MYC regulates metabolism through vesicular transfer of glycolytic kinases

Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.5713034.Copyright © 2021 The Authors. Amplification of the proto-oncogene MYCN is a key molecular aberration in high-risk neuroblastoma and predictive of poor outcome in this childhood malignancy. We investigated the role of MYCN in regulating the protein cargo of extracellular vesicles (EVs) secreted by tumour cells that can be internalized by recipient cells with functional consequences. Using a switchable MYCN system coupled to mass spectrometry analysis, we found that MYCN regulates distinct sets of proteins in the EVs secreted by neuroblastoma cells. EVs produced by MYCN-expressing cells or isolated from neuroblastoma patients induced the Warburg effect, proliferation and c-MYC expression in target cells. Mechanistically, we linked the cancer-promoting activity of EVs to the glycolytic kinase pyruvate kinase M2 (PKM2) that was enriched in EVs secreted by MYC-expressing neuroblastoma cells. Importantly, the glycolytic enzymes PKM2 and hexokinase II were detected in the EVs circulating in the bloodstream of neuroblastoma patients, but not in those of non-cancer children. We conclude that MYC-activated cancers might spread oncogenic signals to remote body locations through EVs.Neuroblastoma UK to AS and FAPESP SPRINT Award (50356-4); FAPESP (2014/06863-3, 2018/18257-1, 2018/15549-1, 16/50356-4); CNPq “bolsa de produtividade”; Ricerca Finalizzata GR11-172.https://doi.org/10.6084/m9.figshare.c.571303

Impact of SARS-CoV-2 Infection on the Course of Inflammatory Bowel Disease in Patients Treated with Biological Therapeutic Agents: A Case-Control Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has raised concerns in patients with inflammatory bowel disease (IBD), not only due to consequences of coronavirus disease 2019 itself but also as a possible cause of IBD relapse. The main objective of this study was to assess the role of SARS-CoV-2 in IBD clinical recurrence in a cohort of patients undergoing biological therapy. Second, we evaluated the difference in C-reactive protein (CRP) levels between the start and end of the follow-up period (ΔCRP) and the rate of biological therapy discontinuation. Patients with IBD positive for SARS-CoV-2 infection were compared with non-infected patients. IBD recurrence was defined as the need for intensification of current therapy. We enrolled 95 IBD patients with SARS-CoV-2 infection and 190 non-infected patients. During follow-up, 11 of 95 (11.6%) SARS-CoV-2-infected patients experienced disease recurrence compared to 21 of 190 (11.3%) in the control group (p = 0.894). Forty-six (48.4%) SARS-CoV-2-infected patients discontinued biological therapy versus seven (3.7%) in the control group (p < 0.01). In the multivariate analysis, biological agent discontinuation (p = 0.033) and ΔCRP (p = 0.017), but not SARS-CoV-2 infection (p = 0.298), were associated with IBD recurrence. SARS-CoV-2 infection was not associated with increased IBD recurrence rates in this cohort of patients treated with biological agents

Censorship and Self-Censorship

This special issue of "Between" aims to investigate the interplay between censorship and self-censorship in a variety of domains, from literary works to audio-visual media, from criticism to cultural mediation, in order to re-examine the relationship between censorship and artistic expression

A self-administered questionnaire of ulnar neuropathy at the elbow

e report a new self-administered questionnaire for assessment of symptom severity of ulnar neuropathy at the elbow (UNE). The new UNE and Levine's questionnaires were administered to a sample of UNE subjects and for comparison also to a sample of subjects with carpal tunnel syndrome (CTS). We enrolled 89 consecutive patients (32 women, 57 men, mean age 52.3 years) with UNE and 203 consecutive patients (157 women and 46 men, mean age 53.7 years) with CTS. The protocol of the study consisted in self-administration of the new UNE and Levine's questionnaires, as well as scoring of clinical and electrophysiological severity of entrapment syndromes with ordinal scales. The UNE questionnaire (UNEQ) includes nine questions and considers numbness and tingling in the fourth and fifth fingers, elbow pain and modification of pain and paraesthesia with elbow position. A score from 1 (absence of symptom) to 5 (most severe) is assigned for each question. The overall score is calculated as the mean of the nine scores. Test-retest reliability, internal consistency and validity were assessed. Responsiveness was also tested in a sample of patients undergoing conservative treatment. The UNEQ was reproducible. Spearman's correlation coefficient between scores at successive observations (test-retest reliability), assessed in the first 44 patients, was 0.97 and Cohen coefficients kappa for single items were between 0.64 and 0.81. Internal consistency was high: Cronbach's alpha, which summarises interitem correlations among all items of UNEQ, was 0.87. Validity was demonstrated by a direct correlation with UNE clinical and electrophysiological severity scores (0.65 and 0.35). On the contrary, Spearman's correlation coefficients between UNEQ and clinical and electrophysiological CTS severity scores were low (0.11 and 0.02, respectively). Responsiveness was calculated at 6-8 months follow-up in 25 cases. The effect size was 0.46. The Wilcoxon rank-test showed significant improvement between basal and follow-up UNEQ scores (Z=-2.39, p=0.017), but not Boston Questionnaire scores. There was also significant correlation between UNEQ changes and an arbitrary scale of patient satisfaction at follow-up (r=0.85, p<0.001). The UNEQ is reproducible, internally consistent and valid. Although further studies are required to test its responsiveness to clinical changes, UNEQ may be also considered responsive. UNEQ can be used to measure subjective discomfort in UNE patients

Gut barrier in health and disease: focus on childhood

The gut barrier is a functional unit, organized as a multi-layer system, made up of two main components: a physical barrier surface, which prevents bacterial adhesion and regulates paracellular diffusion to the host tissues, and a deep functional barrier, that is able to discriminate between pathogens and commensal microorganisms, organizing the immune tolerance and the immune response to pathogens. Other mechanisms, such as gastric juice and pancreatic enzymes (which both have antibacterial properties) participate in the luminal integrity of the gut barrier. From the outer layer to the inner layer, the physical barrier is composed of gut microbiota (that competes with pathogens to gain space and energy resources, processes the molecules necessary to mucosal integrity and modulates the immunological activity of deep barrier), mucus (which separates the intraluminal content from more internal layers and contains antimicrobial products and secretory IgA), epithelial cells (which form a physical and immunological barrier) and the innate and adaptive immune cells forming the gut-associated lymphoid tissue (which is responsible for antigen sampling and immune responses). Disruption of the gut barrier has been associated with many gastrointestinal diseases, but also with extra-intestinal pathological condition, such as type 1 diabetes mellitus, allergic diseases or autism spectrum disorders. The maintenance of a healthy intestinal barrier is therefore of paramount importance in children, for both health and economic reasons. Many drugs or compounds used in the treatment of gastrointestinal disorders act through the restoration of a normal intestinal permeability. Several studies have highlighted the role of probiotics in the modulation and reduction of intestinal permeability, considering the strong influence of gut microbiota in the modulation of the function and structure of gut barrier, but also on the immune response of the host. To date, available weapons for the maintenance and repair of gut barrier are however few, even if promising. Considerable efforts, including both a better understanding of the gut barrier features and mechanisms in health and disease, and the development of new pharmacological approaches for the modulation of gut barrier components, are needed for the prevention and treatment of gastrointestinal and extraintestinal diseases associated with gut barrier impairment

Gut microbiota and immunotherapy of renal cell carcinoma

The gut microbiome has recently been proposed as a key player in cancer development and progression. Several studies have reported that the composition of the gut microbiome plays a role in the response to immune checkpoint inhibitors (ICIs). The gut microbiome modulation has been investigated as a potential therapeutic strategy for cancer, mainly in patients undergoing therapy with ICIs. In particular, modulation through probiotics, FMT or other microbiome-related approaches have proven effective to improve the response to ICIs. In this review, we examine the role of the gut microbiome in enhancing clinical responses to ICIs in the treatment of renal cancer