Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets.

Mesenchymal stem cells (MSCs) display pleiotropic functions, which include secretion of soluble factors with immunosuppressive activity implicated in cancer progression. We compared the immunomodulatory effects on natural killer (NK) cells of paired intratumor (T)- and adjacent non-tumor tissue (N)-derived MSCs from patients with squamous cell lung carcinoma (SCC). We observed that T-MSCs were more strongly immunosuppressive than N-MSCs and affected both NK function and phenotype, as defined by CD56 expression. T-MSCs shifted NK cells toward the CD56 <sup>dim</sup> phenotype and differentially modulated CD56 <sup>bright/dim</sup> subset functions. Whereas MSCs affected both degranulation and activating receptor expression in the CD56 <sup>dim</sup> subset, they primarily inhibited interferon-γ production in the CD56 <sup>bright</sup> subset. Pharmacological inhibition of prostaglandin E2 (PGE2) synthesis and, in some MSCs, interleukin-6 (IL-6) activity restored NK function, whereas NK cell stimulation by PGE2 alone mimicked T-MSC-mediated immunosuppression. Our observations provide insight into how stromal responses to cancer dampen NK cell activity in human lung SCC

The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma.

Expression of the SS18/SYT-SSX fusion protein is believed to underlie the pathogenesis of synovial sarcoma (SS). Recent evidence suggests that deregulation of the Wnt pathway may play an important role in SS but the mechanisms whereby SS18-SSX might affect Wnt signaling remain to be elucidated. Here, we show that SS18/SSX tightly regulates the elevated expression of the key Wnt target AXIN2 in primary SS. SS18-SSX is shown to interact with TCF/LEF, TLE and HDAC but not β-catenin in vivo and to induce Wnt target gene expression by forming a complex containing promoter-bound TCF/LEF and HDAC but lacking β-catenin. Our observations provide a tumor-specific mechanistic basis for Wnt target gene induction in SS that can occur in the absence of Wnt ligand stimulation

Exceptionally potent human monoclonal antibodies are effective for prophylaxis and therapy of tetanus in mice

Human monoclonal antibodies were used here to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate them as a safe preventive and therapeutic substitute of hyperimmune sera for tetanus in mice. By screening memory B cells of immune donors, we selected two monoclonal antibodies specific for tetanus neurotoxin with exceptionally high neutralizing activities, which were extensively characterized both structurally and functionally. We found that these antibodies interfere with the binding and translocation of the neurotoxin into neurons by interacting with two epitopes, whose definition pinpoints crucial events in the cellular pathogenesis of tetanus. This information explains the unprecedented neutralization ability of these antibodies, which were found to be exceptionally potent in preventing experimental tetanus when injected in mice long before the neurotoxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential therapeutic use via intrathecal injection. As such, these human monoclonal antibodies, as well as their Fab derivatives, meet all requirements for being considered for prophylaxis and therapy of human tetanus and are ready for clinical trials

Burden of epilepsy in Latin America and The Caribbean: a trend analysis of the Global Burden of Disease Study 1990 – 2019.

Background: The epilepsy prevalence in Latin America and the Caribbean (LAC) had remained high over the last 20 years. Data on the burden of epilepsy are needed for healthcare planning and resource allocation. However, no systematic analysis had been performed for epilepsy burden in LAC. Methods: We extracted data of all LAC countries from the Global Burden of Disease (GBD) study from 1990 to 2019. Epilepsy burden was measured as prevalence, mortality, and disability-adjusted life-years (DALYs; defined by the sum of years of life lost [YLLs] for premature mortality and years lived with disability [YLDs]), by age, sex, year, and country. Absolute numbers, rates, and 95% uncertainty intervals were reported. We performed correlational analyses among burden metrics and Socio-demographic Index (SDI). Findings: The burden of epilepsy decreased around 20% in LAC, led by YLLs reduction. In 2019, 6·3 million people were living with active epilepsy of all causes (95% UI 5·3 - 7·4), with 3·22 million (95% UI 2·21 - 4·03) and 3·11 million (95% UI 2·21 to 4·03) cases of epilepsy with identifiable aetiology and idiopathic epilepsy, respectively. The number of DALYs represented the 9·51% (1.37 million, 95% UI 0·99 -1·86) of the global epilepsy burden in 2019. The age-standardized burden was 175·9 per 100 000 population (95% UI 119·4 - 253·3), which tend to have a bimodal age distribution (higher in the youth and elderly) and was driven by high YLDs estimates. The burden was higher in men and older adults, primarily due to high YLLs and mortality. Alcohol use was associated with 17% of the reported DALYs. The SDI estimates significantly influenced this burden (countries with high SDI have less epilepsy burden and mortality, but not prevalence or disability). Interpretation: The epilepsy burden has decreased in LAC over the past 30 years. Even though, LAC is still ranked as the third region with the highest global epilepsy burden. This reduction was higher in children, but burden and mortality increased for older adults. The epilepsy burden is disability predominant; however, the mortality-related estimates are still higher than in other regions. Alcohol consumption and countries’ development are important determinants of this burden. There is an urgent need to improve access to epilepsy care in LAC, particularly for older adults. Strengthening primary care with online learning and telemedicine tools, and promoting risk factors modification should be prioritized in the region. Funding: This research was self-funded by the authors

Five-year review of an international clinical research-training program

The exponential increase in clinical research has profoundly changed medical sciences. Evidence that has accumulated in the past three decades from clinical trials has led to the proposal that clinical care should not be based solely on clinical expertise and patient values, and should integrate robust data from systematic research. As a consequence, clinical research has become more complex and methods have become more rigorous, and evidence is usually not easily translated into clinical practice. Therefore, the instruction of clinical research methods for scientists and clinicians must adapt to this new reality. To address this challenge, a global distance-learning clinical research-training program was developed, based on collaborative learning, the pedagogical goal of which was to develop critical thinking skills in clinical research. We describe and analyze the challenges and possible solutions of this course after 5 years of experience (2008-2012) with this program. Through evaluation by students and faculty, we identified and reviewed the following challenges of our program: 1) student engagement and motivation, 2) impact of heterogeneous audience on learning, 3) learning in large groups, 4) enhancing group learning, 5) enhancing social presence, 6) dropouts, 7) quality control, and 8) course management. We discuss these issues and potential alternatives with regard to our research and background

Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex

Evidence by functional imaging studies suggests the role of left dorsolateral prefrontal cortex (DLPFC) in the inhibitory control of nociceptive transmission system. Repetitive transcranial magnetic stimulation (rTMS) is able to modulate pain response to capsaicin. In the present study, we evaluated the effect of DLPFC activation (through rTMS) on nociceptive control in a model of capsaicin-induced pain. The study was performed on healthy subjects that underwent capsaicin application on right or left hand. Subjects judged the pain induced by capsaicin through a 0–100 VAS scale before and after 5 Hz rTMS over left and right DLPFC at 10 or 20 min after capsaicin application in two separate groups (8 subjects each). Left DLPFC-rTMS delivered either at 10 and 20 min after capsaicin application significantly decreased spontaneous pain in both hands. Right DLPFC rTMS showed no significant effect on pain measures. According to these results, stimulation of left DLPFC seems able to exert a bilateral control on pain system, supporting the critical antinociceptive role of such area. This could open new perspectives to non-invasive brain stimulation protocols of alternative target area for pain treatment

Short- and long-lasting tinnitus relief induced by transcranial direct current stimulation

A significant proportion of the population suffers from tinnitus, a bothersome auditory phantom perception that can severely alter the quality of life. Numerous experimental studies suggests that a maladaptive plasticity of the auditory and limbic cortical areas may underlie tinnitus. Accordingly, repetitive transcranial magnetic stimulation (rTMS) has been repeatedly used with success to reduce tinnitus intensity. The potential of transcranial direct current stimulation (tDCS), another promising method of noninvasive brain stimulation, to relieve tinnitus has not been explored systematically. In a double-blind, placebo-controlled and balanced order design, 20 patients suffering from chronic untreatable tinnitus were submitted to 20 minutes of 1 mA anodal, cathodal and sham tDCS targeting the left temporoparietal area. The primary outcome measure was a change in tinnitus intensity or discomfort assessed with a Visual Analogic Scale (VAS) change-scale immediately after tDCS and 1 hour later. Compared to sham tDCS, anodal tDCS significantly reduced tinnitus intensity immediately after stimulation; whereas cathodal tDCS failed to do so. The variances of the tinnitus intensity and discomfort VAS change-scales increased dramatically after anodal and cathodal tDCS, whereas they remained virtually unchanged after sham tDCS. Moreover, several patients unexpectedly reported longer-lasting effects (at least several days) such as tinnitus improvement, worsening, or changes in tinnitus features, more frequently after real than sham tDCS. Anodal tDCS is a promising therapeutic tool for modulating tinnitus perception. Moreover, both anodal and cathodal tDCS seem able to alter tinnitus perception and could, thus, be used to trigger plastic changes