Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.

Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy

Il servizio WCTS del Geoportale Nazionale

The 2007/2/CE INSPIRE directive requires every Member State to implement a set of services to facilitate the interchange of spatial data; the Coordinate Transformation Service (CTS) is one of the geometric transformation services required by the directive. The Italian National Geoportal (GN) has recently published a new set of public access services that enable the users to transform and convert the coordinate reference system of geographic data within the Italian territory using the high-accuracy correction data provided by the Istituto Geografico Militare Italiano (IGM). This article will illustrate these newly published services: a browser-based web application to transform raster and vector files or sets of coordinates and an OGC-compliant Web Coordinate Transformation Service (WCTS) that performs on the fly transformation of GML (Geography Markup Language) data

Erodibilidade de latossolos no Vale do Rio Doce, região centro-leste do Estado de Minas Gerais.

A capacidade de um solo sofrer erosão hídrica, ou seja, a sua susceptibilidade à erosão pode ser obtida através do fator erodibilidade, o qual é um atributo intrínseco de cada solo. O objetivo deste trabalho foi determinar os valores de erodibilidade para um Latossolo Vermelho (LV) e um Latossolo Vermelho-Amarelo (LVA) no Vale do Rio Doce, região Centro-Leste do Estado de Minas Gerais. Foram utilizados dados de perdas de solo e água coletados durante o período de 2002 a 2008, em parcelas (4 x 24 m) instaladas no campo, sob chuva natural, em solo sem cobertura

A daily diary investigation on the job-related affective experiences fueled by work addiction

Background and aims: We studied the quality of the job-related emotional experiences associated with work addiction. We hypothesized that work addiction would fuel both a higher level of daily job-related negative affect and a lower level of daily job-related positive affect and that such affective experiences would mediate the relationship between work addiction and emotional exhaustion reported at the end of the working day. Additionally, in light of typical behaviors and cognitions associated with work addiction, we also hypothesized that work addiction would modify the relationships between day workload and same day emotional strain reactions (i.e., job-related negative affect and job-related positive affect). Methods: Participants were 213 workers (42.5% female), most of whom holding a high-profile job position, who were followed for 10 consecutive working days in the context of a daily diary study. Results: Multilevel analyses controlling for neuroticism revealed that work addiction was uniquely and positively related to daily job-related negative affect and that the latter mediated the relationship between work addiction and daily emotional exhaustion. On the other hand, work addiction was not negatively related to daily job-related positive affect; this relationship emerged only when removing neuroticism from the model. Additionally, work addiction strengthened the relationship between day workload and day job-related negative affect. Discussion: Results indicate that work addicted are characterized by the experience of a negatively connotated affect during work, and that this kind of affect may be a mechanism explaining the work addiction-burnout relationship

TLR9 ligation in pancreatic stellate cells promotes tumorigenesis

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis

Drought adaptation of Italian silver fir genotypes in a climate change perspective

Resilience of Mediterranean forest ecosystems is closely linked to their ability to adapt to drought and increasingly hot temperatures. Such ability can be influenced by genetic differences between and within species, or provenances. Therefore, it is essential to define management guidelines that consider the role of local provenances in forest adaptation to climate change, and to promote the conservation and sustainable management of resilient forest genetic resources. In this study, we analyse growth responses to drought of silver fir (Abies alba) in the Tuscan-Emilian Apennines National Park, while comparing the physiological performance of three provenances of this species in Italy: (a) Piedmont - (b) Northern Apennines (local) - (c) Southern Apennines. Drought severity was defined through the Standardised Precipitation-Evapotranspiration Index (SPEI). We carried out dendrochronological analyses by assessing climate-growth relationships, applying drought 'resilience indices' (RRR) based on tree ring width, and estimating water use efficiency (iWUE) through carbon isotope analyses (δ13C) on wood samples. Finally, we used FORMIND, an individual-tree process-based model, to simulate growth under two climate scenarios (R.C.P. 4.5 and 8.5). We used field data to parametrize allometric and growth equations used by FORMIND to describe provenance-specific behaviour. Artificial forests had a faster growth than natural forests (BAIart= 16.4 cm2, BAInat= 13.2 cm2), also showing higher resilience during severe droughts and higher recovery during severe and extreme droughts. Fir provenances differed slightly in growth rate (BAIa= 17.5 cm2, BAIb= 19.0 cm2, BAIc=22.8 cm2), with higher performance by the southern provenance. The southern Italian provenance also had better recovery and resilience during moderate and extreme dry years. Preliminary modelling results confirmed these trends, even if the differences between climate scenarios were not significant. Isotope analysis on tree rings will be performed soon. The workflow proposed in this paper couples morphological with eco-physiological analyses, allowing a comprehensive overview of tree response to drought. These results provide important information on the adaptive response of silver fir under climate change, underlying the importance of local genetic diversity for adaptation. Southern provenances have shown better growth and resilience against drought, proving to be a very important resource in a climate change perspective. Thanks to the strong collaboration with the National Park and local forest managers, these results may find concrete application e.g. by planning assisted migration activities in the Park forests, and providing better protection of local fir provenances in natural forests

Distinct Contributions of Median Raphe Nucleus to Contextual Fear Conditioning and Fear-Potentiated Startle

Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also reduced the amount of freezing and the fear-potentiated startle. Freezing is a prominent response of contextual fear conditioning, but does not seem to be crucial for the enhancement of the startle reflex by explicit aversive cues. As fear-potentiated startle may be produced in posttraining lesioned rats that are unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, contextual fear and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN

"war to the knife" against thromboinflammation to protect endothelial function of COVID-19 patients

In this viewpoint, we summarize the relevance of thromboinflammation in COVID-19 and discuss potential mechanisms of endothelial injury as a key point for the development of lung and distant organ dysfunction, with a focus on direct viral infection and cytokine-mediated injury. Entanglement between inflammation and coagulation and resistance to heparin provide a rationale to consider other therapeutic approaches in order to preserve endothelial function and limit microthrombosis, especially in severe forms. These strategies include nebulized heparin, N-acetylcysteine, plasma exchange and/or fresh frozen plasma, plasma derivatives to increase the level of endogenous anticoagulants (tissue factor pathway inhibitor, activated protein C, thrombomodulin, antithrombin), dipyridamole, complement blockers, different types of stem cells, and extracellular vesicles. An integrated therapy including these drugs has the potential to improve outcomes in COVID-19