Background: MicroRNAs (miRNAs) have been reported as deregulated in active brain lesions derived from patients with multiple sclerosis (MS). In there, these post-transcriptional regulators may elicit very important effects but proper identification of miRNA candidates as potential biomarkers and/or therapeutic targets is scarcely available. Objective: The aim of the study was to detect the presence of a set of candidate miRNAs in cell-free cerebrospinal fluid (CSF) and to determine their association with gadolinium-enhancing (Gd+) lesions in order to assess their value as biomarkers of MS activity. Methods: Assessment of 28 miRNA candidates in cell-free CSF collected from 46 patients with MS (26 Gd+ and 20 Gd− patients) was performed by TaqMan assays and qPCR. Variations in their relative abundance were analyzed by the Mann-Whitney U test and further evaluated by receiver operating characteristic (ROC) analysis. Signaling pathways and biological functions of miRNAs were analyzed using bioinformatic tools (miRTarBase, Enrichr, REVIGO, and Cytoscape softwares). Results: Seven out of 28 miRNA candidates were detected in at least 75% of CSF samples. Consistent increase of miR-21 and miR-146a/b was found in Gd+ MS patients. This increase was in parallel to the number of Gd+ lesions and neurofilament light chain (NF-L) levels. Gene Ontology enrichment analysis revealed that the target genes of these miRNAs are involved in biological processes of key relevance such as apoptosis, cell migration and proliferation, and in cytokine-mediated signaling pathways. Conclusion: Levels of miR-21 and miR-146a/b in cell-free CSF may represent valuable biomarkers to identify patients with active MS lesions.

COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3—a master checkpoint regulator of inflammatory cytokine signaling and immune response—silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)—the central component of the replication/transcription machinery of SARS-CoV-2—silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

Aim: Some clinical and biological characteristics have been described as prognostic factors for clinical conversion into clinically definite multiple sclerosis in radiologically isolated syndrome (...

Here, we report on our study of plasma lipidomics profiles of patients with type 1 diabetes (T1DM) and explore potential associations. One hundred and seven patients with T1DM were consecutively recruited. Ultrasound imaging of peripheral arteries was performed using a high image resolution B-mode ultrasound system. Untargeted lipidomics analysis was performed using UHPLC coupled to qTOF/MS. The associations were evaluated using machine learning algorithms. SM(32:2) and ether lipid species (PC(O-30:1)/PC(P-30:0)) were significantly and positively associated with subclinical atherosclerosis (SA). This association was further confirmed in patients with overweight/obesity (specifically with SM(40:2)). A negative association between SA and lysophosphatidylcholine species was found among lean subjects. Phosphatidylcholines (PC(40:6) and PC(36:6)) and cholesterol esters (ChoE(20:5)) were associated positively with intima-media thickness both in subjects with and without overweight/obesity. In summary, the plasma antioxidant molecules SM and PC differed according to the presence of SA and/or overweight status in patients with T1DM. This is the first study showing the associations in T1DM, and the findings may be useful in the targeting of a personalized approach aimed at preventing cardiovascular disease in these patients.

The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (<20%) category after neoadjuvant treatment. By contrast, no statistically significant changes in Ki67 occurred in residual tumors of the control treatment arm (p = 0.293). There is an urgent need for innovative therapeutic strategies aiming to provide the protective effects of decreasing Ki67 after neoadjuvant treatment even if pCR is not achieved. Metformin would be evaluated as a safe candidate to decrease the aggressiveness of residual disease after neoadjuvant (pre-operative) systemic therapy of BC patients.