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Background: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. Methods: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. Results: PD-1 positive (+) was significantly associated with current smoking status ( P =0.02) and with the presence of KRAS mutations ( P =0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology ( P =0.005) and with presence of EGFR mutations ( P =0.001). In patients treated with EGFR tyrosine kinase inhibitors ( N =95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P =0.01) time to progression (TTP: P <0.0001) and survival (OS: P =0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative ( P =0.01). Conclusions: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

Multiple sclerosis (MS) is a chronic inflammatory disease characterised by myelin and axonal loss. Lack of remyelination is primarily attributed to the failure of oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes. The neuromodulator adenosine can influence OPC differentiation, and by selectively stimulating A 2A and A 2B receptors (A 2A R, A 2B R), it inhibits OPC maturation. In the efforts of developing remyelinating and neuroprotective agents, this study evaluated the ability of a novel dual A 2A R/A 2B R antagonist, P626, in the experimental autoimmune encephalomyelitis (EAE) mouse model and cultured OPCs. EAE mice, 14 days after MOG 35–55 immunisation, received intranasal administration of P626 for 2 weeks, which improved motor symptoms, as evidenced by reduced clinical scores and enhanced performance on the rotarod test, and alleviated thermal and mechanical hypersensitivity without significantly affecting body weight. In spinal cord sections, P626 protected from the reduction of Luxol Fast Blue staining and increased myelin basic protein staining in immunohistochemical analysis. Patch‐clamp experiments on cultured OPCs exposed to high extracellular adenosine concentrations demonstrated that P626 prevented the A 2A R‐ and A 2B R‐mediated reduction in sustained I K and transient I A currents, both essential for cell differentiation. In conclusion, P626 showed efficacy in reducing neurological symptoms and demyelination in an MS model.

Multiple sclerosis (MS) is a chronic inflammatory disease characterised by myelin and axonal loss. Lack of remyelination is primarily attributed to the failure of oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes. The neuromodulator adenosine can influence OPC differentiation, and by selectively stimulating A2A and A2B receptors (A2AR, A2BR), it inhibits OPC maturation. In the efforts of developing remyelinating and neuroprotective agents, this study evaluated the ability of a novel dual A2AR/A2BR antagonist, P626, in the experimental autoimmune encephalomyelitis (EAE) mouse model and cultured OPCs. EAE mice, 14 days after MOG35–55 immunisation, received intranasal administration of P626 for 2 weeks, which improved motor symptoms, as evidenced by reduced clinical scores and enhanced performance on the rotarod test, and alleviated thermal and mechanical hypersensitivity without significantly affecting body weight. In spinal cord sections, P626 protected from the reduction of Luxol Fast Blue staining and increased myelin basic protein staining in immunohistochemical analysis. Patch‐clamp experiments on cultured OPCs exposed to high extracellular adenosine concentrations demonstrated that P626 prevented the A2AR‐ and A2BR‐mediated reduction in sustained IK and transient IA currents, both essential for cell differentiation. In conclusion, P626 showed efficacy in reducing neurological symptoms and demyelination in an MS model.

Virtual reality (VR) may be useful for situating school-based vocational education in work-life by simulating a work situation such that learners viewing this VR work situation are located inside it. The reason for this assumption is that VR can fully spatially include its viewer. Research on the utility of viewer-including VR work situations for learners has, therefore, already started. However, no study has yet investigated their utility for teachers. This is particularly relevant for work situations involving environmental planning, as VR is expected to facilitate such a task. We, therefore, asked horticultural teachers to assess the educational usefulness of a VR work situation when they were located outside and inside it. For this purpose, we enabled them to plan a basic garden in the VR work situation when its environment was spatially excluding them and when it was including them. We found the teachers to perceive the viewer-including VR work situation as more useful for their teaching than its viewer-excluding version. This suggests that the perceived educational usefulness of a VR work situation depends on the spatial relation of its viewer and environment, that is, the spatial human-environment relation it involves.

Cerebrospinal fluid (CSF) biomarkers (protein tau, phosphorylated tau and amyloid Beta 1–42) are recognized as a supportive feature in diagnosis of Alzheimer’s disease (AD) and their role in identifying atypical variants of AD is currently under investigation. We dosed these proteins in nine patients clinically and instrumentally affected by posterior cortical atrophy (PCA), a rare disorder characterized by a progressive neurodegenerative process that involves primarily the posterior brain regions. We compared the obtained values with a large group of AD patients ( N  = 117), recruited in our neurological department. Our data revealed no differences in the CSF profile between PCA and AD, showing abnormal values of protein tau, phosphorylated tau and amyloid Beta 1–42 in both groups of patients. This study underlines the diagnostic importance of CSF biomarkers in PCA patients, supporting the hypothesis that PCA is an atypical variant of AD with an onset before the age of 65.

Safranal, contained in Crocus sativus L., exerts anti‐inflammatory and analgesic effects. However, the underlying mechanisms for such effects are poorly understood. We explored whether safranal targets the transient receptor potential ankyrin 1 (TRPA1) channel, which in nociceptors mediates pain signals. Safranal by binding to specific cysteine/lysine residues, stimulates TRPA1, but not the TRP vanilloid 1 and 4 channels (TRPV1 and TRPV4), evoking calcium responses and currents in human cells and rat and mouse dorsal root ganglion (DRG) neurons. Genetic deletion or pharmacological blockade of TRPA1 attenuated safranal‐evoked release of calcitonin gene‐related peptide (CGRP) from rat and mouse dorsal spinal cord, and acute nociception in mice. Safranal contracted rat urinary bladder isolated strips in a TRPA1‐dependent manner, behaving as a partial agonist. After exposure to safranal the ability of allyl isothiocyanate (TRPA1 agonist), but not that of capsaicin (TRPV1 agonist) or GSK1016790A (TRPV4 agonist), to evoke currents in DRG neurons, contraction of urinary bladder strips and CGRP release from spinal cord slices in rats, and acute nociception in mice underwent desensitization. As previously shown for other herbal extracts, including petasites or parthenolide, safranal might exert analgesic properties by partial agonism and selective desensitization of the TRPA1 channel.

IntroductionMulticentre preclinical randomised controlled trials (pRCT) are emerging as a necessary step to confirm efficacy and improve translation into the clinic. The aim of this project is to perform two multicentre pRCTs (one in rats and one in mice) to investigate the efficacy of remote ischaemic conditioning (RIC) in an experimental model of severe ischaemic stroke.Methods and analysisSeven research laboratories within the Italian Stroke Organization (ISO) Basic Science network will participate in the study. Transient endovascular occlusion of the proximal right middle cerebral artery will be performed in two species (rats and mice) and in both sexes. Animals will be randomised to receive RIC by transient surgical occlusion of the right femoral artery, or sham surgery, after reperfusion. Blinded outcome assessment will be performed for dichotomised functional neuroscore (primary endpoint) and infarct volume (secondary endpoint) at 48 hours. A sample size of 80 animals per species will yield 82% power to detect a significant difference of 30% in the primary outcome in both pRCTs. Analyses will be performed in a blind status and according to an intention-to-treat paradigm. The results of this study will provide robust, translationally oriented, high-quality evidence on the efficacy of RIC in multiple species of rodents with large ischaemic stroke.Ethics and disseminationThis is approved by the Animal Welfare Regulatory Body of the University of Milano Bicocca, under project license from the Italian Ministry of Health. Trial results will be subject to publication according to the definition of the outcome presented in this protocol.Trial registration numberPCTE0000177.

Significant advances in the field of regenerative medicine have intensified the search for novel sources of stem cells with potential for therapy. Although embryonic and adult tissues can be used for the isolation of pluripotent stem cells, significant limitations including ethical concerns, complexity of isolation/culture and tumorigenicity have hindered translation of laboratory findings to clinical practice.