Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to ...restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease.
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•Control of M. tuberculosis is impaired in mice lacking extrinsic or intrinsic apoptosis•Caspase-8 mediates apoptosis of infected macrophages downstream of TNF•Intrinsic apoptosis functions primarily to eliminate neutrophils•Enhancing apoptosis with IAP antagonists promotes Mtb clearance in vivo
Killing infected cells via apoptosis promotes elimination of intracellular pathogens, but this host defense was thought to be abrogated by Mycobacterium tuberculosis. Stutz et al. demonstrate that the apoptosis pathways promote tuberculosis control by clearing distinct populations of infected phagocytes and enhancing development of adaptive immune responses.
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. Immunotherapy with immune checkpoint inhibitors (ICI) has significantly improved outcomes in some patients, ...however 80-85% of patients receiving immunotherapy develop primary resistance, manifesting as a lack of response to therapy. Of those that do have an initial response, disease progression may occur due to acquired resistance. The make-up of the tumour microenvironment (TME) and the interaction between tumour infiltrating immune cells and cancer cells can have a large impact on the response to immunotherapy. Robust assessment of the TME with accurate and reproducible methods is vital to understanding mechanisms of immunotherapy resistance. In this paper we will review the evidence of several methodologies to assess the TME, including multiplex immunohistochemistry, imaging mass cytometry, flow cytometry, mass cytometry and RNA sequencing.
Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid ...high‐throughput drug screening (HTS) and patient‐derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high‐risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high‐risk pediatric cancer patients.
Synopsis
A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients.
Treatment options could be identified for 70% of patients across the four‐part platform.
HTS provided orthogonal proof of drug efficacy suggested by molecular analyses and identified many new drug responses without prior molecular hallmarks.
Effective treatments were observed in more than half of PDX models.
There was a strong correlation between HTS and PDX results, and the clinical responses in patients.
A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients.
Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM ...activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.
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•Activated TRM-like cells are enriched in the lungs of ever-smoker individuals•TRM-like cells of any specificity present before tumor growth accelerate immune evasion•Tumors grown in TRM cell-rich environments become resistant to immune checkpoint blockade
Weeden et al. find that ever-smoker lungs have greater activation of T cells with a tissue-resident memory phenotype (TRM). Lung tumors growing in TRM cell-rich environments develop immune evasion, leading to immune checkpoint therapy resistance. These findings identify that the “soil” in which tumors are grown has lasting effects on tumor immunogenicity and therapy response.
This paper examined the psychological impact of contextual influences (i.e., contract type and playing experience) on sport anxiety in elite women cricketers participating in The Hundred. A sample of ...71 elite female cricketers playing during the 2021–2022 season took part. Forty-nine of the sample (69%) held professional contracts, and 22 (31%) had yet to sign a professional contract. Participants provided details about their contract type and playing experience and completed self-report measures assessing sport anxiety, mental toughness, and general self-efficacy. Since mental toughness and self-efficacy are non-cognitive constructs, which buffer competitive trait anxiety, analysis controlled for these variables. Multivariate analyses of covariance examined sport anxiety scores among participants in relation to Hundred matches played (either 0, 1–10, or more than 10) and contract type (whether participants had a professional contract in place or not). Subfactors of Worry, Somatic, and Confusion assessed sports anxiety. No significant main effects existed. However, alongside a significant interaction, a covariate mental toughness effect occurred. Examination of the interaction revealed Worry scores were lower in cricketers who were yet to play a Hundred match who had not received a professional contract. Furthermore, Worry and Somatic scores were higher in cricketers that had played more than 10 Hundred matches and had not received a professional contract. These findings have important implications for the development of elite women cricketers. Particularly, they highlight the need to differentially support players through their career progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This thesis sought to investigate the relationships between measures of established individual differences - intelligence and personality - in relation to different methods of measuring creativity in ...the individual. The thesis is organised into two theoretical chapters, three experimental chapters and a conclusion and summary chapter. The first theoretical chapter constituted a thorough literature review of creativity with regards to intelligence and personality. The second theoretical chapter examined the assessment of creativity and presented a new heuristic model for creativity measurement. The first experimental chapter examined the relationship of measures of divergent thinking with regards to established measures of individual differences intelligence and personality. The second experimental chapter examined the relationship of self-reported creativity, using both self-report scales of creativity and self-ratings in relation to established measures of individual differences. The self-report chapter was divided into two sections: objective and subjective self- reported creativity. The objective self-report creativity section was concerned with the relationship of established measures of individual differences with objective measures or scales of creativity. The subjective self-report section was concerned with the relationship of measures of individual differences with self-rated subjective assessments of personal creativity a self-rating and self-reported engagement in creative activities. The third experimental chapter examined the relationship of rated creativity in reference to established measures of individual differences. Each experimental chapter is followed by an interim conclusion. The final chapter of the thesis provided an overall conclusion and summary of the research. This chapter also contains a consideration of the limitations and implications of the research.
Information multiplexing in ptychography Batey, Darren J.; Claus, Daniel; Rodenburg, John M.
Ultramicroscopy,
March 2014, 2014-Mar, 2014-03-00, Letnik:
138
Journal Article
Recenzirano
We show for the first time that ptychography (a form of lensless diffractive imaging) can recover the spectral response of an object through simultaneous reconstruction of multiple images that ...represent the object's response to a particular mode present in the illumination. We solve the phase problem for each mode independently, even though the intensity arriving at every detector pixel is an incoherent superposition of several uncorrelated diffracted waves. Until recently, the addition of incoherent modes has been seen as a nuisance in diffractive imaging: here we show that not only can the difficulties they pose be removed, but that they can also be used to discover much more information about the object. If the illumination function is also mode-specific, we show that we can also solve simultaneously for a multiplicity of such illumination modes. The work opens exciting possibilities for information multiplexing in ptychography over all visible, X-ray and electron wavelengths.
•Demonstration of information multiplexing in ptychography, which we refer to as ptychographic information multiplexing (PIM).•PIM is capable to recover both different modes in illumination function and object function (also recovers relative intensity between the different illumination functions).•PIM could successfully be demonstrated in reflection and transmissionmode, modes, for phase and modulus multiplexing respectively.•It could be demonstrated that the imaging performance when employing PIM compared to a single mode ptychographic experiment has hardly been affected.•PIM as demonstrated can be applied to many different fields such as in the visible (colour imaging, polarization imaging and optical metrology) and X-ray imaging.
The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and ...survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.
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