”Should I stay or should I go?”: A multiple-criteria group decision-making approach to SME internationalization

Due to domestic markets’ current economic conditions, companies increasingly feel that they need to become actively involved in international trade. However, small and medium-sized enterprises (SMEs) typically face financial and intellectual constraints during internationalization processes. This means that decision makers must consider a wide range of different variables before deciding to internationalize firms. This study sought to integrate cognitive mapping and the Decision EXpert (DEX) method in order to develop a multiple-criteria decision model suitable for the identification and assessment of variables influencing SMEs’ internationalization capability. The results confirm that the dual methodology adopted facilitates the development of a robust evaluation model that can improve decision-making processes in the context in question. More specifically, the proposed model identifies product features as the most important factor in SMEs’ capability for successful internationalization. In addition, internal factors are significantly more relevant than external factors. The model-building process is discussed, including its advantages and limitations.info:eu-repo/semantics/publishedVersio

Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1

Non peer reviewe

Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy

Correction: Volume: 10 Article Number: 932 DOI: 10.1038/s41467-019-08956-x Published: FEB 20 2019 Accession Number: WOS:000459099300001Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-X-L inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X-L co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.Peer reviewe

Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia

Purpose Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. Methods We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Results Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinibtreated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. Conclusions TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.Peer reviewe

IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-alpha is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-alpha in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR beta sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8(+) recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-alpha reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-alpha had costimulatory effects on TCR signaling. Our work supports the combination of IFN-alpha with TKI therapy, as IFN-alpha broadens the immune repertoire and restores immunological function.Peer reviewe

Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML

Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+ TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.Peer reviewe

Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy

Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-X-L inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X-L co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance

Avaliação do Ensino de Empreendedorismo entre Estudantes Universitários por meio do Perfil Empreendedor

Entrepreneurship is a socioeconomic phenomenon that has been valued for its influence on the growth and development of regional and national economies. The main promoter of this phenomenon are entrepreneurs, subjects endowed with multiple features that make up their profiles. They are dynamic and results oriented, benefitting from the fruits of their own personal efforts. Entrepreneurial education is highlighted as one of the most efficient ways to promote an entrepreneurial culture and train new entrepreneurs. However, some difficulty has been observed in assessing the effectiveness of teaching and learning this subject. The objective of this study was to analyze, by means of multivariate techniques, an instrument whose function is to measure the learning of Entrepreneurship, verifying the change in entrepreneur profiles of 407 college students participating or not in an entrepreneurial training process. The results showed that students who participated in Entrepreneurship educational training activities showed significant changes in their entrepreneurial profiles. The main contributions showed growth in the Self-realization, Planner, Innovative and Risks Assumed dimensions

Acceptance of the proposal for a new international standard for list-mode data used in nuclear instrumentation - EMPIR 14SIP07 "DigitalStandard", Deliverable D1; JRC work package 3883 "DiSNU", Deliverable 1

This report is Deliverable D1 of the EMPIR project 14SIP07 "DigitalStandard", which corresponds to Deliverable 1 of the JRC work package 3883 "DiSNU".) The use of digital data acquisition for the detection and measurement of radioactivity is increasing over the years since it offers advantages over data acquisition with conventional modular systems. Modern digital systems sample the signal directly from the radiation detector at a high rate and present data in a digital manner to computer systems for further processing and analysis. However, there currently is no standard for the format of the data presented by such systems, which hinders the interoperability between hardware for data acquisition and software for data analysis. The need for such a standard has been identified earlier by the FP7 EMRP MetroFission project and confirmed by CEN/TC 391 in the frame of Commission mandate M/487 to the European Standardisation Organisations. In the Horizon2020 EMPIR DigitalStandard project, a consortium of four EU Member States has developed a preliminary draft international standard under the lead of JRC, who submitted it together with a New Work Item Proposal to the IEC/TC 45 "Nuclear Instrumentation". The proposal to develop the standard has been accepted, a project team has been appointed by the TC 45 National Committees and a liaison category A has been established between JRC and IEC/TC 45. The liaison officer will lead the project to develop the new standard. Forecast publication date of the standard is March 2019. The first Committee Draft should be finalised and prepared for circulation to the IEC/TC 45 National Committees by October 2016.JRC.D.4-Standards for Nuclear Safety, Security and Safeguard