Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

AIMS: Processes in the development of atherosclerotic lesions can lead to plaque rupture or erosion, which can in turn elicit myocardial infarction or ischaemic stroke. The aims of this study were to determine whether Toll-like receptor 7 (TLR7) gene expression levels influence patient outcome and to explore the mechanisms linked to TLR7 expression in atherosclerosis. METHODS AND RESULTS: Atherosclerotic plaques were removed by carotid endarterectomy (CEA) and subjected to gene array expression analysis (n = 123). Increased levels of TLR7 transcript in the plaques were associated with better outcome in a follow-up study over a maximum of 8 years. Patients with higher TLR7 transcript levels had a lower risk of experiencing major cardiovascular and cerebrovascular events (MACCE) during the follow-up period after CEA (hazard ratio: 2.38, P = 0.012, 95% CI 1.21–4.67). TLR7 was expressed in all plaques by T cells, macrophages and endothelial cells in capillaries, as shown by immunohistochemistry. In short-term tissue cultures, ex vivo treatment of plaques with the TLR7 ligand imiquimod elicited dose-dependent secretion of IL-10, TNF-α, GM-CSF, and IL-12/IL-23p40. This secretion was blocked with a TLR7 inhibitor. Immunofluorescent tissue analysis after TLR7 stimulation showed IL-10 expression in T cells, macrophages and vascular smooth muscle cells. TLR7 mRNA levels in the plaques were correlated with IL-10 receptor (r = 0.4031, P < 0.0001) and GM-CSF receptor A (r = 0.4354, P < 0.0001) transcripts. CONCLUSION: These findings demonstrate that TLR7 is abundantly expressed in human atherosclerotic plaques. TLR7 ligation elicits the secretion of pro-inflammatory and anti-inflammatory cytokines, and high TLR7 expression in plaques is associated with better patient outcome, suggesting that TLR7 is a potential therapeutic target for prevention of complications of atherosclerosis

Risk factors for prostate cancer : analysis of primary data, pooling, and related methodological aspects

Prostate cancer is the second most common cancer among men worldwide, yet its etiology remains poorly understood. Obesity, on the other hand, is a prevalent but preventable medical condition that is associated with hormonal and metabolic changes. Since prostate cancer is a hormone-related cancer, the hypothesis of a link between body fatness and prostate cancer risk has been formulated. Furthermore, the considerable biologic heterogeneity of prostate cancer warrants analyses to be carried out separately by aggressiveness of the disease, differentiating indolent from potentially lethal tumors. This thesis has two aims. First, to elucidate the association between obesity, as measured by body mass index (BMI), and the risk of localized, advanced, and fatal prostate cancer. This is done using both primary data (Paper I) and aggregated data extracted from published epidemiological studies (Paper IV). Second, to deal with some methodological aspects related to the analysis of primary and aggregated data (Paper II; Paper III; Paper V). In Paper I, we used primary data from the Cohort of Swedish Men to examine the association of BMI during early adulthood (30 years of age) and middle-late adulthood (45–79 years of age) with the incidence of localized and advanced prostate cancer and with prostate cancer mortality. BMI during middle-late adulthood was observed to be inversely associated with the incidence of localized prostate cancer, while it was directly associated with the incidence of advanced prostate cancer and with prostate cancer mortality. At the same time, we observed limited evidence of an inverse association between BMI during early-adulthood and the risk of advanced and fatal prostate cancer. In Paper II, we extended the use of quantile regression for censored data to those situations where the time scale of interest is attained age at the event instead of follow-up time. In particular, we described how to use Laplace regression to model percentiles of age at the event in the presence of delayed entries, by conditioning on age at entry. In Paper III, we identified three major misinterpretations of risk and rate advancement periods (RAP): first, equating RAP with the difference in mean survival times; second, interpreting RAP as the time by which the survival curve for the exposed individuals is shifted compared with that for the unexposed; third, equating the RAP to a simple ratio of two log–relative risks. Furthermore, we showed how RAP estimation is sensitive to the specification of the age-disease association. In Paper IV, we carried out a dose–response meta-analysis to summarize the available evidence on the association between BMI during middle-late adulthood and the incidence of localized and advanced prostate cancer. Based on aggregated data extracted from 13 prospective studies, we observed that BMI was inversely associated with the incidence of localized prostate cancer, while it was directly associated with the incidence of advanced prostate cancer. In Paper V, we stressed the importance of assessing the goodness of fit of dose–response metaanalysis models. We presented and discussed three tools (deviance, coefficient of determination, and decorrelated-residuals–versus–exposure plot) that are useful to test, quantify, and visually display the fit of dose–response meta-analysis models, while taking into account the correlation structure of the study-specific log–relative risks. In conclusion, Paper I and Paper IV supported the hypothesis of etiological heterogeneity of prostate cancer in relation to obesity during middle-late adulthood. In particular, BMI was observed to be directly associated with advanced prostate cancer and with prostate cancer mortality. Paper II extended the use of quantile regression for censored data to those situations where attained age is the time scale of interest, Paper III clarified the appropriate use and interpretation of RAP, and Paper V proposed useful and relevant methods for assessing the goodness of fit of dose–response models in research synthesis

Prostate Cancer IRE Study (PRIS): A Randomized Controlled Trial Comparing Focal Therapy to Radical Treatment in Localized Prostate Cancer

The aim of focal treatments (FTs) in prostate cancer (PCa) is to treat lesions while preserving surrounding benign tissue and anatomic structures. Irreversible electroporation (IRE) is a nonthermal technique that uses high-voltage electric pulses to increase membrane permeability and induce membrane disruption in cells, which potentially causes less damage to the surrounding tissue in comparison to other ablative techniques. We summarize the study protocol for the Prostate Cancer IRE Study (PRIS), which involves two parallel randomized controlled trials comparing IRE with (1) robot-assisted radical prostatectomy (RARP) or (2) radiotherapy in men with newly diagnosed intermediate-risk PCa (NCT05513443). To reduce the number of patients for inclusion and the study duration, the primary outcomes are functional outcomes: urinary incontinence in study 1 and irritative urinary symptoms in study 2. Providing evidence of the lower impact of IRE on functional outcomes will lay a foundation for the design of future multicenter studies with an oncological outcome as the primary endpoint. Erectile function, quality of life, treatment failure, adverse events, and cost effectiveness will be evaluated as secondary objectives. Patients diagnosed with Gleason score 3 + 4 or 4 + 3 PCa from a single lesion visible on magnetic resonance imaging (MRI) without any Gleason grade 4 or higher in systematic biopsies outside of the target (unifocal significant disease), aged ≥40 yr, with no established extraprostatic extension on multiparametric MRI, a lesion volume of <1.5 cm3, prostate-specific antigen <20 ng/ml, and stage ≤T2b are eligible for inclusion. The study plan is to recruit 184 men

Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician's choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or 'all' patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician's choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2-ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53-altered patients. In summary, ARPIs outperform taxanes and physician's choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835

Author Correction: Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial.

peer reviewedCorrection to: Nature Medicinehttps://doi.org/10.1038/s41591-024-03204-2, published online 20 August 2024. In the version of the article initially published, Rebecka Bergström’s name appeared incorrectly (as R. Bergström) and has now been amended in the HTML and PDF versions of the article

Optimization and testing of an operando Raman annular reactor for kinetic studies in heterogeneous catalysis

LAUREA MAGISTRALEL’obiettivo di questo lavoro è lo sviluppo e l’uso di un reattore anulare per analisi Raman in operando. Tale configurazione permette una simultanea analisi sia delle prestazioni del catalizzatore, in termini di conversione e selettività, sia della struttura del catalizzatore solido. Utilizzando un reattore anulare è possibile ovviare ai normali aspetti negativi di un reattore di laboratorio, quali grosse perdite di carico o segnali Raman troppo deboli a causa di diluizioni molto spinte. Il reattore anulare può fornire informazioni fondamentali riguardo la cinetica delle reazioni investigate ad elevate portate, i.e. brevi tempi di residenza. Esso evita, inoltre, limitazioni dovute a fenomeni diffusivi di materia e di calore. In definitiva, questa configurazione innovativa permetterebbe di raggiungere una profonda conoscenza della relazione tra i fenomeni sulla superficie del catalizzatore e il meccanismo della reazione chimica. Innanzitutto viene presentata una panoramica delle prime celle spettroscopiche Raman in operando disponibili in letteratura, poi viene descritta la tecnica spettroscopica stessa. Successivamente è brevemente descritto il lavoro di progettazione e modellazione richiesto per la realizzazione dell’impianto sviluppato in un lavoro di tesi precedente. Nel nostro lavoro l’impianto originale ha subito ulteriori miglioramenti (es. installazione di un micro GC, l’uso di due calze, uno stage motorizzato e un riferimento interno), come confermato dalle prove sperimentali svolte sulle reazioni prototipo di CPO e dry reforming del metano. Questi test provano che la nostra cella operando Raman è in grado di replicare le prestazioni di un reattore tradizionale. Le analisi degli spettri ottenuti durante la reazione di cracking del metano ad elevata temperatura, confermano la possibilità di osservare i picchi dovuti alla formazione di specie carboniose sul catalizzatore e la seguente rimozione tramite ossidazione. Al fine di ottenere informazioni non solo qualitative ma anche quantitative, è stato preparato un nuovo catalizzatore con aggiunta di titania. Rifacendosi al metodo dello 9 standard interno già noto in letteratura, questo materiale può fungere da riferimento per quantificare il carbonio formatosi. Infine si studia il meccanismo cinetico del processo di dry reforming, anch’esso già ampliamente trattato in letteratura solamente con reattori tradizionali. Lo schema meccanicistico, opportunamente supportato da numerose prove sperimentali, propone una deidrogenazione dell’idrocarburo fino al deposito di carbonio sul catalizzatore stesso. Questo processo, lento, è affiancato da uno ramo ossidativo di CO2 che genera l’ossidrile in grado di ossidare il carbonio formando CO e H2. La nuova configurazione proposta è in grado di comprovare la formazione di depositi carboniosi al variare della concentrazione di co-reagente quando il ramo ossidativo non è più equilibrato ma assume il ruolo di processo limitante. Si dimostra il dirompente potenziale del reattore anulare con operando Raman, che rappresenta un promettente strumento per una più profonda comprensione dei fenomeni che caratterizzano la catalisi eterogenea attraverso una concomitante analisi sia dei prodotti di reazione sia delle superficie del catalizzatore.The objective of this work is the development and the application of an annular reactor for operando Raman analysis, i.e. Raman analysis under operative conditions. Such a configuration permits a simultaneous analysis of the performance of the catalyst, in terms of conversion and selectivity, together with an investigation of the structure of the solid catalyst. By using an annular reactor, it is possible to overcome the typical drawbacks of a laboratory scale reactor like high pressure drops or undistinguishable signal under ultra-diluted conditions. The annular reactor can provide fundamental information also regarding the kinetics of the investigated reactions under high flowrates, i.e. short residence time. It also avoids the occurrence of heat and mass transfer limitations. Ultimately, this innovative configuration would provide a deeper understanding of the relationship between the phenomena on the catalytic surface and the mechanism of the chemical reactions. First, an overview of the first attempts for operando Raman cells found in literature is provided. Then the spectroscopic technique is described. Afterwards, the previous design and modelling processes, required for the realisation of the rig developed in previous thesis, are briefly described. In our work, the original plant has been furtherly improved (e.g. installation of a micro GC, use of two heating tapes, 3 dimensions motorized stage, internal reference method) as confirmed by the experimental tests carried out for partial oxidation and dry reforming reactions of methane. These tests proved that our operando Raman cell is able to reproduce the activity of a traditional reactor. Analysis of the spectra obtained after high temperature methane cracking confirms the possibility of our rig to observe the peaks related to the formation of carbonaceous species on the catalyst and the following removal by oxidation. In order to obtain not only qualitative but also quantitative information, a new catalyst has been prepared with the addition of titania. Referring to the internal standard method, already known in literature, this material could act as reference to quantify the carbon deposited. 7 Lastly, we studied the kinetic mechanism for the dry reforming process, already widely investigated in literature only with traditional reactors. The mechanistic scheme, confirmed by several experimental tests, suggests a series of dehydrogenations of the hydrocarbon until the formation of a Carbon atom on the surface of the catalyst. This slow process is accompanied by an oxidative pathway for CO2 thus generating OH which can oxidize the deposited C atoms leading to CO and H2. The new configuration here proposed is able to confirm and prove the carbon deposit formation by varying the concentration of the oxidative co-reactant when the oxidative pathway is no more equilibrated, but it becomes the rate determining step. In this work, the breakthrough potential of the operando Raman annular reactor has been demonstrated. It represents a promising tool for a deeper understanding of the phenomena characterizing the heterogeneous catalysis through a concomitant analysis both of the reaction products and of the catalytic surface

Lifestyle and Dietary Factors in Prostate Cancer Prevention

The etiology of prostate cancer (PCa) is still largely unknown and the only well-established risk factors are those that are non-modifiable (age, race, and family history). Therefore, the identification of lifestyle and dietary factors which might prevent PCa development and progression is of paramount importance from a public health point of view. Accumulating evidence indicates that obesity may have a dual effect on PCa: an increased risk of aggressive PCa and a decreased risk of localized PCa. Both occupational and leisure time physical activity have been observed to be associated with a reduced PCa risk. Different dietary factors including coffee have been examined in several epidemiological studies, but results have been mostly inconsistent. However, these inconsistencies can be, at least partly, explained by the fact that the majority of those studies examined total PCa risk only and, in addition, they did not take into account the different genetic characteristics within the study populations. Therefore, the future epidemiological studies should focus on the analysis of PCa subtypes separately in order to examine possible etiological heterogeneity of PCa in relation to some exposures. In addition, differences in the genetic characteristics of the study participants should be taken into account to explore the possibility of gene-environment interactions.</p

Instantaneous geometric rates via generalized linear models

The instantaneous geometric rate represents the instantaneous probability of an event of interest per unit of time. In this article, we propose a method to model the effect of covariates on the instantaneous geometric rate with two models: the proportional instantaneous geometric rate model and the proportional instantaneous geometric odds model. We show that these models can be fit within the generalized linear model framework by using two nonstandard link functions that we implement in the user-defined link programs log igr and logit igr. We illustrate how to fit these models and how to interpret the results with an example from a randomized clinical trial on survival in patients with metastatic renal carcinoma