SCD5 restored expression favors differentiation and epithelial-mesenchymal reversion in advanced melanoma

Our previous data supported a role for the Stearoyl-CoA desaturase (SCD5) in protection against malignancy, whereby it appears to functionally modify tumor stroma impairing tumor spread. SCD5 is significantly expressed in primary melanoma, but becomes barely detectable at tumor advanced stages. Looking for the regulatory mechanisms underlying SCD5 reduced expression during melanoma progression, we demonstrated a significantly lower stability of SCD5 protein as well as the direct targeting of SCD5 mRNA by the oncogenic miR-221 & 222 in metastatic cell lines. Moreover, our results indicated the existence of a negative feedback loop between SCD5 and miR-221 & 222, in good agreement with their opposite functions. Also, we showed how SCD5 re-expression and the direct supplementation of its main product oleic acid (OA) can drive advanced melanoma cell lines toward differentiation and reversion of the epithelial-mesenchymal (EMT)-like process, eventually inducing a less malignant phenotype. Indeed, SCD5 re-established the sensitivity to all-trans retinoic acid in A375M metastatic melanoma, associated with increased levels of Tyrosinase, melanin production and reduced proliferation. As evidenced by the correct modulation of some key transcription factors, SCD5 managed by favoring a partial mesenchymal-to-epithelial (MET) transition in in vitro studies. Interestingly, a more complete MET, including E-cadherin re-expression correctly localized at cell membranes, was obtained in in vivo xenograft models, thus indicating the requirement of direct contacts between tumor cells and the surrounding microenvironment as well as the presence of some essential factors for SCD5 complete function

Sign-Perturbed Sums (SPS) with Asymmetric Noise: Robustness Analysis and Robustification Techniques

Sign-Perturbed Sums (SPS) is a recently developed finite sample system identification method that can build exact confidence regions for linear regression problems under mild statistical assumptions. The regions are well-shaped, e.g., they are centred around the least-squares (LS) estimate, star-convex and strongly consistent. One of the main assumptions of SPS is that the distribution of the noise terms are symmetric about zero. This paper analyses how robust SPS is with respect to the violation of this assumption and how it could be robustified with respect to non-symmetric noises. First, some alternative solutions are overviewed, then a robustness analysis is performed resulting in a robustified version of SPS. We also suggest a modification of SPS, called LAD-SPS, which builds exact confidence regions around the least-absolute deviation (LAD) estimate instead of the LS estimate. LAD-SPS requires less assumptions as the noise needs only to have a conditionally zero median (w.r.t. the past). Furthermore, that approach can also be robustified using similar ideas as in the LS-SPS case. Finally, some numerical experiments are presented

Exosome-mediated transfer of miR-222 is sufficient to increase tumor malignancy in melanoma

BACKGROUND: Growing evidence is showing that metastatic cell populations are able to transfer their characteristics to less malignant cells. Exosomes (EXOs) are membrane vesicles of endocytic origin able to convey their cargo of mRNAs, microRNAs (miRs), proteins and lipids from donors to proximal as well as distant acceptor cells. Our previous results indicated that miR-221&222 are key factors for melanoma development and dissemination. The aim of this study was to verify whether the tumorigenic properties associated with miR-222 overexpression can be also propagated by miR-222-containing EXOs. METHODS: EXOs were isolated by UltraCentrifugation or Exoquick-TC(®) methods. Preparations of melanoma-derived vesicles were characterized by using the Nanosight™ technology and the expression of exosome markers analyzed by western blot. The expression levels of endogenous and exosomal miRNAs were examined by real time PCR. Confocal microscopy was used to evaluate transfer and uptake of microvesicles from donor to recipient cells. The functional significance of exosomal miR-222 was estimated by analyzing the vessel-like process formation, as well as cell cycle rates, invasive and chemotactic capabilities. RESULTS: Besides microvesicle marker characterization, we evidenced that miR-222 exosomal expression mostly reflected its abundance in the cells of origin, correctly paralleled by repression of its target genes, such as p27Kip1, and induction of the PI3K/AKT pathway, thus confirming its functional implication in cancer. The possible differential significance of PI3K/AKT blockade was assessed by using the BKM120 inhibitor in miR-222-transduced cell lines. In addition, in vitro cultures showed that vesicles released by miR-222-overexpressing cells were able to transfer miR-222-dependent malignancy when taken-up by recipient primary melanomas. Results were confirmed by antagomiR-221&222 treatments and by functional observations after internalization of EXOs devoid of these miRs

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, ‘sex’ and ‘gender’ are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs’ identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/genderspecific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. “Being a male or being a female” is indeed important from a health point of view and it is no longer possible to avoid “sex and gender lens” when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward

HOXB1 restored expression promotes apoptosis and differentiation in the HL60 leukemic cell line

BACKGROUND: Homeobox (HOX) genes deregulation has been largely implicated in the development of human leukemia. Among the HOXB cluster, HOXB1 was silent in a number of analyzed acute myeloid leukemia (AML) primary cells and cell lines, whereas it was expressed in normal terminally differentiated peripheral blood cells. METHODS: We evaluated the biological effects and the transcriptome changes determined by the retroviral transduction of HOXB1 in the human promyelocytic cell line HL60. RESULTS: Our results suggest that the enforced expression of HOXB1 reduces cell growth proliferation, inducing apoptosis and cell differentiation along the monocytic and granulocytic lineages. Accordingly, gene expression analysis showed the HOXB1-dependent down-regulation of some tumor promoting genes, paralleled by the up-regulation of apoptosis- and differentiation-related genes, thus supporting a tumor suppressor role for HOXB1 in AML. Finally, we indicated HOXB1 promoter hypermethylation as a mechanism responsible for HOXB1 silencing. CONCLUSIONS: We propose HOXB1 as an additional member of the HOX family with tumour suppressor properties suggesting a HOXB1/ATRA combination as a possible future therapeutic strategy in AML

A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2.

OX40 stimulation is known to enhance activation of effector T cells and to inhibit induction and suppressive function of Treg. Here we uncovered a novel role of OX40 in sustaining Treg competitive fitness in vivo, during repopulation of lymphopenic hosts and reconstitution of BM chimeras. Defective expansion of OX40-null Treg diminished their ability to suppress inflammation in a model of lymphopenia-driven colitis. OX40-mediated promotion of Treg fitness spanned beyond lymphopenic environments, as endogenous Treg in OX40-null mice showed decreased accumulation during thymic development, enhanced susceptibility to antibody-mediated depletion and defective turnover following thymectomy. In vitro, OX40-deficient Treg were found to be intrinsically hyporesponsive to IL-2, in terms of Stat5 phosphorylation and proliferation, according to elevated SOCS1 content and reduced miR155 expression. Therefore, OX40 is a key factor in shaping Treg sensitivity to IL-2 and promoting their proliferation and survival, toward accurate immune regulation

MAPPING THE INTELLECTUAL STRUCTURE OF SOCIAL FINANCE: A BIBLIOMETRIC OVERVIEW

Recently, there has been significant growth in the number of published articles on social finance in academic journals. However, myriad of different terms are often involved in Social Finance discourses. This study provides a bibliometric analysis of the research on social finance. Our results show that the social finance research field is composed of several research hotspots - which represent the core of this research domain – and five main research clusters including impact investing, social entrepreneurship, social impact bonds, and social innovation. The paper also identifies the research institutions and the researchers that contributed to this field of research. Finally, emerging research areas are also mapped and described. The theoretical contribution of this paper lies in its intention to connect the different manifestations of Social Finance under one concept. Using a common umbrella concept allows researchers to find common ground for their otherwise isolated research endeavors

Funding Innovative Healthcare Programs Through Social Impact Bonds: Issues and Challenges

Social Impact Bonds (SIBs) have quickly attracted the attention of policy makers, practitioners, and academics due to their ability to fund innovative health and social programs while generating savings for governments and financial returns for investors. Health Impact Bonds (HIBs) represent the adaptation of these current examples of Social Impact Bonds in recidivism and child removal into new health programs and interventions that encourage investments in cost-saving preventive services in order to reduce the need for more costly remediation and fill the market gap between the private and public sectors. This work provides an overview of this emerging funding scheme and proposes reflections and suggestions useful for both practitioners and policy makers. Thus, the first part of the work presents an overview of the literature about SIBs and HIBs by highlighting the opportunities and challenges related to their implementation, the second part provides qualitative and quantitative data on all the existing HIBs, and the last part provides a discussion and suggestions useful for their implementation

The abrogation of the HOXB7/PBX2 complex induces apoptosis in melanoma through the miR-221&222-c-FOS pathway.

Cutaneous melanoma is the fastest increasing cancer worldwide. Although several molecular abnormalities have been associated with melanoma progression, the underlying mechanisms are still largely unknown and few targeted therapies are under evaluation. Here we show that the HOXB7/PBX2 dimer acts as a positive transcriptional regulator of the oncogenic microRNA-221 and -222. In addition, demonstrating c-FOS as a direct target of miR-221&222, we identify a HOXB7/PBX2→miR-221&222 →c-FOS regulatory link, whereby the abrogation of functional HOXB7/PBX2 dimers leads to reduced miR-221&222 transcription and elevated c-FOS expression with consequent cell death. Taking advantage of the treatment with the peptide HXR9, an antagonist of HOX/PBX dimerization, we recognize miR-221&222 as effectors of its action, in turn confirming the HXR9 efficacy in the treatment of human melanoma malignancy, whilst sparing normal human melanocytes. Our findings, besides suggesting the potential therapeutic of HXR9 or its derivatives in malignant melanoma, suggest the disruption of the HOXB7/PBX2 complexes, miR-221&222 inhibition or even better their combination, as innovative therapeutic approaches