TGF-β-responsive CAR-T cells promote anti-tumor immune function.

A chimeric antigen receptor (CAR) that responds to transforming growth factor beta (TGF-β) enables the engineering of T cells that convert this immunosuppressive cytokine into a potent T-cell stimulant. However, clinical translation of TGF-β CAR-T cells for cancer therapy requires the ability to productively combine TGF-β responsiveness with tumor-targeting specificity. Furthermore, the potential concern that contaminating, TGF-β?producing regulatory T (Treg) cells may preferentially expand during TGF-β CAR-T cell manufacturing and suppress effector T (Teff) cells demands careful evaluation. Here, we demonstrate that TGF-β CAR-T cells significantly improve the anti-tumor efficacy of neighboring cytotoxic T cells. Furthermore, the introduction of TGF-β CARs into mixed T-cell populations does not result in the preferential expansion of Treg cells, nor do TGF-β CAR-Treg cells cause CAR-mediated suppression of Teff cells. These results support the utility of incorporating TGF-β CARs in the development of adoptive T-cell therapy for cancer

PCR-Independent Detection of Bacterial Species-Specific 16S rRNA at 10 fM by a Pore-Blockage Sensor.

A PCR-free, optics-free device is used for the detection of Escherichia coli (E. coli) 16S rRNA at 10 fM, which corresponds to ~100-1000 colony forming units/mL (CFU/mL) depending on cellular rRNA levels. The development of a rapid, sensitive, and cost-effective nucleic acid detection platform is sought for the detection of pathogenic microbes in food, water and body fluids. Since 16S rRNA sequences are species specific and are present at high copy number in viable cells, these nucleic acids offer an attractive target for microbial pathogen detection schemes. Here, target 16S rRNA of E. coli at 10 fM concentration was detected against a total RNA background using a conceptually simple approach based on electromechanical signal transduction, whereby a step change reduction in ionic current through a pore indicates blockage by an electrophoretically mobilized bead-peptide nucleic acid probe conjugate hybridized to target nucleic acid. We investigated the concentration detection limit for bacterial species-specific 16S rRNA at 1 pM to 1 fM and found a limit of detection of 10 fM for our device, which is consistent with our previous finding with single-stranded DNA of similar length. In addition, no false positive responses were obtained with control RNA and no false negatives with target 16S rRNA present down to the limit of detection (LOD) of 10 fM. Thus, this detection scheme shows promise for integration into portable, low-cost systems for rapid detection of pathogenic microbes in food, water and body fluids

Diagnostic performance of imaging investigations in detecting and differentiating cardiac amyloidosis: a systematic review and meta-analysis

AIMS: The study aims to systematically assess the diagnostic performance of cardiac magnetic resonance (CMR) and nuclear scintigraphy (index tests) for the diagnosis and differentiation of subtypes of cardiac amyloidosis. // METHODS AND RESULTS: MEDLINE and Embase electronic databases were searched for studies evaluating the diagnostic performance of CMR or nuclear scintigraphy in detecting cardiac amyloidosis and subsequently in differentiating transthyretin amyloidosis (ATTR) from immunoglobulin light-chain (AL) amyloidosis. In this meta-analysis, histopathological examination of tissue from endomyocardial biopsy (EMB) or extra-cardiac organs were reference standards. Pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were calculated, and a random effects meta-analysis was used to estimate diagnostic odds ratios. Methodological quality was assessed using a validated instrument. Of the 2947 studies identified, 27 met the criteria for inclusion. Sensitivity and specificity of CMR in diagnosing cardiac amyloidosis was 85.7% and 92.0% against EMB reference and 78.9% and 93.9% with any organ histology reference. Corresponding sensitivity and specificity of nuclear scintigraphy was 88.4% and 87.2% against EMB reference and 82.0% and 98.8% with histology from any organ. CMR was unable to reliably differentiate ATTR from AL amyloidosis (sensitivity 28.1-99.0% and specificity 11.0-60.0%). Sensitivity and specificity of nuclear scintigraphy in the differentiation of ATTR from AL amyloidosis ranged from 90.9% to 91.5% and from 88.6% to 97.1%. Pooled negative likelihood ratio and positive likelihood ratio for scintigraphy in this setting were 0.1 and 8, with EMB reference standard. Study quality assessed by QUADAS-2 was generally poor with evidence of bias. // CONCLUSIONS: Cardiac magnetic resonance is a useful test for diagnosing cardiac amyloidosis but is not reliable in further classifying the disease. Nuclear scintigraphy offers strong diagnostic performance in both the detection of cardiac amyloidosis and differentiating ATTR from AL amyloidosis. Our findings support the use of both imaging modalities in a non-invasive diagnostic algorithm that also tests for the presence of monoclonal protein

A randomised controlled trial of mentalization-based treatment versus structured clinical management for patients with comorbid borderline personality disorder and antisocial personality disorder.

BACKGROUND: Antisocial personality disorder (ASPD) is an under-researched mental disorder. Systematic reviews and policy documents identify ASPD as a priority area for further treatment research because of the scarcity of available evidence to guide clinicians and policymakers; no intervention has been established as the treatment of choice for this disorder. Mentalization-based treatment (MBT) is a psychotherapeutic treatment which specifically targets the ability to recognise and understand the mental states of oneself and others, an ability shown to be compromised in people with ASPD. The aim of the study discussed in this paper is to investigate whether MBT can be an effective treatment for alleviating symptoms of ASPD. METHODS: This paper reports on a sub-sample of patients from a randomised controlled trial of individuals recruited for treatment of suicidality, self-harm, and borderline personality disorder. The study investigates whether outpatients with comorbid borderline personality disorder and ASPD receiving MBT were more likely to show improvements in symptoms related to aggression than those offered a structured protocol of similar intensity but excluding MBT components. RESULTS: The study found benefits from MBT for ASPD-associated behaviours in patients with comorbid BPD and ASPD, including the reduction of anger, hostility, paranoia, and frequency of self-harm and suicide attempts, as well as the improvement of negative mood, general psychiatric symptoms, interpersonal problems, and social adjustment. CONCLUSIONS: MBT appears to be a potential treatment of consideration for ASPD in terms of relatively high level of acceptability and promising treatment effects. TRIAL REGISTRATION: ISRCTN ISRCTN27660668 , Retrospectively registered 21 October 2008

Influence of processed Halyomorpha halys bugs on the aroma and taste of 'Chardonnay' and 'Merlot' musts and wines

Native to East Asia, the invasive brown marmorated stink bug (Halyomorpha halys) was accidentally introduced into Switzerland around 2004 and is now spreading all over Europe. This pentatomid is highly polyphagous and attacks vegetables, field and tree crops as well as soft fruits. Moreover, all development stages of H. halys are found in vineyards, suggesting that grapevine is also a host plant for this insect. Nonetheless, its actual effects on European wine production is unclear. As such, we studied the impact of processed H. halys on the aroma and taste of grape musts and wines. We artificially contaminated 'Chardonnay' and 'Merlot' grapes with up to ten H. halys nymphs and adults per kg grapes directly before the vintage was crushed. In the freshly pressed must, the addition of 1 living bug/kg grapes did not affect the olfactory sensation of the 'Chardonnay' juice. However, the aroma and taste of 'Chardonnay' and 'Merlot' musts contaminated with 3 to 10 H. halys individuals/kg grapes could be distinguished from the uncontaminated control juices and were perceived as vegetal and woody. Yet after bottling, the different wines with 0 to 10 H. halys individuals/kg grapes could no longer be differentiated from each other in 2-out-of-5 discrimination tests. Amongst 17 rated organoleptic descriptors to characterise the sensory profile of the four 'Chardonnay' wines, only two showed significant differences; the colour intensity increased and wines’ finesse decreased with the number of added bugs. For the three 'Merlot' wines, none of the 21 organoleptic descriptors of the sensory profiles differed significantly. In addition, winegrowers did not dislike H. halys contaminated 'Chardonnay' and 'Merlot' wines compared to their uncontaminated controls one year after bottling. It therefore seems that the molecules responsible for the off-flavours in contaminated musts volatilise to a large part during the fermentation process. Our results consequently indicate that a contamination of the vintage with H. halys has the potential to alter the quality of grape musts and potentially grape juices but that there is little risk for influencing the taste of processed wines. Nonetheless, we recommend monitoring the development of H. halys in vineyards in order to anticipate quantitative and qualitative problems at harvest

Efficacy of kaolin treatments against Drosophila suzukii and their impact on the composition and taste of processed wines

Drosophila suzukii is a very polyphagous species that can also tack and develop in a great variety of grape cultivars. In Switzerland, the control of D. suzukii mainly relies on prophylactic measures and kaolin, a white inert aluminosilicate mineral who's particles stick to the leaf surface and form a physical barrier that help to reduce ovipositions by the pest. Here we present a synthesis of our recent insights on the efficacy of kaolin against D. suzukii as well as on the chemical and sensory properties of the wines vinified from kaolin treated grapes. In autumn 2016, kaolin (Surround WP®) was applied in 23 field trials on various cultivars located in various winegrowing regions of Switzerland. Overall, kaolin achieved an average efficiency of 54 % and no significant differences could be observed between kaolin applications at 1 % and 2 % with 56.8 % and 57.1 % efficacy, respectively. At the higher concentration, the preventive and curative strategy were also nearly as effective with efficacies at 67.4 % and 50.3 %, respectively. In addition, a field experiment was set up on the red grape cultivar 'Mara' in 2015. This experiment revealed that three applications of kaolin at 1 % or 2 % did neither affect fermentation nor the usual chemical properties of kaolin treated wines compared to the untreated control. However, aluminum concentration within wines increased with the applied dosage of kaolin but the measured aluminum levels were 38-times lower than the maximal German threshold of 8 mg·L-1. Moreover, tasters were also not able to distinguish the aroma and the taste of wines processed from kaolin treated grapes from the untreated control. We therefore conclude that kaolin applications are effective against D. suzukii and do not cause any major risks to the environment, to wine quality and to human health

Impact of processed earwigs and their faeces on the aroma and taste of 'Chasselas' and 'Pinot Noir' wines

The abundance of the European earwig Forficula auricularia L. (Dermaptera, Forficulidae) in European vineyards increased considerably over the last few years. Although earwigs are omnivorous predators that prey on viticultural pests such as grape moths, they are also known to erode berries and to transfer fungal spores. Moreover, they are suspected to affect the human perception of wines both directly by their processing with the grapes and indirectly by the contamination of grape clusters with their faeces. In this study we artificially contaminated grapes with F. auricularia adults and/or their faeces and determined the impact on aroma and taste of white 'Chasselas' and red 'Pinot noir' wines. Whereas the addition of five living adults/kg grapes affected the olfactory sensation of 'Chasselas' wines only marginally, 0.6 gram of earwig faeces/kg grapes had a strong effect on colour, aroma and the general appreciation of 'Chasselas' wines. Faeces-contaminated wines were less fruity and less floral, the aroma was described as faecal and they were judged to be of lower quality. The contamination of 'Pinot noir' grapes with four different densities of living earwig adults (e.g. 0, 5, 10 and 20 individuals/kg grapes) showed that only wines contaminated with more than 10 earwigs/kg grapes smelled and tasted significantly different than the uncontaminated control wine. Earwig-contaminated 'Pinot noir' wines were judged to be of lower quality. The descriptors “animal”, “reductive”, “vegetal”, “acidic”, “bitter” and “tannic” characterised their sensory perception. In conclusion, our results show that there is a real risk of wine contamination by F. auricularia. In particular, earwig faeces and earwig adults at densities above a threshold of 5 to 10 individuals/kg grapes have the potential to reduce the quality of wines. The evolution of earwig populations in vineyards should therefore be monitored carefully in order to anticipate problems during vinification.