Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy.

Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy

Assessing the effectiveness of business support services in England: evidence from a theory based evaluation

In England, publicly supported advisory services for small firms are organised primarily through the Business Link (BL) network. Based on the programme theory underlying this business support services we develop four propositions and test these empirically using data from a new survey of over 3,000 English small firms. Our empirical results provide a broad validation of the programme theory underlying BL assistance for small firms in England during 2003, and more limited support for its effectiveness. More specifically, we find strong support for the value of BL operators maintaining a high profile as a way of boosting take-up. We also find some support for the approach to market segmentation adopted by BL allowing more intensive assistance to be targeted on younger firms and those with limited liability status. In terms of the outcomes of BL support, and allowing for issues of sample selection, we find no significant effects on growth from ‘other’ assistance but do find positive and significant employment growth effects from intensive assistance. This provides partial support for the programme theory assertion that BL support will lead to improvements in business growth performance and stronger support for the proposition that there would be differential outcomes from intensive and other assistance. The positive employment growth outcomes identified here from intensive assistance, even allowing for sample selection, suggest something of an improvement in the effectiveness of the BL network since the late 1990s

Assessment of an Average Controller for a DC/DC Converter via Either a PWM or a Sigma-Delta-Modulator

Sliding mode control is a discontinuous control technique that is, by its nature, appropriate for controlling variable structure systems, such as the switch regulated systems employed in power electronics. However, when designing control laws based on the average models of these systems a modulator is necessary for their experimental implementation. Among the most widely used modulators in power electronics are the pulse width modulation (PWM) and, more recently, the sigma-delta-modulator (Σ-Δ-modulator). Based on the importance of achieving an appropriate implementation of average control laws and the relevance of the trajectory tracking task in DC/DC power converters, for the first time, this research presents the assessment of the experimental results obtained when one of these controllers is implemented through either a PWM or a Σ-Δ-modulator to perform such a task. A comparative assessment based on the integral square error (ISE) index shows that, at frequencies with similar efficiency, the Σ-Δ-modulator provides a better tracking performance for the DC/DC Buck converter. In this paper, an average control based on differential flatness was used to perform the experiments. It is worth mentioning that a different trajectory tracking controller could have been selected for this research

Identification of a Cranberry Juice Product that Inhibits Enteric CYP3A-Mediated First-Pass Metabolism in Humans

An in vivo study in rats showed a cranberry juice product to inhibit the intestinal first-pass metabolism of the CYP3A substrate nifedipine. However, a clinical study involving the CYP3A probe substrate midazolam and a different cranberry juice product showed no interaction. Because the composition of bioactive components in natural products can vary substantially, a systematic in vitro-in vivo approach was taken to identify a cranberry juice capable of inhibiting enteric CYP3A in humans. First, the effects of five cranberry juices, coded A through E, were evaluated on midazolam 1′-hydroxylation activity in human intestinal microsomes. Juice E was the most potent, ablating activity at 0.5% juice (v/v) relative to control. Second, juice E was fractionated to generate hexane-, chloroform-, butanol-, and aqueous-soluble fractions. The hexane- and chloroform-soluble fractions at 50 μg/ml were the most potent, inhibiting by 77 and 63%, respectively, suggesting that the CYP3A inhibitors reside largely in these more lipophilic fractions. Finally, juice E was evaluated on the oral pharmacokinetics of midazolam in 16 healthy volunteers. Relative to water, juice E significantly increased the geometric mean area under the curve (AUC)0-∞ of midazolam by ∼30% (p = 0.001), decreased the geometric mean 1′-hydroxymidazolam/midazolam AUC0-∞ ratio by ∼40% (p < 0.001), and had no effect on geometric mean terminal half-life, indicating inhibition of enteric, but not hepatic, CYP3A-mediated first-pass metabolism of midazolam. This approach both showed a potential drug interaction liability with cranberry juice and substantiated that rigorous in vitro characterization of dietary substances is required before initiation of clinical drug-diet interaction studies

Employment and SMEs during crises

The persistent increasing duration of unemployment has become an issue during economic crises. Although lay-offs at large firms normally make headlines during crises, we still know little about the potential impact of firm size on adjustment behavior in a crisis. We studied effects of firm size on employment growth during economic slowdowns using a rich microeconomic database for the 1988-2007 period in Portuguese manufacturing industry. The results show that economic downturns affect firm growth negatively. This negative effect is found to be higher for larger firms, both during and immediately following crisis periods. Small and medium-sized enterprises (SMEs) emerge as potential stabilizers in downturn periods. However, larger firms seem to be able to quickly recover from downturn periods. Our results contribute to the scarce literature and to the understanding of the Portuguese case, where many SMEs secure most jobs. These first results may be useful, because SMEs play a determinant role in other European Union economies

Informe: Derecho del trabajo y de la seguridad social en España en 2013. Algunos puntos críticos

Este documento intenta reflejar algunos de los principales cambios y novedades del ordenamiento laboral español en 2013, levantando acta de cómo la mutabilidad de nuestro Derecho del Trabajo es imparable. Este informe, consciente de ello, ofrece una selección de elementos esenciales, a juicio de sus autores, especialistas en cada una de las materias, encuadrados en la Sección Juvenil de la Asociación Española de Derecho del Trabajo y de la Seguridad Social. En él, conforme a la organización de dicha Sección en grupos de trabajo, se abordan las novedades más relevantes en materia de derechos fundamentales inespecíficos, contratación laboral, vicisitudes del contrato de trabajo, Derecho colectivo, conciliación y corresponsabilidad, protección social y prevención de riesgos laborales. This paper tries to show some of the many changes and novelties in Spanish Labour Law during 2013, drawing up a record of the unstoppable character of our Labour legal system. This report offers a selection of essential elements, according to its authors, all of them specialists in each one of the subjects, being part of the Young Scholars’ Section of the Spanish Association for Labour and Social Security Law. According to the organization of the said Section in working groups, we can find novelties concerning unspecific fundamental rights, work contracts, the life of the work contract and collective Labour Law, reconciliation and co responsibility, social protection and occupational risk prevention

El derecho del trabajo y de la seguridad social en España en 2014

Este documento intenta reflejar algunos de los principales cambios y novedades del ordenamiento laboral español en 2014, levantando acta de cómo la mutabilidad de nuestro Derecho del Trabajo es imparable. Este informe, consciente de ello, ofrece una selección de elementos esenciales, a juicio de sus autores, especialistas en cada una de las materias, encuadrados en la Sección Juvenil de la Asociación Española de Derecho del Trabajo y de la Seguridad Social. En él, conforme a la organización de dicha Sección en grupos de trabajo, se abordan las novedades más relevantes en materia de derechos fundamentales inespecíficos, contratación laboral, vicisitudes del contrato de trabajo, Derecho colectivo, conciliación y corresponsabilidad, protección social y prevención de riesgos laborales. This paper tries to show some of the many changes and novelties in Spanish Labour Law during 2014, drawing up a record of the unstoppable character of our Labour legal system. This report offers a selection of essential elements, according to its authors, all of them specialists in each one of the subjects, being part of the Young Scholars’ Section of the Spanish Association for Labour and Social Security Law. According to the organization of the said Section in working groups, we can find novelties concerning unspecific fundamental rights, work contracts, the life of the work contract and collective Labour Law, work-life balance and co responsibility, social protection and occupational risk prevention