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We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103 + T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61 + tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies. CD103 + T cells are associated with control over tumors but how this is mediated is unclear. Here the authors show that CD61 colocalizes and functionally combines with CD103 in the T cell synaptic response to promote antitumor T cell responses.

Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tissue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with three longitudinal samples over 5 years. Case 2 was a single time point after the development of treatment-related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all samples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, and 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small-cell neuroendocrine and ductal prostatic carcinoma can have a common ancestry. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

The human endometrium is a dynamic tissue, which undergoes repeated cycles of growth and regression every menstrual cycle in preparation for pregnancy. These cycles are orchestrated by steroid hormones and a host of local mediators that are secreted within the endometrium. Prokineticins, namely prokineticin (PROK) 1 and 2, are two newly identified proteins that signal through two highly homologous G protein-coupled receptors (PROKR1 and PROKR2 with 85% amino acid identity). Both prokineticins can bind and activate their receptors with similar agonist potency. Prokineticins regulate multiple biological processes via apparent selectivity of ligand/receptor pairing. For example, PROK2/PROKR2 signalling regulates neurogenesis of the olfactory bulb whereas PROK2/PROKR1 signalling plays a dominant role in pain perception. Other functions attributed to prokineticins include regulation of endothelial cell function, circadian clock output, smooth muscle contractility and haematopoiesis. Recent data in our laboratory demonstrate that PROK1/PROKR1 signalling may regulate endometrial/decidual and early placental functions. Investigation of the temporal pattern of expression of prokineticins in non-pregnant and pregnant endometrium has shown that PROK1, but not PROK2, is elevated in the endometrium during the window of implantation. In the event of pregnancy both PROK1 and PROKR1, but not PROK2/PROKR2, are significantly elevated in first trimester decidua and placenta. The sites of expression of these factors in the endometrium/placenta suggest important roles for PROK1-PROKR1 in regulation of vascular, immune and trophoblast cell function. In reproductive tissues, prokineticins are regulated by steroid hormones and hypoxia which are important regulators of endometrial/placental function during implantation and early pregnancy. In order to investigate the potential role of PROK1, we have conducted a genome wide array study using Ishikawa cells stably expressing PROKR1 to elucidate the target genes activated by PROK1 stimulation. A host of genes known to play important roles in endometrial and placental function during the window of implantation and early pregnancy were shown to be up-regulated by PROK1-PROKR1 interaction. These include: cyclooxygenase 2 (COX2), leukaemia inhibitory factor (LIF), interleukin 6, 8 and 11, growth regulated protein (GRO), heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin. We have also demonstrated that regulation of PROK1 and downstream genes such as LIF can be mediated by human chorionic gonadotrophin. PROK1 via PROKR1 regulates expression of target genes in endometrial cells via diverse intracellular signalling pathways which include: cross-talk with receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and downstream phosphorylation of ERK1/2, mobilization of calcium and activation of the calcineurin-NFAT signalling pathway. Current research is focussed on elucidation of the potential functions regulated by PROK1 PROKR1 during the period of implantation and in early pregnancy.

The pleiotropic cytokine interleukin-11 (IL-11) up-regulates the proliferative and invasive capacity of many human cancer cells in vitro. Co-expression of gp130 and IL-11 receptor alpha (IL-11rα) is necessary for high affinity binding of IL-11 to IL-11rα. Recently we have established a role for prostaglandin F2α (PGF) receptor (FP) signalling in the regulation of tumorigenic genes in endometrial adenocarcinomas. This study investigated the expression of IL-11 and role of PGF-FP receptor signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Human adenocarcinoma biopsies were obtained in accordance with Lothian Research Ethics Committee guidance with informed patient consent. Localisation of IL-11, IL-11rα and gp130 expression was performed by immunohistochemistry. IL-11 mRNA expression was determined by real-time RT-PCR analysis using Ishikawa endometrial adenocarcinoma cells expressing the FP receptor to the levels observed in endometrial adenocarcinomas (FPS cells). IL-11 mRNA expression was significantly elevated in endometrial adenocarcinoma samples compared to normal endometrium (0.4 ± 0.1 vs 0.03 ± 0.01 arbitrary units; p<0.05) and localized with IL-11rα and gp130 in the glandular epithelium of endometrial adenocarcinomas. To investigate PGF-FP receptor signaling to IL-11 in endometrial adenocarcinoma cells, FPS cells were treated with vehicle, 100nM PGF or 100nM PGF in the absence/presence of the FP receptor antagonist AL8810 or chemical inhibitors of protein kinase A (PKA; 4C3MQ), protein kinase C (PKC; RO318220), calcineurin (cyclosporine A), Calcium (EGTA) or NFAT (INCa6). Treatment of FPS cells with PGF for 24 hours significantly elevated the expression of IL-11 mRNA (95.1 ± 6.4 fold above vehicle treated cells, P<0.05). Co-incubation of FPS cells with PGF and the FP receptor antagonist AL8810 (8.4 ± 6.4 fold above vehicle treated cells; P<0.01) or chemical inhibitors of PKC (9.6 ± 4.1 fold; P<0.01), calcineurin (17.7 ± 3.7 fold; P<0.01), calcium (15.8 ± 9.5 fold; P<0.05) or NFAT (18.3 ± 10.2 fold; P<0.01) but not PKA (96.5 ± 32.7 fold; P<0.01) significantly reduced the PGF-mediated increase in IL-11 mRNA expression. These data demonstrate that PGF regulation of IL-11 mRNA is mediated via the activation of PKC and the calcium-calcineurin pathway and suggest a possible mechanism for control of endometrial tumorigenesis by PGF-FP receptor via activation of signaling to cytokines such as IL-11.

The parathyroid extracellular calcium (Ca[2+][0])-sensing receptor (CaR) is a G protein-coupled receptor, which plays a crucial role in Ca[2+][0] homeostasis (Brown, et al, 1993). This receptor is also expressed in non-parathyroid tissues, where its functions are still a subject of intense research. The progress of such studies has been difficult due to intrinsic properties of the receptor, such as low expression levels and conditional efficacy, as well as the properties of the receptor ligands, which include low specificity, selectivity and binding affinity. In the present work the use of antisense technology has been evaluated for its ability to reduce CaR expression and therefore its possible application in the study of the role of CaR in non-parathyroid tissues. An antisense cDNA sequence was efficient at reducing the expression and function of the CaR in transfected human embryonic kidney cells (HEK293). These results show the potential of antisense technology as a powerful tool in the study of roles of the CaR in different tissues. In addition, a role for the CaR in aminoglycoside antibiotic (AGA)-induced cellular toxicity in the proximal tubule was investigated. AGAs are commonly used for treatment of Gram-negative infections in spite of its nephro- and ototoxic side-effects. The mechanism by which AGAs exert toxicity remains unclear. Previous studies have shown that the CaR is expressed at the kidney proximal tubule (Riccardi, et al, 1998). Moreover, it has been shown that AGAs can activate signalling cascades, known to be coupled to the CaR in opossum kidney proximal tubule-derived cells (OK; Ward, et al, 2002). Hence, a putative role for the CaR as a molecular mechanism of AGA toxicity in proximal tubule cells was investigated. Results from the present study show that acute treatment with AGAs induces the activation of signalling cascades known to be involved in proliferation and cell survival, which correlates with a proliferative effect induced by short term treatment with the AGA gentamicin and high Ca[2+][0] (both CaR agonists) in OK cells. Furthermore, long term treatment with gentamicin induced cell death in OK cells and CaR transfected HEK 293 cells (CaR-HEK). The latter could be reproduced in OK cells by using other CaR agonists (i.e. spermine and poly-arginine) and inhibited by a CaR antagonist (i.e. NPS 89636) in CaR-HEK cells. Taken together, these observations indicate that AGAs induce an initial cell proliferation effect followed by induction of cell death both in OK and CaR-HEK cells, and that the CaR plays an important role in the cellular effects induced by AGAs at the kidney proximal tubule.

Chemotaxis toward organic acids has been associated with colonization fitness and virulence and the opportunistic pathogen Pseudomonas aeruginosa exhibits taxis toward several tricarboxylic acid intermediates. In this study, we used high-throughput ligand screening and isothermal titration calorimetry to demonstrate that the ligand binding domain (LBD) of the chemoreceptor PA2652 directly recognizes five C4-dicarboxylic acids with K D values ranging from 23 µM to 1.24 mM. In vivo experimentation showed that three of the identified ligands act as chemoattractants whereas two of them behave as antagonists by inhibiting the downstream chemotaxis signalling cascade. In vitro and in vivo competition assays showed that antagonists compete with chemoattractants for binding to PA2652-LBD, thereby decreasing the affinity for chemoattractants and the subsequent chemotactic response. Two chemosensory pathways encoded in the genome of P. aeruginosa , che and che2 , have been associated to chemotaxis but we found that only the che pathway is involved in PA2652-mediated taxis. The receptor PA2652 is predicted to contain a sCACHE LBD and analytical ultracentrifugation analyses showed that PA2652-LBD is dimeric in the presence and the absence of ligands. Our results indicate the feasibility of using antagonists to interfere specifically with chemotaxis, which may be an alternative strategy to fight bacterial pathogens.

The interferon-induced transmembrane protein, IFITM3, has been shown to restrict influenza virus infection in murine and in vitro settings for ten years, but no explanation has been found to explain why this virus infection is so highly contagious and infects most individuals it comes in contact with. We confirm that the expression level of IFITM3 plays a role in determining the level of viral infection through manipulation of IFITM3 levels with interferon (IFN) stimulation and overexpression systems. Low basal expression may put some immune cells, including lymphocytes and lung-resident macrophages, at risk of influenza virus infection. Investigating the induction of IFITM3 by IFN, we find a strong preference for Type I IFN in IFITM3 induction in both cell lines and primary human cells. While myeloid cells can increase expression following stimulation by Type I IFN, lymphocytes show minimal induction of IFITM3 following IFN stimulation, suggesting that they are always at risk of viral infection. Surprisingly, we found that the time it takes for maximal induction of IFITM3 is relatively slow for an interferon-stimulated gene at around 36 hours. Low basal expression and slow induction of IFITM3 could increase the risk of influenza virus infection in selected immune cells.

This work proposes for the first time protecting–reflecting on both sides of plated mirrors and a solution to polycarbonate surface vulnerability to weathering and scratching using tungsten disulfide (WS2) by mechanical polishing. The ability of the dynamic chemical plating (DCP) technique to deposit Ag films at the nanometer scale on a polycarbonate (PC) substrate and its characteristics to be metallized is also shown. These deposits hold significant promise for concentrated solar power (CSP) applications. Complementarily, the application of WS2 as a reflective film for CSP by mechanical polishing on smooth polycarbonate surfaces is both novel and practical. This technique is innovative and scalable without needing reactants or electrical potential, making it highly applicable in real-world scenarios, including, potentially, on-site maintenance. The effects of surface morphology and adhesion, and the reflectivity parameters of the silver metallic surfaces were investigated. Wettability was investigated because it is important for polymeric surfaces in the activation and metal deposition immediately after redox reactions. The flame technique improved wettability by modifying the surface with carbonyl and carboxyl functional groups, with PC among the few industrial polymers that resisted such a part of the process. The change in the chemical composition, roughness, and wettability of the surfaces effectively improved the adhesion between the Ag film and the PC substrate. However, it did not significantly affect the adhesion between PC and WS2 and showed its possible implementation as a first surface mirror. Overall, this work provides a scalable, innovative method for improving the durability and reflectivity of polycarbonate-based mirrors, with significant implications for CSP applications.

Photocatalytic semiconductors require maintaining stability and pursuing higher efficiencies. The studied systems were silicon nanowires (SiNWs), silicon nanowires with cobalt oxide nanoparticles (SiNWs-CoONPs), and silicon nanowires with copper nanoparticles (SiNWs-CuNPs). SiNWs were synthesized by metal-assisted chemical etching (MACE) from silicon wafers keeping the remaining silver nanoparticles for all three sample types. The nanowires were about 23–30 µm in length. CoONPs and CuNPs were deposited on SiNWs by the autocatalytic reduction processes (electroless). There were many factors in the process that affect the resulting structures and degradation efficiencies. This work shows the degradation of methyl orange (MO) together with the chemisorption of methylene blue (MB), and rhodamine 6G (Rh6G) by direct illumination with visible radiation. The MO degradation kinetics were in the sequence SiNWs-CuNPs (88.9%) > SiNWs (85.3%) > SiNWs-CoONPs (49.3%), with the SiNWs-CuNPs having slightly faster kinetics. However, SiNWs-CoONPs have slow degradation kinetics. The chemisorptions of MB and Rh6G were SiNWs-CuNPs (87.2%; 86.88%) > SiNWs (86%; 87%) > SiNWs-CoONPs (17.3%; 12%), showing dye desorptions together with lower chemisorption capacities. This work shows iridescence in optical microscopy images by the visible light interference caused by the spaces between the nanowire bundles.