Carboxyl-modified single-wall carbon nanotubes improve bone tissue formation in vitro and repair in an in vivo rat model.

The clinical management of bone defects caused by trauma or nonunion fractures remains a challenge in orthopedic practice due to the poor integration and biocompatibility properties of the scaffold or implant material. In the current work, the osteogenic properties of carboxyl-modified single-walled carbon nanotubes (COOH-SWCNTs) were investigated in vivo and in vitro. When human preosteoblasts and murine embryonic stem cells were cultured on coverslips sprayed with COOH-SWCNTs, accelerated osteogenic differentiation was manifested by increased expression of classical bone marker genes and an increase in the secretion of osteocalcin, in addition to prior mineralization of the extracellular matrix. These results predicated COOH-SWCNTs' use to further promote osteogenic differentiation in vivo. In contrast, both cell lines had difficulties adhering to multi-walled carbon nanotube-based scaffolds, as shown by scanning electron microscopy. While a suspension of SWCNTs caused cytotoxicity in both cell lines at levels >20 μg/mL, these levels were never achieved by release from sprayed SWCNTs, warranting the approach taken. In vivo, human allografts formed by the combination of demineralized bone matrix or cartilage particles with SWCNTs were implanted into nude rats, and ectopic bone formation was analyzed. Histological analysis of both types of implants showed high permeability and pore connectivity of the carbon nanotube-soaked implants. Numerous vascularization channels appeared in the formed tissue, additional progenitor cells were recruited, and areas of de novo ossification were found 4 weeks post-implantation. Induction of the expression of bone-related genes and the presence of secreted osteopontin protein were also confirmed by quantitative polymerase chain reaction analysis and immunofluorescence, respectively. In summary, these results are in line with prior contributions that highlight the suitability of SWCNTs as scaffolds with high bone-inducing capabilities both in vitro and in vivo, confirming them as alternatives to current bone-repair therapies

GARP promotes the proliferation and therapeutic resistance of bone sarcoma cancer cells through the activation of TGF-β

Sarcomas are mesenchymal cancers with poor prognosis, representing about 20% of all solid malignancies in children, adolescents, and young adults. Radio- and chemoresistance are common features of sarcomas warranting the search for novel prognostic and predictive markers. GARP/LRRC32 is a TGF-β-activating protein that promotes immune escape and dissemination in various cancers. However, if GARP affects the tumorigenicity and treatment resistance of sarcomas is not known. We show that GARP is expressed by human osteo-, chondro-, and undifferentiated pleomorphic sarcomas and is associated with a significantly worse clinical prognosis. Silencing of GARP in bone sarcoma cell lines blocked their proliferation and induced apoptosis. In contrast, overexpression of GARP promoted their growth in vitro and in vivo and increased their resistance to DNA damage and cell death induced by etoposide, doxorubicin, and irradiation. Our data suggest that GARP could serve as a marker with therapeutic, prognostic, and predictive value in sarcoma. We propose that targeting GARP in bone sarcomas could reduce tumour burden while simultaneously improving the efficacy of chemo- and radiotherapy.Instituto de Salud Carlos IIIEuropean Union (EU) PI15/00794 PI18/00826 CPII15/00032 PI15/02015Junta de Andalucía C-0013-2018Spanish Government PEJ-2014-A-46314Agencia Estatal de Investigación (AEI) [MICINN/Fondo Europeo de Desarrollo Regional (FEDER)] SAF-2016-75286-RISCIII/FEDER [Miguel Servet Program] CPII16/00049ISCIII/FEDER [Sara Borrell Program] CD16/00103Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III PT17/0015/0023Fundación Bancaria Cajastur PT17/0015/0023ISCIII/FEDER [Consorcio CIBERONC] CB16/12/0039

Tumor Angiogenesis and Vascular Patterning: A Mathematical Model

Understanding tumor induced angiogenesis is a challenging problem with important consequences for diagnosis and treatment of cancer. Recently, strong evidences suggest the dual role of endothelial cells on the migrating tips and on the proliferating body of blood vessels, in consonance with further events behind lumen formation and vascular patterning. In this paper we present a multi-scale phase-field model that combines the benefits of continuum physics description and the capability of tracking individual cells. The model allows us to discuss the role of the endothelial cells' chemotactic response and proliferation rate as key factors that tailor the neovascular network. Importantly, we also test the predictions of our theoretical model against relevant experimental approaches in mice that displayed distinctive vascular patterns. The model reproduces the in vivo patterns of newly formed vascular networks, providing quantitative and qualitative results for branch density and vessel diameter on the order of the ones measured experimentally in mouse retinas. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of different parameters in this process, hence underlining the necessary collaboration between mathematical modeling, in vivo imaging and molecular biology techniques to improve current diagnostic and therapeutic tools

ADAMTS proteases in vascular biology.

ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases comprise the most recently discovered branch of the extracellular metalloenzymes. Research during the last 15years, uncovered their association with a variety of physiological and pathological processes including blood coagulation, tissue repair, fertility, arthritis and cancer. Importantly, a frequent feature of ADAMTS enzymes relates to their effects on vascular-related phenomena, including angiogenesis. Their specific roles in vascular biology have been clarified by information on their expression profiles and substrate specificity. Through their catalytic activity, ADAMTS proteases modify rather than degrade extracellular proteins. They predominantly target proteoglycans and glycoproteins abundant in the basement membrane, therefore their broad contributions to the vasculature should not come as a surprise. Furthermore, in addition to their proteolytic functions, non-enzymatic roles for ADAMTS have also been identified expanding our understanding on the multiple activities of these enzymes in vascular-related processes

Endocrine Modulation in Long-Term Karate Practitioners

Purpose. Karate is a martial arts discipline which is widely practiced in the Western world as a form of self-defense, as well as a discipline to achieve physical and mental balance. However, little is known with respect to its specific psychobiological effects, particularly in relation to the influence that it may exert on the endocrine system. Thus, in the present study, we examined the effects of karate on several hormonal parameters of the Hypothalamic-Pituitary-Adrenal and Hypothalamic-Pituitary-Thyroid axes in long-time practitioners. Methods. Twenty-two healthy volunteer subjects (12 experimental and 10 controls) participated in the study. Experimental subjects were karate players with a minimum of 3 years of practice in this discipline. Blood samples for the quantification of hormonal parameters were taken in both groups. The Mann-Whitney U test was performed for each variable in order to analyze the differences between groups. Results. Statistically significant differences were found in cortisol and thyroid hormones, with the karate group showing lower levels of these hormones as compared to control. Conclusions. These findings, therefore, reveal that long-term karate practice is associated with a significant endocrine modulation, which suggests interesting psychobiological and clinical implications. Further research is needed to verify these preliminary results, as well as properly assessing its possible use as a psychosomatic intervention tool

Immunological Modulation in Long-Term Karate Practitioners

Karate is a Japanese martial arts system with potential physical and psychological benefits. However, karate has been scarcely investigated from a psychobiological perspective, and its effects on the immune system remain virtually unknown. We designed the present study with the aim of analyzing the effects of karate practice on immunological parameters. 27 healthy male volunteer subjects participated in the study, 15 in the experimental group and 12 in the control. Experimental subjects were all karate players who had practiced this martial art for a minimum of three years attending regular lessons at a karate training center, in the evening, two to three days per week. Blood samples for the quantification of immunological parameters (total leukocytes, neutrophils, monocytes, eosinophils, basophils, lymphocytes, IgG, IgA, and IgM) were taken in both groups. A t-test for independent groups was performed in each dependent variable; a value of p<0.05 was considered to be significant. Karate practitioners exhibited a significantly higher number of total leukocytes (p<0.02), monocytes (p<0.01), and lymphocytes (p<0.01), a higher percentage of monocytes (p<0.01), and greater serum concentrations of IgG (p<0.02) and IgM (p<0.01). Our findings show that long-term karate practice is related to a broad modulation of immune parameters, including total and specific leukocyte counts, as well as immunoglobulin concentrations. This peculiar immunomodulatory profile, apart from its psychobiological relevance, may have noteworthy clinical implications