Ischemic Preconditioning Modulates the Peripheral Innate Immune System to Promote Anti-Inflammatory and Protective Responses in Mice Subjected to Focal Cerebral Ischemia

The development of tolerance triggered by a sublethal ischemic episode (preconditioning, PC) involves a complex crosstalk between neurons, astrocytes and microglia, although the role of the peripheral immune system in this context is largely unexplored. Here, we report that severe cerebral ischemia caused by transient middle cerebral artery occlusion (MCAo) in adult male mice elevates blood counts of inflammatory neutrophils and monocytes, and plasma levels of miRNA-329-5p. These inflammatory responses are prevented by ischemic PC induced by 15 min MCAo, 72h before the severe insult (1h MCAo). As compared with sham-operated animals, mice subjected to either ischemic PC, MCAo or a combination of both (PC+MCAo) display spleen contraction. However, protein levels of Ym1 (a marker of polarization of myeloid cells towards M2/N2 protective phenotypes) are elevated only in spleen from the experimental groups PC and PC+MCAo, but not MCAo. Conversely, Ym1 protein levels only increase in circulating leukocytes from mice subjected to 1h MCAo, but not in preconditioned animals, which is coincident with a dramatic elevation of Ym1 expression in the ipsilateral cortex. By immunofluorescence analysis, we observe that expression of Ym1 occurs in amoeboid-shaped myeloid cells, mainly representing inflammatory monocytes/macrophages and neutrophils. As a result of its immune-regulatory functions, ischemic PC prevents elevation of mRNA levels of the pro-inflammatory cytokine interleukin (IL)-1β in the ipsilateral cortex, while not affecting IL-10 mRNA increase induced by MCAo. Overall, the elevated anti-inflammatory/pro-inflammatory ratio observed in the brain of mice pre-exposed to PC is associated with reduced brain infarct volume and ischemic edema, and with amelioration of functional outcome. These findings reaffirm the crucial and dualistic role of the innate immune system in ischemic stroke pathobiology, extending these concepts to the context of ischemic tolerance and underscoring their relevance for the identification of novel therapeutic targets for effective stroke treatment

A continuous infusion of a minor histocompatibility antigen-immunodominant peptide induces a delay of male skin graft rejection.

We previously reported that an inhibition of antigen-specific Interferon-gamma release and cytotoxicity occurs after a continuous infusion of an HY immunodominant peptide although this treatment is not able to cause a significant delay of male skin grafts rejection. In vivo administration of high doses of an HY peptide, through mini-osmotic pumps, in naïve female mice was used to study the effects on the male skin grafts rejection. A continuous infusion of 1mg of an HY peptide induces a significant delay of male skin graft rejection. In vitro HY-specific Interferon-gamma release was inhibited adding peptide-specific suppressor cells: the ability to inhibit Interferon-gamma release was evident when two HY peptides were present on the same dendritic cells indicating that the suppressor cells exert "linked-suppression". The phenotype of the suppressor cells is CD8(+)CD28(-) and these cells express more CD62 ligand and FOXP3 than controls. Suppressor cells were able to cause a significant delay of rejection of male skin grafts when injected in naive female mice. The inhibitory effects of these suppressor cells seem to be due to the impairment of antigen presentation; down-regulation of B7 molecules on dendritic cells occurred. Taken all together, our data demonstrate that a continuous infusion of an immunodominant HY peptide induces a T CD8 suppressor subset able to inhibit immune responses to male tissues and cells

Tuning inflammation in tuberculosis: the role of decoy receptors

Decoy receptors are "silent scavengers" of CC chemokines and cytokines, which play a key role in damping inflammation and tissue damage. In this review we discuss on recent findings demonstrating that these receptors set the balance between antimicrobial resistance, immune activation and inflammatory response in Mycobacterium tuberculosis infection

Unresectable stage III non-small cell lung cancer: could durvalumab be safe and effective in real-life clinical scenarios? Results of a single-center experience

IntroductionThe standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by consolidation durvalumab as shown in the PACIFIC trial. The purpose of this study is to evaluate clinical outcomes and toxicities regarding the use of durvalumab in a real clinical scenario. MethodsA single-center retrospective study was conducted on patients with a diagnosis of unresectable stage III NSCLC who underwent radical CRT followed or not by durvalumab. Tumor response after CRT, pattern of relapse, overall survival (OS) and progression-free survival (PFS), and toxicity profile were investigated. ResultsEighty-five patients met the inclusion criteria. The median age was 67 years (range 45-82 years). Fifty-two patients (61.2%) started sequential therapy with durvalumab. The main reason for excluding patients from the durvalumab treatment was the expression of PD-L1 < 1%. Only two patients presented a grade 4 or 5 pneumonitis. A median follow-up (FU) of 20 months has been reached. Forty-five patients (52.9%) had disease progression, and 21 (24.7%) had a distant progression. The addition of maintenance immunotherapy confirmed a clinical benefit in terms of OS and PFS. Two-year OS and PFS were respectively 69.4% and 54.4% in the durvalumab group and 47.9% and 24.2% in the no-durvalumab group (p = 0.015, p = 0.007). ConclusionIn this real-world study, patients treated with CRT plus durvalumab showed clinical outcomes and toxicities similar to the PACIFIC results. Maintenance immunotherapy after CRT has been shown to be safe and has increased the survival of patients in clinical practice

Neuroanatomical abnormalities in first-episode psychosis across independent samples: a multi-centre mega-analysis

Abstract Background Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. Methods Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. Results FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms. Conclusions This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria

Neuroanatomical abnormalities in first-episode psychosis across independent samples: a multi-centre mega-analysis

Background Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. Methods Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. Results FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease-gyrus rectus-was negatively correlated with the severity of positive and negative symptoms. Conclusions This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.This study was supported by the European Commission (PSYSCAN – Translating neuroimaging findings from research into clinical practice) (P.M., grant number 603196); International Cooperation and Exchange of the National Natural Science Foundation of China (Q.G. and A.M., grant numbers 81220108013, 8122010801, 81621003, 81761128023 and 81227002); Wellcome Trusts Innovator Award (A.M., grant number 208519/ Z/17/Z) Italian Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (C.R, grant number art.1, commi 314-337 legge 232/2016) and the Foundation for Science and Technology (FCT) (S.V., grant number SFRH/BD/ 103907/2014)

Construction of reference chromosome-scale pseudomolecules for potato: integrating the potato genome with genetic and physical maps

The genome of potato, a major global food crop, was recently sequenced. The work presented here details the integration of the potato reference genome (DM) with a new STS marker based linkage map and other physical and genetic maps of potato and the closely related species tomato. Primary anchoring of the DM genome assembly was accomplished using a diploid segregating population, which was genotyped with several types of molecular genetic markers to construct a new ~936 cM linkage map comprising 2,469 marker loci. In silico anchoring approaches employed genetic and physical maps from the diploid potato genotype RH and tomato. This combined approach has allowed 951 superscaffolds to be ordered into pseudomolecules corresponding to the 12 potato chromosomes. These pseudomolecules represent 674 Mb (~93%) of the 723 Mb genome assembly and 37,482 (~96%) of the 39,031 predicted genes. The superscaffold order and orientation within the pseudomolecules is closely collinear with independently constructed high density linkage maps. Comparisons between marker distribution and physical location reveal regions of greater and lesser recombination, as well as regions exhibiting significant segregation distortion. The work presented here has led to a greatly improved ordering of the potato reference genome superscaffolds into chromosomal 'pseudomolecules'.Fil: Carboni, Martín Federico. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires. Estación Experimental Agropecuaria Balcarce; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: D'ambrosio, Juan Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional San Cristobal de Huamanga. Laboratorio de Genética y Biotecnología Vegetal; PerúFil: Sharma, Sanjeev Kumar. The James Hutton Institute; Reino UnidoFil: Bolser, Daniel. University of Dundee; Reino UnidoFil: de Boer, Jan. Wageningen University & Researc; Países BajosFil: Sønderkær, Mads . Aalborg University; DinamarcaFil: Amoros, Walter. International Potato Center; PerúFil: de la Cruz, Germán. Universidad Nacional San Cristobal de Huamanga; PerúFil: Di Genova, Alex. Universidad de Chile; ChileFil: Douches, David S.. Michigan State University; Estados UnidosFil: Eguiluz, Maria. Universidad Peruana Cayetano Heredia; PerúFil: Guo, Xiao. Shandong Academy of Agricultural Sciences; ChinaFil: Guzman, Frank. Universidad Peruana Cayetano Heredia; PerúFil: Hackett, Christine A.. Biomathematics and Statistics Scotland; Reino UnidoFil: Hamilton, John P.. Crops Environment and Land Use Programme; IrlandaFil: Li, Guangcun. Shandong Academy of Agricultural Sciences; ChinaFil: Li, Ying. The New Zealand Institute for Plant & Food Research; Nueva ZelandaFil: Lozano, Roberto. Universidad Peruana Cayetano Heredia; PerúFil: Maass, Alejandro. Universidad de Chile; ChileFil: Marshall, David. The James Hutton Institute; Reino UnidoFil: Martinez, Diana. Universidad Peruana Cayetano Heredia; PerúFil: McLean, Karen. The James Hutton Institute; Reino UnidoFil: Mejía, Nilo. Instituto de Investigaciones Agropecuarias. Centro Regional de Investigación La Platina; ChileFil: Milne, Linda. The James Hutton Institute; Reino UnidoFil: Munive, Susan. International Potato Center; PerúFil: Nagy, Istvan. Crops Environment and Land Use Programme; IrlandaFil: Ponce, Olga. Universidad Peruana Cayetano Heredia; PerúFil: Ramirez, Manuel. Universidad Peruana Cayetano Heredia; PerúFil: Simon, Reinhard. International Potato Center; PerúFil: Thomson, Susan J.. Chinese Academy of Agricultural Sciences; Chin