Association of combined PD- L1 expression and tumour- infiltrating lymphocyte features with survival and treatment outcomes in patients with metastatic melanoma

BackgroundRecent advances obtained with immune checkpoint inhibitors (ICIs) targeting the programmed cell death- 1 (PD- 1) protein have significantly improved the outcome of patients with metastatic melanoma. The PD- L1 expression in tumour cells as detected by immunohistochemistry is a predictive biomarker in some solid tumours, but appears insufficient as prognostic or predictive factor of response to ICIs in metastatic melanomas.ObjectivesWe investigated whether the presence and the features of pretreatment CD8+tumour- infiltrating T lymphocytes (TILs) could be a complementary prognostic or predictive biomarker in patients with metastatic melanoma.MethodsIn this retrospective study, we evaluated the association of PD- L1 expression - ¥5% of tumour cells combined with TIL features (CD8, CD28, Ki67) with the overall survival (OS) among 51 patients treated with ICIs and 54 patients treated with other treatment options (non- ICIs).ResultsPD- L1 positivity was observed in 33% and 39% of primary melanomas and matched metastases, respectively, with, however, poor concordance between the primary and the matched metastatic site (κ = 0.283). No significant association was noted between PD- L1 expression and CD8+TIL profile analysed as single markers and OS or response to immunotherapy. Instead, their combined analysis in primary melanoma samples showed that the PD- L1- /CD8+status was significantly associated with prolonged OS in the whole population (P = 0.04) and in the subgroup treated with non- ICIs (P = 0.009). Conversely, the PD- L1+/CD8+ status was a good prognostic factor in patients treated with ICIs (P = 0.022), whereas was significantly associated with poor prognosis in patients treated with non- ICIs (P = 0.014). While the expression of CD28 was not related to outcome, the Ki67 expression was significantly associated with poor OS in the subgroup CD8+TIL+/PD- L1- (P = 0.02).ConclusionsThe pretreatment combination of PD- L1 expression with the level of CD8+TILs could better assess OS and predict therapeutic response of patients with metastatic melanoma treated by either immunotherapy or other treatment regimens.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155478/1/jdv16016_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155478/2/jdv16016.pd

Non-linear magnetohydrodynamic modeling of plasma response to resonant magnetic perturbations

The interaction of static Resonant Magnetic Perturbations (RMPs) with the plasma flows is modeled in toroidal geometry, using the non-linear resistive MHD code JOREK, which includes the X-point and the scrape-off-layer. Two-fluid diamagnetic effects, the neoclassical poloidal friction and a source of toroidal rotation are introduced in the model to describe realistic plasma flows. RMP penetration is studied taking self-consistently into account the effects of these flows and the radial electric field evolution. JET-like, MAST, and ITER parameters are used in modeling. For JET-like parameters, three regimes of plasma response are found depending on the plasma resistivity and the diamagnetic rotation: at high resistivity and slow rotation, the islands generated by the RMPs at the edge resonant surfaces rotate in the ion diamagnetic direction and their size oscillates. At faster rotation, the generated islands are static and are more screened by the plasma. An intermediate regime with static islands which slightly oscillate is found at lower resistivity. In ITER simulations, the RMPs generate static islands, which forms an ergodic layer at the very edge (ψ ≥0.96) characterized by lobe structures near the X-point and results in a small strike point splitting on the divertor targets. In MAST Double Null Divertor geometry, lobes are also found near the X-point and the 3D-deformation of the density and temperature profiles is observed

The role of Probiotics in allergic diseases

Allergic disorders are very common in the pediatric age group. While the exact etiology is unclear, evidence is mounting to incriminate environmental factors and an aberrant gut microbiota with a shift of the Th1/Th2 balance towards a Th2 response. Probiotics have been shown to modulate the immune system back to a Th1 response. Several in vitro studies suggest a role for probiotics in treating allergic disorders. Human trials demonstrate a limited benefit for the use of probiotics in atopic dermatitis in a preventive as well as a therapeutic capacity. Data supporting their use in allergic rhinitis are less robust. Currently, there is no role for probiotic therapy in the treatment of bronchial asthma. Future studies will be critical in determining the exact role of probiotics in allergic disorders

Maggot secretions suppress pro-inflammatory responses of human monocytes through elevation of cyclic AMP

AIMS/HYPOTHESIS: Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As monocytes may contribute to the excessive inflammatory responses in such wounds, this study focussed on the effects of maggot secretions on the pro-inflammatory activities of these cells. METHODS: Freshly isolated monocytes were incubated with a range of secretions for 1 h and then stimulated with lipopolysaccharides (range 0-100 ng/ml) or lipoteichoic acid (range 0-5 microg/ml) for 18 h. The expression of cell surface molecules, cytokine and chemokine levels in culture supernatants, cell viability, chemotaxis, and phagocytosis and killing of Staphylococcus aureus were measured. RESULTS: Maggot secretions dose-dependently inhibited production of the pro-inflammatory cytokines TNF-alpha, IL-12p40 and macrophage migration inhibitory factor by lipopolysaccharides- and lipoteichoic acid-stimulated monocytes, while enhancing production of the anti-inflammatory cytokine IL-10. Expression of cell surface receptors involved in pathogen recognition remained unaffected by secretions. In addition, maggot secretions altered the chemokine profile of monocytes by downregulating macrophage inflammatory protein-1beta and upregulating monocyte chemoattractant protein-1 and IL-8. Nevertheless, chemotactic responses of monocytes were inhibited by secretions. Furthermore, maggot secretions did not affect phagocytosis and intracellular killing of S. aureus by human monocytes. Finally, secretions induced a transient rise in the intracellular cyclic AMP concentration in monocytes and Rp-cyclic AMPS inhibited the effects of secretions. CONCLUSIONS/INTERPRETATION: Maggot secretions inhibit the pro-inflammatory responses of human monocytes through a cyclic AMP-dependent mechanism. Regulation of the inflammatory processes by maggots contributes to their beneficial effects on chronic wound

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Editorial: Immunology of Vitiligo

Disappearance of melanocytes is the pathogenic hallmark of vitiligo. Progressive depigmentation of the skin has a high negative impact on patients’ quality of life. To date, vitiligo remains a therapeutic challenge. Several theories have been proposed to explain disease pathogenesis, considering the roles of increased inflammatory and cytotoxic immune responses, neuropeptides, microvascular anomalies, intrinsic abnormalities in melanocyte and keratinocyte adhesion, as well as oxidative stress. Over the past decades, clinical, basic, and translational research on patient samples as well as in vitro and in vivo models have tremendously improved our understanding of the pathophysiology of the disease and highlighted its complexity. Such progress is of utmost importance to identify appropriate therapeutic targets and treatments to halt progression of the disease and to induce repigmentation. “Immunology of vitiligo” is a collection of six review articles and four original articles focusing on complementary aspects of the immune pathways involved in vitiligo, from a pathophysiologic to a therapeutic perspective

Histopathological features due to the SARS-CoV-2

The infection due to the SARS-CoV-2 leads lesions mainly observed at the respiratory tract level, but not exclusively. The analyses of these lesions benefited from different autopsy studies. Thus, these lesions were observed in different organs, tissues and cells. These observations allowed us to rapidly improve the knowledge of the pathophysiological mechanisms associated with this emergent infectious disease. The virus can be detected in formalin fixed paraffin embedded tissues using immunohistochemistry, in situ hybridization, molecular biology and/or electron microscopy approaches. However, many uncertainties are still present concerning the direct role of the SARS-CoV-2 on the different lesions observed in different organs, outside the lung, such as the heart, the brain, the liver, the gastrointestinal tract, the kidney and the skin. In this context, it is pivotal to keep going to increase the different tissue and cellular studies in the COVID-19 positive patients aiming to better understanding the consequences of this new infectious disease, notably considering different epidemiological and co-morbidities associated factors. This could participate to the development of new therapeutic strategies too. The purpose of this review is to describe the main histological and cellular lesions associated with the infection due to the SARS-CoV-2