HLA-DR in Cytotoxic T lymphocytes predicts breast cancer patients' response to neoadjuvant chemotherapy

Prediction of breast cancer response to Neoadjuvant Chemotherapy (NACT) is an urgent need to promptly direct non-responder patients to alternative therapies. Infiltrating T lymphocytes, namely cytotoxic T lymphocytes (CTLs) have been appointed as predictors of response. However, cancer cells have the ability to dampen CTLs' activity and thus, the prognostic value of the CTLs, per se, is debatable. Here, we disclose that more than the occurrence of CTLs, it is their activation state, revealed by HLA-DR expression, that can accurately predict response to NACT. Flow cytometry analysis of breast cancer biopsies showed that the frequency of CTLs and other lymphocytes were similar regardless disease stage and between NACT responders and non-responders. However, only breast cancer patients without axillary lymph node metastasis and NACT responders have HLA-DRhi CTLs. Interestingly, HLA-DR levels in tumor CTLs is correlated with HLA-DR levels in systemic CTLs. These HLA-DR+ CTLs produce IFN-γ and Granzyme B, enlightening their effector and probable anti-tumor activity profile. Moreover, the level of HLA-DR in CTLs is negatively correlated with the level of HLA-DR in T regulatory lymphocytes and with immunosuppressive and pro-tumor molecules in the tumor microenvironment. Hence, HLA-DR levels in CTLs is a highly sensitive and specific potential predictive factor of NACT-response, which can be assessed in blood to guide therapeutic decisions.Fundacao para a Ciencia e Tecnologia: PD/BD/114023/2015; PTDC/BBB-BMD/4497/2014. Liga Portuguesa Contra o Cancroinfo:eu-repo/semantics/publishedVersio

Filamentary fragmentation in a turbulent medium

We present the results of smoothed particle hydrodynamic simulations investigating the evolution and fragmentation of filaments that are accreting from a turbulent medium. We show that the presence of turbulence, and the resulting inhomogeneities in the accretion flow, play a significant role in the fragmentation process. Filaments which experience a weakly turbulent accretion flow fragment in a two-tier hierarchical fashion, similar to the fragmentation pattern seen in the Orion Integral Shaped Filament. Increasing the energy in the turbulent velocity field results in more sub-structure within the filaments, and one sees a shift from gravity-dominated fragmentation to turbulence-dominated fragmentation. The sub-structure formed in the filaments is elongated and roughly parallel to the longitudinal axis of the filament, similar to the fibres seen in observations of Taurus, and suggests that the fray and fragment scenario is a possible mechanism for the production of fibres. We show that the formation of these fibre-like structures is linked to the vorticity of the velocity field inside the filament and the filament's accretion from an inhomogeneous medium. Moreover, we find that accretion is able to drive and sustain roughly sonic levels of turbulence inside the filaments, but is not able to prevent radial collapse once the filaments become supercritical. However, the supercritical filaments which contain fibre-like structures do not collapse radially, suggesting that fibrous filaments may not necessarily become radially unstable once they reach the critical line-density.Comment: (Accepted for publication in MNRAS

Intrapatient variability of the pupillary pain index to remifentanil

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Internet sales as a new mode of internationalization

The way that organizations explore the Internet has been the focus of a substantial body of scientific studies and non-academic reflection. The main goal of this study is to analyze the potential of the internet as a mode of internationalization and the factors that influence the results of the adoption of this mean to access foreign markets. For this purpose, we examine the determinants of the level of international sales made via internet estimating an ordered probit model. The results show that the importance of previous experience in using the internet and developing international activity, together with the level of internet marketing budget , the level of investment on internet sophistication, the firm dimension, the business age and the type pf activity are variables that determine the results obtain in the international sales trough the internet.info:eu-repo/semantics/publishedVersio