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Although smartphone ownership among minors has become an important social phenomenon, its impact on children's and adolescents' well-being, as well as the mechanisms by which this might take place are not yet sufficiently well-established. To date, no research has examined the effect of smartphone ownership on the well-being of minors through the consumption of influencer-generated content, nor has it explored the effectiveness of the main prevention strategies employed by parents in this context. To fill those gaps, 800 Spanish minors (50% female) aged from 8 to 16 years old (M = 12.33, SD = 2.38) participated in a correlational study in which the ownership of electronic devices, the consumption of influencer generated content, the parasocial relationship with the influencer, and the most common parental mediation strategies were considered. The results showed a positive association between electronic device ownership and psychological discomfort, problematic usage, and imitation of dangerous behaviors. This association was mediated by the consumption of influencer-generated content and the parasocial relationship established by the minor with the influencer. Regarding preventive strategies, only active mediation was inversely related to poorer well-being indicators, however this positive effect significantly decreased when a smartphone or a similar electronic device was owned by the minor (vs. no owned). These findings contribute to the understanding of how smartphone ownership can affect the well-being of children, emphasizing the need for thoughtful consideration when deciding whether to provide smartphones to minors. [ABSTRACT FROM AUTHOR]

Copyright of Anales de Psicología is the property of Servicio de Publicaciones de la Universidad de Murcia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of oncolytic virus is an innovative approach that has shown promising results as a treatment in oncology. Epithelial-derived tumors are the most frequent neoplasms in dogs, but gold standard therapies can be highly invasive procedures. Due to the accessible localization of these tumors, the intratumoral administration is feasible. Therefore, we propose to determine the safety and efficacy of intratumoral administration of oncolytic adenovirus ICOCAV15, in canine patients with epithelial-derived tumors. Eight dogs with carcinoma/adenocarcinoma were intratumorally treated with ICOCAV15. No clinically relevant changes were observed in the blood count, biochemistry and coagulation test analyzed during follow-up. The survival time of the 6/8 dogs exceeded the median survival time with chemotherapy, showing a partial response rate of 25% and 75% of stable disease. ICOCAV15 was detected in the target lesion by qPCR and immunohistochemistry. Also, some of the non-treated metastasis showed an infiltration of ICOCAV15 by immunohistochemistry. The immune populations were evaluated, and an increase of CD8+, MAC387+, CD3+ and CD20+ cells was reported in some of the patients after the inoculation. These results show that intratumoral ICOCAV15 is safe and well tolerated by dogs. Also, they suggest ICOCAV15 could be a new tool in veterinary oncology for accessible carcinomas/adenocarcinomas. The use of oncolytic viruses is an innovative approach to lyse tumor cells and induce antitumor immune responses. Eight dogs diagnosed with carcinoma/adenocarcinoma were intratumorally treated with ICOCAV15, an oncolytic canine adenovirus (CAV). To evaluate the treatment's safety, a blood count, biochemistry, and coagulation test were performed before treatment and during follow-up. Immune populations were analyzed by flow cytometry. Anti-adenovirus antibodies were also determined. The immune infiltration, vascularization, and viral presence in the tumor were determined by CD3, CD4, CD20, CD31 and CAV by immunohistochemistry. All the dogs maintained a good quality of life during follow-up, and some had increased median survival time when compared with dogs treated with chemotherapy. No treatment-related adverse effects were detected. The Response Evaluation Criteria In Solid Tumors criteria were also assessed: two patients showed a partial response and the rest showed stable disease at various times during the study. ICOCAV15 was detected inside the tumor during follow-up, and antiviral antibodies were detected in all patients. Furthermore, the tumor-infiltrating immune cells increased after viral administration. Therefore, we suggest that intratumorally administered ICOCAV15 could represent as a new tool for the treatment of canine carcinoma because it is safe, well-tolerated by dogs, and shows promising results. [ABSTRACT FROM AUTHOR]

Copyright of Revista Internacional de Humanidades is the property of Common Ground Research Networks and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy uses oncolytic viruses that selectively replicate in cancer cells. The use of cellular vehicles with migration ability to tumors has been considered to increase their delivery to target sites. Following this approach, the antitumor efficacy of the treatment Celyvir (mesenchymal stem cells infected with the oncolytic adenovirus ICOVIR-5) has been demonstrated in patients with neuroblastoma. However, the better efficacy of syngeneic or allogeneic mesenchymal stem cells as cell carriers and the specific role of the immune system in this therapy are still unknown. In this study we use our virotherapy Celyvir with syngeneic and allogeneic mouse mesenchymal stem cells to determine their antitumor efficacy in a C57BL/6 murine adenocarcinoma model. Adoptive transfer of splenocytes from treated mice to new tumor-bearing mice followed by a secondary adoptive transfer to a third group was performed. Similar reduction of tumor growth and systemic activation of the innate and adaptive immune system was observed in groups treated with syngeneic or allogeneic mesenchymal stem cells loaded with ICOVIR-5. Moreover, a different pattern of infiltration was observed by immunofluorescence in Celyvir-treated groups. While non-treated tumors presented higher density of infiltrating immune cells in the periphery of the tumor, both syngeneic and allogeneic Celyvir-treated groups presented higher infiltration of CD45+ cells in the core of the tumor. Therefore, these results suggest that syngeneic and allogeneic Celyvir induce systemic activation of the immune system, similar antitumor effect and a higher intratumoral infiltration of leukocytes. [ABSTRACT FROM AUTHOR]

Background: Age-associated changes in genomic DNA methylation have been primarily attributed to 5-methylcytosine (5mC). However, the recent discovery of 5-hydroxymethylcytosine (5hmC) suggests that this epigenetic mark might also play a role in the process.Methods: Here, we analyzed the genome-wide profile of 5hmc in mesenchymal stem cells (MSCs) obtained from bone-marrow donors, aged 2-89 years.Results: We identified 10,685 frequently hydroxymethylated CpG sites in MSCs that were, as in other cell types, significantly associated with low density CpG regions, introns, the histone posttranslational modification H3k4me1 and enhancers. Study of the age-associated changes to 5hmC identified 785 hyper- and 846 hypo-hydroxymethylated CpG sites in the MSCs obtained from older individuals.Conclusions: DNA hyper-hydroxymethylation in the advanced-age group was associated with loss of 5mC, which suggests that, at specific CpG sites, this epigenetic modification might play a role in DNA methylation changes during lifetime. Since bone-marrow MSCs have many clinical applications, and the fact that the epigenomic alterations in this cell type associated with aging identified in this study could have associated functional effects, the age of donors should be taken into account in clinical settings. [ABSTRACT FROM AUTHOR]

A novel phototriggered drug delivery nanocarrier, which exhibits very high tumor cytotoxicity against human tumoral cells, is presented. This device is based on mesoporous silica nanoparticles decorated with a biocompatible protein shell cleavable by light irradiation. The proteins that compose the protein shell (avidin, streptavidin and biotinylated transferrin) act as targeting and capping agents at the same time, avoiding the use of redundant systems. The light responsive behavior is provided by a biotinylated photocleavable cross-linker covalently grafted on the mesoporous surface, which suffers photocleavage by UV radiation (366 nm). Human tumoral cells incubated in the presence of a very low particle concentration enter into the apoptotic stage after a short irradiation time. Thus, the system described here could be applied to the treatment of exposed tumors that affect the skin, oesophagus, and stomach, among others, and are easily accessible for light irradiation. [ABSTRACT FROM AUTHOR]

Homing is an inherent, complex, multistep process performed by cells such as human bone marrow mesenchymal stem cells (hMSCs) to travel from a distant location to inflamed or damaged tissue and tumors. This ability of hMSCs has been exploited as a tumor-targeting strategy in cell-based cancer therapy. The purpose of this study was to investigate the applicability of 111In-oxine for tracking hMSCs in vivo by combining single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). 111In-labeled hMSCs (106 cells) were infused intraperitoneally in neuroblastoma-bearing mice, whereas a control group received a dose of free 111In-oxine. SPECT and MRI studies were performed 24 and 48 hours afterwards. Initially, the images showed similar activity in the abdomen in both controls and hMSC-injected animals. In general, abdominal activity decreases at 48 hours. hMSC-injected animals showed increased uptake in the tumor area at 48 hours, whereas the control group showed a low level of activity at 24 hours, which decreased at 48 hours. In conclusion, tracking 111In-labeled hMSCs combining SPECT and MRI is feasible and may be transferable to clinical research. The multimodal combination is essential to ensure appropriate interpretation of the images. [ABSTRACT FROM AUTHOR]

As the nervous system exerts direct and indirect effects on stem cells mobilization and catecholamines mobilize hematopoietic stem cells, we hypothesized that dopamine might induce mesenchymal progenitor cells (MPCs) mobilization. We show that dopamine induced in vitro MPCs migration through D2-class receptors, and their alternative phosphoinositide 3-kinase/Akt pathways. Also, administration of catecholamines induced in vivo mobilization of colony-forming unit-fibroblast in mice. In contrast, in vitro and in vivo MPCs migration was suppressed by D2-class receptors antagonists and blocking antibodies, consistent with dopamine signaling pathway implication. In humans, patients treated with L-dopa or catecholaminergic agonists showed a significant increase of a MPC-like population (CD45−CD31−CD34−CD105+) in their peripheral blood. These findings reveal a new link between catecholamines and MPCs mobilization and suggest the potential use of D2-class receptors agonists for mobilization of MPCs in clinical settings. S tem C ells 2014;32:2529-2538 [ABSTRACT FROM AUTHOR]

The relevance of tumor microenvironment for the development and progression of tumor cells in hematological malignancies has been extensively reported. Identification of factors involved in the information exchange between the malignant cells and the bone marrow mesenchymal stem cells (BM-MSCs) and the knowledge on their functioning may provide important information to eliminate leukemic cells from protective BM niches. We evaluated changes in BM-MSCs obtained from children with acute lymphoblastic leukemia (ALL) at different times in the course of disease. Whereas ALL-MSCs did not exhibit phenotypic changes compared to BM-derived MSCs isolated from healthy donors, they exhibited increased adipogenic capacity. In addition, the viability of healthy CD34+ hematopoietic progenitors was significantly reduced when co-cultured with ALL-MSCs. ALL-MSCs grow less efficiently, although gradually recover normal growth with treatment. Accordingly, proliferation is particularly low in MSCs obtained at diagnosis and in the first days of treatment (+15 days), recovering to control levels after 35 days of treatment. Correlating these results with bone morphogenetic protein 4 (BMP4) production, a molecule demonstrated to affect MSC biology, we found higher production of BMP4 in ALL-MSCs derived from patients over the course of disease but not in those free of leukemia. However, no significant differences in the expression of different members of the BMP4 signaling pathway were observed. Furthermore, an inverse correlation between high levels of BMP4 production in the cultures and MSC proliferation was found, as observed in MSCs derived from patients at diagnosis that produce high BMP4 levels. In addition, co-culturing ALL-MSC with the REH leukemia cell line, but not CD34+ hematopoietic progenitors, powerfully enhanced BMP4 production, suggesting an intimate crosstalk among ALL-MSCs isolated from BM colonized by ALL cells that presumably also occurs in situ conditions. Our data may support the participation of BMP4 in BM niche, but the mechanism remains to be elucidated. [ABSTRACT FROM AUTHOR]

Clinical interest on human mesenchymal progenitor cells (hMPC) relies on their potential applicability in cell-based therapies. An in vitro characterization is usually performed in order to define MPC potency. However, in vitro predictions not always correlate with in vivo results and thus there is no consensus in how to really assess cell potency. Our goal was to provide an in vivo testing method to define cell behavior before therapeutic usage, especially for bone tissue engineering applications. In this context, we wondered whether bone marrow stromal cells (hBMSC) would proceed in an osteogenic microenvironment. Based on previous approaches, we developed a fibrin/ceramic/BMP-2/hBMSCs compound. We implanted the compound during only 2 weeks in NOD-SCID mice, either orthotopically to assess its osteoinductive property or subcutaneously to analyze its adequacy as a cell potency testing method. Using fluorescent cell labeling and immunohistochemistry techniques, we could ascertain cell differentiation to bone, bone marrow, cartilage, adipocyte and fibrous tissue. We observed differences in cell potential among different batches of hBMSCs, which did not strictly correlate with in vitro analyses. Our data indicate that the method we have developed is reliable, rapid and reproducible to define cell potency, and may be useful for testing cells destined to bone tissue engineering purposes. Additionally, results obtained with hMPCs from other sources indicate that our method is suitable for testing any potentially implantable mesenchymal cell. Finally, we propose that this model could successfully be employed for bone marrow niche and bone tumor studies. [ABSTRACT FROM AUTHOR]

Over the last decade, genetic and cell biology studies have indicated that tumour growth is not only determined by malignant cancer cells themselves, but also by the tumour microenvironment. Cells present in the tumour microenvironment include fibroblasts, vascular, smooth muscle, adipocytes, immune cells and mesenchymal stem cells (MSC). The nature of the relationship between MSC and tumour cells appears dual and whether MSC are proor anti-tumorigenic is a subject of controversial reports. This review is focused on the role of MSC and bone marrow (BM) niches in cancer. [ABSTRACT FROM AUTHOR]

Human sarcomas have been modeled in mice by expression of specific fusion genes in mesenchymal stem cells (MSCs). However, sarcoma models based on human MSCs are still missing. We attempted to develop a model of liposarcoma by expressing FUS (FUsed in Sarcoma; also termed TLS, Translocated in LipoSarcoma)-CHOP (C/EBP HOmologous Protein; also termed DDIT3, DNA Damage-Inducible Transcript 3), a hallmark mixoid liposarcoma-associated fusion oncogene, in wild-type and p53-deficient mouse and human adipose-derived mesenchymal stem/stromal cells (ASCs). FUS-CHOP induced liposarcoma-like tumors when expressed in p53 but not in wild-type (wt) mouse ASCs (mASCs). In the absence of FUS-CHOP, p53 mASCs forms leiomyosarcoma, indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype. FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs. In a human setting, p53-deficient human ASCs (hASCs) displayed a higher in vitro growth rate and a more extended lifespan than wt hASCs. However, FUS-CHOP expression did not induce further changes in culture homeostasis nor initiated liposarcoma in either wt or p53-depleted hASCs. These results indicate that FUS-CHOP expression in a p53-deficient background is sufficient to initiate liposarcoma in mouse but not in hASCs, suggesting the need of additional cooperating mutations in hASCs. A microarray gene expression profiling has shed light into the potential deregulated pathways in liposarcoma formation from p53-deficient mASCs expressing FUS-CHOP, which might also function as potential cooperating mutations in the transformation process from hASCs. S C 2011; 29:179-192 [ABSTRACT FROM AUTHOR]

A paracrine regulation was recently proposed in human embryonic stem cells (hESCs) grown in mouse embryonic fibroblast (MEF)-conditioned media (MEF-CM), where hESCs spontaneously differentiate into autologous fibroblast-like cells to maintain culture homeostasis by producing TGF-β and insulin-like growth factor-II (IGF-II) in response to basic fibroblast growth factor (bFGF). Although the importance of TGF-β family members in the maintenance of pluripotency of hESCs is widely established, very little is known about the role of IGF-II. In order to ease hESC culture conditions and to reduce xenogenic components, we sought (i) to determine whether hESCs can be maintained stable and pluripotent using CM from human foreskin fibroblasts (HFFs) and human mesenchymal stem cells (hMSCs) rather than MEF-CM, and (ii) to analyze whether the cooperation of bFGF with TGF-β and IGF-II to maintain hESCs in MEF-CM may be extrapolated to hESCs maintained in allogeneic mesenchymal stem cell (MSC)-CM and HFF-CM. We found that MSCs and HFFs express all FGF receptors (FGFR1-4) and specifically produce TGF-β in response to bFGF. However, HFFs but not MSCs secrete IGF-II. Despite the absence of IGF-II in MSC-CM, hESC pluripotency and culture homeostasis were successfully maintained in MSC-CM for over 37 passages. Human ESCs derived on MSCs and hESCs maintained in MSC-CM retained hESC morphology, euploidy, expression of surface markers and transcription factors linked to pluripotency and displayed in vitro and in vivo multilineage developmental potential, suggesting that IGF-II may be dispensable for hESC pluripotency. In fact, IGF-II blocking had no effect on the homeostasis of hESC cultures maintained either on HFF-CM or on MSC-CM. These data indicate that hESCs are successfully maintained feeder-free with IGF-II-lacking MSC-CM, and that the previously proposed paracrine mechanism by which bFGF cooperates with TGF-β and IGF-II in the maintenance of hESCs in MEF-CM may not be fully extrapolated to hESCs maintained in CM from human MSCs.Cell Research (2009) 19:698–709. doi: 10.1038/cr.2009.35; published online 24 March 2009 [ABSTRACT FROM AUTHOR]

Improvements in chemotherapy and radiotherapy have contributed to the high survival rate (∼70%) of childhood acute lymphoblastic leukemia (ALL). However, during treatment, lack of physical activity and treatment cause various short- to long-term side effects, such as muscle atrophy and physical deconditioning. The purpose of this study was to determine the effects of an intra-hospital, short-duration (8 weeks) exercise training program on muscle strength and endurance and functional mobility of children with ALL. Seven children (4 boys and 3 girls; 4-7 years of age) who were in the maintenance phase of treatment for ALL were selected as subjects. Three training sessions of 90- to 120-minute duration were performed each week. Each session included 11 different strength exercises engaging the major muscle groups and aerobic training. Gains in strength and endurance were assessed with a 6 repetition maximum test for upper (seated bench press and seated lateral row) and lower extremities (leg press). Gains in functional mobility were assessed with the time up and go test (TUG) and the timed up and down stairs test (TUDS). Performance was significantly improved after the training program in all strength tests (p < 0.01 for seated bench press and p < 0.05 for both seated lateral row and seated leg press) and in the TUG test (p < 0.05). In summary, a period of time as short as 8 weeks is enough to produce clinically relevant early-phase adaptations in children receiving treatment against ALL (i.e., improved functional mobility and muscle strength). Although more research is needed in the area of exercise training and pediatric cancer, exercise sciences can play a beneficial role in assisting both oncologists in treating cancer and improving children's quality of life during and after treatment. [ABSTRACT FROM AUTHOR]

Previous studies have shown the relevance of bone marrow-derived MSCs (BM-MSCs) in controlling graft-versus-host disease (GVHD) after allogeneic transplantation. Since adipose tissue-derived MSCs (Ad-MSCs) may constitute a good alternative to BM-MSCs, we have expanded MSCs derived from human adipose tissue (hAd-MSCs) and mouse adipose tissue (mAd-MSCs), investigated the immunoregulatory properties of these cells, and evaluated their capacity to control GVHD in mice. The phenotype and immunoregulatory properties of expanded hAd-MSCs were similar to those of human BM-MSCs. Moreover, hAd-MSCs inhibited the proliferation and cytokine secretion of human primary T cells in response to mitogens and allogeneic T cells. Similarly, ex vivo expanded mAd-MSCs had an equivalent immunophenotype and exerted immunoregulatory properties similar to those of hAd-MSCs. Moreover, the infusion of mAd-MSCs in mice transplanted with haploidentical hematopoietic grafts controlled the lethal GVHD that occurred in control recipient mice. These findings constitute the first experimental proof that Ad-MSCs can efficiently control the GVHD associated with allogeneic hematopoietic transplantation, opening new perspectives for the clinical use of Ad-MSCs. [ABSTRACT FROM AUTHOR]

Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A long-pursued goal in cancer treatment is to deliver a therapy specifically to metastases. As a result of the disseminated nature of the metastatic disease, carrying the therapeutic agent to the sites of tumor growth represents a major step for success. We hypothesized that tumor cells injected intravenously (i.v.) into an animal with metastases would respond to many of the factors driving the metastatic process, and would target metastases. Using a model of spontaneous metastases, we report here that i.v. injected tumor cells localized on metastatic lesions. Based on this fact, we used genetically transduced tumor cells for tumor targeting of anticancer agents such as a suicide gene or an oncolytic virus, with evident antitumoral effect and negligible systemic toxicity. Therefore, autologous tumor cells may be used as cellular vehicles for systemic delivery of anticancer therapies to metastatic tumors.Cancer Gene Therapy (2005) 12, 341-349. doi:10.1038/sj.cgt.7700801 Published online 14 January 2005 [ABSTRACT FROM AUTHOR]

Neural stem cells giving rise to neurons and glia cells have been isolated from the embryonic and adult central nervous system. The extent to which they are able to differentiate into cells of non-neural lineages, such as the hematopoietic lineage, is nonetheless unclear. We previously reported the isolation of stem cells from the mouse olfactory bulb neuroepithelium. In the present study, we analysed whether olfactory bulb stem cells (OBSC) can generate cells with hematopoietic features. Cells were prepared from the olfactory bulbs of transgenic mice expressing enhanced green fluorescent protein (EGFP). In culture, transgenic cells proliferated with the same kinetics as wild-type cells. Following mitogen removal, both cell types gave rise to similar numbers of neurons, astrocytes and oligodendrocytes, indicating that EGFP overexpression does not alter OBSC proliferation and differentiation patterns. When these cells were injected into the tail vein of irradiated mice, no hematopoietic cells derived from the OBSC could be recovered in their peripheral blood, spleen or bone marrow. By contrast, when OBSC were transplanted into the adult brain, EGFP-positive cells were found in the striatum and corpus callosum; differentiated cells expressed antigenic markers of neurons and astrocytes. These results suggest that embryonic olfactory bulb stem cells are not endowed with the potential to produce hematopoiesis. [ABSTRACT FROM AUTHOR]

Keratoconjunctivitis sicca (KCS) is characterized by ocular discomfort, conjunctival hyperaemia, and corneal scarring, causing reduced aqueous tear production that can be measured using the standard Schirmer tear test (STT). Canine adipose tissue-derived MSCs (cATMSCs) have been proposed as treatment due to their anti-inflammatory effect, by releasing cytokines and immunomodulatory soluble factors. Purpose: The aim of this study was to evaluate the effect of the systemic administration of cATMSCs on tear production in dogs with immune-mediated KCS, compared to classical Cyclosporine A (CsA) treatment. Methods: Twenty-eight client-owned dogs with spontaneous KCS were allocated in the experimental group (n = 14, treated with systemic cATMSCs or control group (n = 14, treated with CsA). SST values increased significantly at days 15 (p = 0.002), 45 (p = 0.042) and 180 (p = 0.005) with no observed side-effects in the experimental group. Eyes with an initial STT value of 11–14 mm/min maintained significant improvement at day 180, needing only artificial tears as treatment. Eyes with an initial STT value <11 mm/min needed cyclosporin treatment at day 45, so follow-up was stopped. Control animals treated with CsA did not improve their STT at day 180. Results and Conclusions: Systemic allogeneic cATMSCs application appeared to be a feasible and effective therapy with positive outcome in dogs with initial STT between 11–14 mm/min, with a significant improvement in tear production. The STT increment was maintained for at least 180 days, without needing additional medication, thus suggesting it could constitute an alternative therapy to classical immunosuppressive treatments. [ABSTRACT FROM AUTHOR]

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)—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. [ABSTRACT FROM AUTHOR]

Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations. [ABSTRACT FROM AUTHOR]

Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a type of bone tumour characterized by considerable levels of phenotypic heterogeneity, aneuploidy, and a high mutational rate. The life expectancy of osteosarcoma patients has not changed during the last three decades and thus much remains to be learned about the disease biology. Here, we employ a RGB-based single-cell tracking system to study the clonal dynamics occurring in a de novo-induced murine osteosarcoma model. We show that osteosarcoma cells present initial polyclonal dynamics, followed by clonal dominance associated with adaptation to the microenvironment. Interestingly, the dominant clones are composed of subclones with a similar tumour generation potential when they are re-implanted in mice. Moreover, individual spontaneous metastases are clonal or oligoclonal, but they have a different cellular origin than the dominant clones present in primary tumours. In summary, we present evidence that osteosarcomagenesis can follow a neutral evolution model, in which different cancer clones coexist and propagate simultaneously. Osteosarcoma is a heterogeneous bone tumour with a high mutational rate. Here the authors use an RGB-based single-cell tracking system to track clonal dynamics in a mouse model of osteosarcoma, which their findings indicate follows a neutral evolution model in which different clones simultaneously coexist and propagate. [ABSTRACT FROM AUTHOR]