Deciphering the Neuronal Circuitry Controlling Local Blood Flow in the Cerebral Cortex with Optogenetics in PV::Cre Transgenic Mice

Although it is know since more than a century that neuronal activity is coupled to blood supply regulation, the underlying pathways remains to be identified. In the brain, neuronal activation triggers a local increase of cerebral blood flow (CBF) that is controlled by the neurogliovascular unit composed of terminals of neurons, astrocytes, and blood vessel muscles. It is generally accepted that the regulation of the neurogliovascular unit is adjusted to local metabolic demand by local circuits. Today experimental data led us to realize that the regulatory mechanisms are more complex and that a neuronal system within the brain is devoted to the control of local brain-blood flow. Recent optogenetic experiments combined with functional magnetic resonance imaging have revealed that light stimulation of neurons expressing the calcium binding protein parvalbumin (PV) is associated with positive blood oxygen level-dependent (BOLD) signal in the corresponding barrel field but also with negative BOLD in the surrounding deeper area. Here, we demonstrate that in acute brain slices, channelrhodopsin-2 (ChR2) based photostimulation of PV containing neurons gives rise to an effective contraction of penetrating arterioles. These results support the neurogenic hypothesis of a complex distributed nervous system controlling the CBF

Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

Acknowledgments This work was supported by a Diabetes UK project grant to Dr M. Delibegović (BDARD08/0003597), Tenovus Scotland grant to Dr. M. Delibegovic and Dr. A. Agouni and travel grants from the Physiological Society and Company of Biologists to Dr. A. Agouni. Dr Delibegovic is also funded by an RCUK Fellowship, British Heart Foundation, EFSD/Lilly diabetes programme grant and the Royal Society. Dr Agouni is funded by the Royal Society and the Physiological Society. This work is supported by the INSERM and CHU of Angers. The authors are thankful to the functional imaging center of Angers (CIFAB) for the use of echocardiography.Peer reviewedPostprin

Microparticles from patients with metabolic syndrome induce vascular hypo-reactivity via Fas/Fas-ligand pathway in mice

Peer reviewedPublisher PD

1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders

This work was supported by the Ministry of Health of the Czech Republic [no. NV15-28967 A], Specific Research Project of Faculty of Science, University of Hradec Kralove [no. 2103-2017], National Institute of Mental Health [NIMH CZ; no. ED2.1.00/03.0078] from the European Regional Development Fund, COST CA15135, The Alzheimer’s Society (specifically The Barcopel Foundation), The Rosetrees trust and The Biotechnology and Biological Sciences Research Council (BBSRC) [no. BB/J01446X/1]. Funding from Ministry of Economy and competitiveness, Spain [no. SAF2012-37979-C03-01] is also acknowledged.Several neurodegenerative disorders including Alzheimer’s disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease’s progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.Publisher PDFPeer reviewe

Attention Supports Verbal Short-Term Memory via Competition between Dorsal and Ventral Attention Networks

Interactions between the neural correlates of short-term memory (STM) and attention have been actively studied in the visual STM domain but much less in the verbal STM domain. Here we show that the same attention mechanisms that have been shown to shape the neural networks of visual STM also shape those of verbal STM. Based on previous research in visual STM, we contrasted the involvement of a dorsal attention network centered on the intraparietal sulcus supporting task-related attention and a ventral attention network centered on the temporoparietal junction supporting stimulus-related attention. We observed that, with increasing STM load, the dorsal attention network was activated while the ventral attention network was deactivated, especially during early maintenance. Importantly, activation in the ventral attention network increased in response to task-irrelevant stimuli briefly presented during the maintenance phase of the STM trials but only during low-load STM conditions, which were associated with the lowest levels of activity in the dorsal attention network during encoding and early maintenance. By demonstrating a trade-off between task-related and stimulus-related attention networks during verbal STM, this study highlights the dynamics of attentional processes involved in verbal ST

Interleukin-10 controls the protective effects of circulating microparticles from patients with septic shock on tissue-engineered vascular media

During sepsis, inflammation can be orchestrated by the interaction between circulating and vascular cells that, under activation, release MPs (microparticles). Previously, we reported that increased circulating MPs in patients with sepsis play a pivotal role in ex vivo vascular function suggesting that they are protective against vascular hyporeactivity. The present study was designed to investigate the effects of MPs from patients with sepsis on the contractile response of TEVM (tissue-engineered vascular media). TEVM that were composed only of a media layer were produced by tissue engineering from human arterial SMCs (smooth muscle cells) isolated from umbilical cords. TEVM was incubated with MPs isolated from whole blood of 16 patients with sepsis. TEVM were incubated for 24 h with MPs and used for the study of vascular contraction, direct measurements of NO and O2- (superoxide anion) production by EPR and quantification of mRNA cytokine expression. MPs from patients with sepsis increased contraction induced by histamine in TEVM. This effect was not associated with inflammation, neither linked to the activation of NF-kappaB (nuclear factor kappaB) pathway nor to the increase in iNOS (inducible NO synthase) and COX (cyclo-oxygenase)-2 expression. In contrast, mRNA expression of IL (interleukin)-10 was enhanced. Then, we investigated the effect of IL-10 on vascular hyporeactivity induced by LPS (lipopolysaccharide). Although IL-10 treatment did not modify the contractile response in TEVM by itself, this interleukin restored contraction in LPS-treated TEVM. In addition, IL-10 treatment both prevented vascular hyporeactivity induced by LPS injection in mice and improved survival of LPS-injected mice. These findings show an association between the capacity of MPs from patients with sepsis to restore vascular hyporeactivity induced by LPS and their ability to increase IL-10 in the tissue-engineered blood vessel model

Isatuximab in combination with lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma: Updated safety run-in results from the randomized phase 3 ithaca study

Background: Results from a randomized, Phase 3 study by the Spanish Myeloma Group (PETHEMA/GEM) previously showed that treatment with lenalidomide plus dexamethasone (Rd) may delay progression to active disease in patients (pts) with high-risk smoldering multiple myeloma (SMM), compared with observation. To further improve outcomes, addition of the anti-CD38 antibody isatuximab (Isa) to lenalidomide and dexamethasone (Isa-Rd) for the treatment of pts with high-risk SMM is being evaluated in the ongoing, randomized, multi-center, Phase 3 ITHACA study (NCT04270409). Initial findings from the safety run-in analysis of this trial have shown a manageable safety profile and encouraging, preliminary anti-myeloma activity. We now report updated safety and efficacy results from the safety run-in part of ITHACA at a median follow-up of 19.4 months. Methods: Pts were included in the study if they had been diagnosed within 5 years with SMM (per the International Myeloma Working Group [IMWG] criteria) and had high-risk SMM according to the Mayo '20-2-20' and/or updated PETHEMA model criteria. Pts who had received prior anti-myeloma treatment were not eligible. Enrolled pts received Isa 10 mg/kg IV on day (D) 1, 8, 15, and 22 in cycle (C) 1, D1 and D15 C2-12, D1 C13-36; plus R D1-21 (25 mg C1-9; 10 mg C10-24) and d weekly (40 mg, 20 mg for ≥75 yr-old pts C1-9; 20 mg C10-24). Cycle duration was 28 days. Safety evaluations included treatment-emergent AEs (TEAEs)/serious AEs and laboratory parameters, graded by NCI-CTCAE v5.0. Response was determined by IMWG criteria (2016). Mandatory imaging by MRI and/or low-dose whole-body CT/PET-CT, and assessments of minimal residual disease (MRD, by next-generation sequencing in pts with very good partial response [VGPR] or better), were performed at protocol-defined time points. The primary study objective for the safety run-in was to confirm the recommended dose of Isa in combination with Rd. Overall response rate (ORR) and MRD negativity rate at 10-5 sensitivity were included as secondary endpoints.Sanof

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Three-Dimensional Microscopy Characterization of Death Receptor 5 Expression by Over-Activated Human Primary CD4+ T Cells and Apoptosis

Activation-induced cell death is a natural process that prevents tissue damages from over-activated immune cells. TNF-Related apoptosis ligand (TRAIL), a TNF family member, induces apoptosis of infected and tumor cells by binding to one of its two death receptors, DR4 or DR5. TRAIL was reported to be secreted by phytohemagglutinin (PHA)-stimulated CD4+ T cells in microvesicles

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen