression, and life satisfaction. Confirmatory factor analysis showed a single-factor structure with adequate fit indices. Reliability of GAIN scores was satisfactory, with McDonald’s omega equal to .91. Items yielded adequate homogeneity indices. Validity evidence based on relationships with other variables was provided by positive correlations between GAIN scores and life satisfaction, and negative correlations with burden, general mental health problems, stress, anxiety, and depression. All these correlations were statistically significant, and most of them were of moderate magnitude. The Spanish version of the GAIN has a single-factor structure and satisfactory psychometric properties. It is quick and easy to apply and given the association between GAIN scores and other variables, it may be used to provide information about a caregiver’s psychological health status. Funding for open access charge: Universidad de Málaga.

The relationship between caregiving and cognition remains unclear. We investigate this association comparing four cognitive tasks and exploring the role of potential explanatory pathways such as healthy behaviours (healthy caregiver hypothesis) and depression (stress process model).Respondents were from English Longitudinal Study of Ageing (ELSA) (Being a caregiver was positively associated with immediate and delayed recall, verbal fluency but not with serial 7. For immediate and delayed recall, these associations were partially attenuated when adjusting for health behaviours, and depression. For verbal fluency, associations were partially attenuated when adjusting for depression but fully attenuated when adjusting for health behaviours. No associations were found for serial 7.Our findings show that caregivers have higher level of memory and executive function compared to non-caregivers. For memory, we found that although health behaviours and depression can have a role in this association, they do not fully explain it. However, health behaviours seem to have a clear role in the association with executive function. Public health and policy do not need to target specifically cognitive function but other areas as the promotion of healthy behaviours and psychological adjustment such as preventing depression and promoting physical activity in caregivers.

Factor de impacto: 13,751 Q1 Osteosarcoma is the most common malignant solid tumor that affects bones, however, survival rates of patients with relapsed osteosarcoma have not improved in the last 30 years. Oncolytic virotherapy, which uses viruses designed to selectively replicate in cancer cells, has emerged as a promising treatment for solid tumors. Our group uses mesenchymal stem cells (MSCs) to transport oncolytic adenoviruses (OAds) to the tumor site, a therapeutic strategy called Celyvir. This treatment has been already applied in human patients, canine patients and different mouse models. In parallel, previous results have probed that administration of granulocyte-colony stimulating factor (G-CSF) increased immune infiltration in tumors. We then hypothesized that the mobilization of immune cells by G-CSF may increase the antitumor efficacy of Celyvir treatment by increasing the immune infiltration into the tumors. In this study, we use a murine version of Celyvir consisting in murine MSCs carrying the murine OAd dlE102-here called OAd-MSCs-in an immunocompetent model of osteosarcoma. We tested the antitumoral efficacy of the combination of OAd-MSCs plus G-CSF. Our results show that treatment with OAd-MSCs or the union of OAd-MSCs with G-CSF (Combination) significantly reduced tumor growth of osteosarcoma in vivo. Moreover, treated tumors presented higher tumor infiltration of immune cells-especially tumor-infiltrating lymphocytes-and reduced T cell exhaustion, which seems to be enhanced in tumors treated with the Combination. The comparison of our results to those obtained from a cohort of pediatric osteosarcoma patients showed that the virotherapy induces immunological changes similar to those observed in patients with good prognosis. The results open the possibility of using cellular virotherapy for the treatment of bone cancers. Indeed, its combination with G-CSF may be considered for the improvement of the therapy. This study was funded by the Instituto de Salud Carlos III of Spain (grant numbers PI14CIII/00005 and PI17CIII/00013), Consejería de Educación, Juventud y Deporte of Comunidad de Madrid (grant number P2017/BMD-3692), Fundación Oncohematología Infantil, Asociación Pablo Ugarte and AFANION, whose support we gratefully acknowledge. Sí

COVID-19 is a zoonotic disease caused by SARS-CoV-2. Infections of animals with SARS-CoV-2 have recently been reported, and an increase of severe lung pathologies in domestic dogs has also been detected by veterinarians in Spain. Therefore, further descriptions of the pathological processes in those animals that show symptoms similar to those described in humans affected by COVID-19 would be highly valuable. The potential for companion animals to contribute to the continued transmission and community spread of this known human-to-human disease is an urgent issue to be considered. Forty animals with pulmonary pathologies were studied by chest X-ray, ultrasound analysis, and computed tomography. Nasopharyngeal and rectal swabs were analyzed to detect canine pathogens, including SARS-CoV-2. An additional twenty healthy dogs living in SARS-CoV-2-positive households were included. Immunoglobulin detection by several immunoassays was performed. Our findings show that sick dogs presented severe alveolar or interstitial patterns with pulmonary opacity, parenchymal abnormalities, and bilateral lesions. The forty sick dogs were negative for SARS-CoV-2 but Mycoplasma spp. was detected in 26 of 33 dogs. Five healthy and one pathological dog presented IgG against SARS-CoV-2. Here we report that despite detecting dogs with α-SARS-CoV-2 IgG, we never obtained a positive RT-qPCR for SARS-SoV-2, not even in dogs with severe pulmonary disease; suggesting that even in the case of canine infection, transmission would be unlikely. Moreover, dogs living in COVID-19-positive households could have been more highly exposed to infection with SARS-CoV-2. Study funded by Fundación Universidad Alfonso X el Sabio (1.011.115 grant to A.J.P-B.; 1.011.101 to A.B-F.) and Comunidad de Madrid (COV20/01398 grant to A.J.P-B. and A.B-F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Neuroblastoma is a highly metastatic tumor that emerges from neural crest cell progenitors. Focal Adhesion Kinase (FAK) is a regulator of cell migration that binds to the receptor Neogenin-1 and is upregulated in neuroblastoma. Here, we show that Netrin-1 ligand binding to Neogenin-1 leads to FAK autophosphorylation and integrin β1 activation in a FAK dependent manner, thus promoting neuroblastoma cell migration. Moreover, Neogenin-1, which was detected in all tumor stages and was required for neuroblastoma cell migration, was found in a complex with integrin β1, FAK, and Netrin-1. Importantly, Neogenin-1 promoted neuroblastoma metastases in an immunodeficient mouse model. Taken together, these data show that Neogenin-1 is a metastasis-promoting protein that associates with FAK, activates integrin β1 and promotes neuroblastoma cell migration. This work was supported by the Comisión Nacional de Investigación Científica y Tecnológica [21130521]; Fondo Nacional de Desarrollo Científico y Tecnológico [1140697]; Fondo Nacional de Desarrollo Científico y Tecnológico [1180495]; Red Temática de Investigación Cooperativa en Cancer [RD12/0036/0027]; SAF [SAF2015-65175-R]; Red Temática de Investigación Cooperativa en Cancer [RD12/0036/0027]; PSG: Ministerio de Ciencia, Innovación y Universidades and FEDER funds (RTI2018-093596); JGC: Ministerio de Economía y Competitividad of Spain (PI17CIII/00013), Consejería de Educación, Juventud y Deporte, Comunidad de Madrid (P2017/BMD-3692), Fundación Oncohematología Infantil, AFANION, and Asociación Pablo Ugarte. Sí

WHAT IS KNOWN ON THE SUBJECT?: The role of informal caregiver can have both negative and positive consequences for a person's well-being. The main theoretical framework for explaining these consequences is the stress process model, which considers contextual variables, stressors and mediating/moderating factors. The latter are psychosocial factors such as coping strategies, personal mastery, social support or beliefs and values which may influence caregiver well-being. The perception of gains in caregiving has also been proposed as a mediating variable since it may act as a coping strategy. However, few studies have examined values and perceived gains as mediating variables with life satisfaction as the outcome. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This study explores the role of character strengths and caregiver gains as mediators between stressors and life satisfaction in informal caregivers of persons with dementia. The results identify hope as a key character strength, its lack being one pathway through which stress may lead to low life satisfaction and low perceived gains from caregiving. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Caregivers who experience a lack of hope may be less able to generate goals and be less motivated to achieve them. Our findings are relevant to gerontological nursing based on the Senses Framework as they confirm the importance of the senses of purpose and achievement. Nursing and care staff can play an active role in helping informal caregivers to meet their goals by promoting these two senses, thereby fostering a more positive caregiving experience. ABSTRACT: Introduction Being an informal caregiver can have both negative and positive consequences for well-being. Within the framework of the stress process model, few studies have examined values and perceived gains of caregiving as mediating variables of life satisfaction. Aim To explore the role of character strengths and perceived gains as mediators in the association between life satisfaction and primary and secondary stressors in informal caregivers of persons with dementia. Method Participants were 112 informal caregivers. Hierarchical regression, correlation and mediation analyses were performed. Results Lower life satisfaction was associated with being female, unmarried, caring for someone with greater cognitive impairment, a higher level of stress, having restricted leisure time and perceiving financial difficulties. Hope mediated the associations between perceived stress and both life satisfaction and perceived gains of caregiving. Discussion Hope is a key strength and its lack is one pathway through which stress may cause low satisfaction and low perceived gains from caregiving. Implications for practice Without hope, it is difficult for caregivers to generate goals and be motivated to achieve them. Nursing and care staff should aim to promote a sense of purpose and achievement among informal caregivers so as to foster a more positive caring experience.

Oncolytic virotherapy uses viruses designed to selectively replicate in cancer cells. An alternative to intratumoral administration is to use mesenchymal stem cells (MSCs) to transport the oncolytic viruses to the tumor site. Following this strategy, our group has already applied this treatment to children and adults in a human clinical trial and a veterinary trial, with good clinical responses and excellent safety profiles. However, the development of immunocompetent cancer mouse models is still necessary for the study and improvement of oncolytic viroimmunotherapies. Here we have studied the antitumor efficacy, immune response, and mechanism of action of a complete murine version of our cellular virotherapy in mouse models of renal adenocarcinoma and melanoma. We used mouse MSCs infected with the mouse oncolytic adenovirus dlE102 (OAd-MSCs). In both models, treatment with OAd-MSCs significantly reduced tumor volumes by 50% and induced a pro-inflammatory tumor microenvironment. Furthermore, treated mice harboring renal adenocarcinoma and melanoma tumors presented increased infiltration of tumor-associated macrophages (TAMs), natural killer cells, and tumor-infiltrating lymphocytes (TILs). Treated mice also presented lower percentage of TILs expressing programmed cell death protein 1 (PD-1)&mdash, the major regulator of T cell exhaustion. In conclusion, treatment with OAd-MSCs significantly reduced tumor volume and induced changes in tumor-infiltrating populations of melanoma and renal cancer.