De bijdrage van toevoeging van cacao aan tabak aan rookverslaving

In this report the effect of these compounds on the addiction to cigarette smoking was assessed, using currently available information in the literature on psychoactive compounds of cocoa. The investigated psychoactive cocoa compounds were theobromine, caffeine, serotonin, histamine, tryptophan, tryptamine, tyramine, phenylethylamine, octopamine and anandamide. The general conclusion is that the level of these compounds in added cocoa in cigarettes is not sufficient to increase the addiction to cigarette smoking.In dit rapport wordt de mogelijke bijdrage van cacao aan rookverslaving beschreven. Cacao wordt aan tabak toegevoegd om de smaak te verbeteren. Daarnaast bevat cacao tal van psychoactieve stoffen die mogelijk bijdragen aan rookverslaving Dit literatuuronderzoek beschrijft de blootstelling, farmacologie, farmacokinetiek, toxicologie, interacties en verslavende eigenschappen van de tien meest bekende stoffen in cacao. De onderzochte stoffen zijn theobromine, caffeine, serotonine, histamine, tryptofaan, tryptamine, tyramine, fenylethylamine, octopamine en anandamide. Deze stoffen komen ook via dranken en voedsel het lichaam binnen of worden door het lichaam zelf aangemaakt. Dit rapport laat zien dat de aan roken gerelateerde blootstelling aan de psychoactieve stoffen uit cacao gering is ten opzichte van de inname via voeding en dranken en/of de lichaamseigen productie van deze stoffen. Een systemisch effect lijkt derhalve onwaarschijnlijk ook al omdat lichaamseigen stoffen snel worden afgebroken. Daarnaast kunnen deze stoffen, omdat ze geinhaleerd worden, een direct effect op de luchtwegen hebben. Daarmee zou de opname van nicotine beinvloed kunnen worden. De nicotine opname zou bijvoorbeeld kunnen toenemen via luchtwegverwijding door theobromine en cafe6ne of kunnen afnemen door luchtwegvernauwing door histamine. Dit rapport laat zien dat de aan roken gerelateerde blootstelling aan deze stoffen waarschijnlijk te gering is voor een direct effect op de luchtwegen. Verder dient te worden opgemerkt dat de hoeveelheid tryptamine, tyramine en fenylethylamine die via cacao wordt toegevoegd verwaarloosbaar is ten opzichte van de hoeveelheid die in tabak zelf aanwezig is. Tot slot is aandacht besteed aan de verbrandingsproducten van cacao. Amine verbindingen als serotonin, tryptofaan, tyramine, tryptamine en fenylethylamine vormen tijdens het roken stoffen die het enzym mono amine oxidase (MAO) remmen. MAO-remmers hebben een anti-depressieve werking en kunnen op die manier bijdragen aan rookverslaving. De conclusie van dit literatuur onderzoek is dat de afzonderlijke psychoactieve stoffen in tabak als gevolg van toevoeging van cacao niet direct bijdragen aan rookverslaving. De verbrandingsproducten van cacao doen dit, via remming van het enzym mono amine oxidase, mogelijk wel. Ook de smaak van cacao wordt geassocieerd met verslaving. De literatuur biedt geen inzicht in het effect op gezondheid en verslaving van het inhaleren van de combinatie van de 10 onderzochte stoffen uit cacao

The relative contributions of subjective and musical factors in music for sleep

Previous research into music for sleep has focused on describing the types of musical characteristics associated with such music (Kirk & Timmers, in press; Scarratt et al., 2023). The current study aimed to increase understanding of sleep music by investigating subjective perceptions of listeners associated with music that is considered sleep inducing, including conceptualisations related to arousal, emotions, and distraction (Jespersen & Vuust, 2012). Musical features of the stimuli presented were extracted to compare the relative contribution of subjective and objective aspects. Our results reveal differing but important roles for valence and arousal, and highlight notions of comfort, liking, and dissociation that attribute to music that is most sleep inducing. The musical properties of sleep music conformed with previous research (Jespersen et al., 2022), with an additional emphasis on brightness (Kirk & Timmers, in press), however the subjective ratings overshadowed the musical features in predicting what music was most sleep inducing. Our findings have implications for how music used to facilitate sleep is selected and highlight the importance of personalisation

Two novel conjugative plasmids from a single strain of Sulfolobus

Two conjugative plasmids (CPs) were isolated and characterized from the same 'Sulfolobus islandicus' strain, SOG2/4, The plasmids were separated from each other and transferred into Sulfolobus soltataricus. One has a high copy number and is not stable (pSOG1) whereas the other has a low copy number and is stably maintained (pSOG2). Plasmid pSOG2 is the first Sulfolobus CP found to have these characteristics. The genomes of both pSOG plasmids have been sequenced and were compared to each other and the available Sulfolobus CPs. Interestingly, apart from a very well-conserved core, 70% of the pSOG 1 and pSOG2 genomes is largely different and composed of a mixture of genes that often resemble counterparts in previously described Sulfolobus CPs. However, about 20% of the predicted genes do not have known homologues, not even in other CPs. Unlike pSOG1, pSOG2 does not contain a gene for the highly conserved PIrA protein nor for obvious homologues of partitioning proteins. Unlike pNOB8 and pKEF9, both pSOG plasmids lack the so-called clustered regularly interspaced short palindrome repeats (CRISPRs). The sites of recombination between the two genomes can be explained by the presence of recombination motifs previously identified in other Sulfolobus CPs. Like other Sulfolobus CPs, the pSOG plasmids possess a gene encoding an integrase of the tyrosine recombinase family. This integrase probably mediates plasmid site-specific integration into the host chromosome at the highly conserved tRNA(Glu) loci

DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus

Background: DNA methylation is of pivotal importance during development. Previous genome-wide studies identified numerous differentially methylated regions upon differentiation of stem cells, many of them associated with transcriptional start sites. Results: We present the first genome-wide, single-base-resolution view into DNA methylation dynamics during differentiation of a mammalian epithelial stem cell: the mouse small intestinal Lgr5+ stem cell. Very little change was observed at transcriptional start sites and our data suggest that differentiation-related genes are already primed for expression in the stem cell. Genome-wide, only 50 differentially methylated regions were identified. Almost all of these loci represent enhancers driving gene expression in the differentiated part of the small intestine. Finally, we show that binding of the transcription factor Tcf4 correlates with hypo-methylation and demonstrate that Tcf4 is one of the factors contributing to formation of differentially methylated regions. Conclusions: Our results reveal limited DNA methylation dynamics during small intestine stem cell differentiation and an impact of transcription factor binding on shaping the DNA methylation landscape during differentiation of stem cells in vivo

Stratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning

Applied immunology; Predictive markers; Viral infectionImmunologia aplicada; Marcadors predictius; Infecció viralInmunología aplicada; Marcadores predictivos; Infección viralQuantitative or qualitative differences in immunity may drive clinical severity in COVID-19. Although longitudinal studies to record the course of immunological changes are ample, they do not necessarily predict clinical progression at the time of hospital admission. Here we show, by a machine learning approach using serum pro-inflammatory, anti-inflammatory and anti-viral cytokine and anti-SARS-CoV-2 antibody measurements as input data, that COVID-19 patients cluster into three distinct immune phenotype groups. These immune-types, determined by unsupervised hierarchical clustering that is agnostic to severity, predict clinical course. The identified immune-types do not associate with disease duration at hospital admittance, but rather reflect variations in the nature and kinetics of individual patient’s immune response. Thus, our work provides an immune-type based scheme to stratify COVID-19 patients at hospital admittance into high and low risk clinical categories with distinct cytokine and antibody profiles that may guide personalized therapy.This work was supported by Health Holland LSHM20056 grant (PDK), in part from the European Union’s Horizon 2020 research and innovation program under grant agreement No 779295 (PDK), in part supported by the Erasmus foundation (BJAR), grant PI20/00416 from the Instituto de Salud Carlos III (RPB) and the European Regional Development Fund (ERDF) (RPB)

Patient-Derived Xenografts and Organoids Recapitulate Castration-Resistant Prostate Cancer with Sustained Androgen Receptor Signaling

Castration-resistant prostate cancer (CRPC) remains an incurable and lethal malignancy. The development of new CRPC treatment strategies is strongly impeded by the scarcity of representative, scalable and transferable preclinical models of advanced, androgen receptor (AR)-driven CRPC. Here, we present contemporary patient-derived xenografts (PDXs) and matching PDX-derived organoids (PDXOs) from CRPC patients who had undergone multiple lines of treatment. These models were comprehensively profiled at the morphologic, genomic ( n = 8) and transcriptomic levels ( n = 81). All are high-grade adenocarcinomas that exhibit copy number alterations and transcriptomic features representative of CRPC patient cohorts. We identified losses of PTEN and RB1, MYC amplifications, as well as genomic alterations in TP53 and in members of clinically actionable pathways such as AR, PI3K and DNA repair pathways. Importantly, the clinically observed continued reliance of CRPC tumors on AR signaling is preserved across the entire set of models, with AR amplification identified in four PDXs. We demonstrate that PDXs and PDXOs faithfully reflect donor tumors and mimic matching patient drug responses. In particular, our models predicted patient responses to subsequent treatments and captured sensitivities to previously received therapies. Collectively, these PDX-PDXO pairs constitute a reliable new resource for in-depth studies of treatment-induced, AR-driven resistance mechanisms. Moreover, PDXOs can be leveraged for large-scale tumor-specific drug response profiling critical for accelerating therapeutic advances in CRPC. </p

The clonal relation of primary upper urinary tract urothelial carcinoma and paired urothelial carcinoma of the bladder

The risk of developing urothelial carcinoma of the bladder (UCB) in patients treated by radical nephroureterectomy (RNU) for an upper urinary tract urothelial carcinoma (UTUC) is 22% to 47% in the 2 years after surgery. Subject of debate remains whether UTUC and the subsequent UCB are clonally related or represent separate origins. To investigate the clonal relationship between both entities, we performed targeted DNA sequencing of a panel of 41 genes on matched normal and tumor tissue of 15 primary UTUC patients treated by RNU who later developed 19 UCBs. Based on the detected tumor-specific DNA aberrations, the paired UTUC and UCB(s) of 11 patients (73.3%) showed a clonal relation, whereas in four patients the molecular results did not indicate a clear clonal relationship. Our results support the hypothesis that UCBs following a primary surgically resected UTUC are predominantly clonally derived recurrences and not separate entities

Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition

Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors. In vivo intermittent treatment of 3 ICB-resistant solid tumor (melanoma, mesothelioma or pancreatic cancer) with ITK inhibitor significantly improved ICB therapy. ITK inhibition directly reinvigorate exhausted CTL in vitro as it enhanced cytokine production, decreased inhibitory receptor expression, and downregulated the transcription factor TOX. Our study demonstrates that intermittent ITK inhibition can be used to directly ameliorate CTL exhaustion and enhance immunotherapies even in solid tumors that are ICB resistant.</p