Cotargeting among microRNAs in the brain

MicroRNAs (miRNAs) play roles in diverse developmental and disease processes. Distinct miRNAs have hundreds to thousands of conserved mRNA binding sites but typically direct only modest repression via single sites. Cotargeting of individual mRNAs by different miRNAs could potentially achieve stronger and more complex patterns of repression. By comparing target sets of different miRNAs, we identified hundreds of pairs of miRNAs that share more mRNA targets than expected (often by twofold or more) relative to stringent controls. Genetic perturbations revealed a functional overlap in neuronal differentiation for the cotargeting pair miR-138/miR-137. Clustering of all cotargeting pairs revealed a group of nine predominantly brain-enriched miRNAs that share many targets. In reporter assays, subsets of these miRNAs together repressed gene expression by five- to 10-fold, often showing cooperative repression. Together, our results uncover an unexpected pattern in which combinations of miRNAs collaborate to robustly repress cotargets, and suggest important developmental roles for cotargeting

Unilateral versus bilateral cerebral perfusion during aortic surgery for acute type A aortic dissection: a multicentre study

The aim of this retrospective multicentre study was to investigate and compare clinical outcomes of unilateral and bilateral antegrade cerebral perfusion (ACP) strategies on cerebral protection during surgery for type A aortic dissection

Coronavirus disease 2019 (COVID-19) in the heart transplant population: a single-centre experience

OBJECTIVES: Few anecdotal cases have been reported in the literature regarding heart transplant recipients and infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report our experience with 6 patients hospitalized in Northern Italy during the outbreak.METHODS: Of the 396 living heart transplant recipients from 1985 to 2020 included in the study, 6 patients developed the novel 2019 coronavirus disease. Risk factors, last follow-up characteristics, onset presentation, in-hospital course of disease and blood examinations data were collected for these patients.RESULTS: All patients were symptomatic and had positive results from a nasopharyngeal swab test for SARS-CoV-2. Of the 6 patients, 5 were hospitalized and 1 remained self-quarantined at home. Two patients died and 3 were discharged home. Two patients were admittted to the intensive care unit. Immunosuppressive therapy was modified with a median reduction comprising doses that were 50% cyclosporine and 50% mycophenolate. All patients received a medium-dose of corticosteroids as a bolus medication in addition to their therapy. All hospitalized patients received hydroxychloroquine; 2 patients received ritonavir/lopinavir. Broad-spectrum antibiotics for prophylaxis were administered to all. One patient had an ischaemic stroke and died of sepsis.CONCLUSIONS: In the absence of any strong evidence regarding the treatment of heart transplant recipients infected with SARS-CoV-2, we faced a new challenge in managing viral infection in an immunosuppressed population. Because immunomodulation interaction with the infection seems to be crucial for developing severe forms of the disease, we managed to reduce immunosuppressive therapy by adding medium doses of corticosteroids. Despite the limited number of affected patients, this report suggests that special considerations should be given to treating coronavirus disease in the heart transplant recipient population

Impact of Continuous Flow Left Ventricular Assist Device on Heart Transplant Candidates: A Multi-State Survival Analysis

19si(1) Objectives: The aim of this study was to investigate the impact of the prolonged use of continuous-flow left ventricular assist devices (LVADs) on heart transplant (HTx) candidates. (2) Methods: Between January 2012 and December 2019, we included all consecutive patients diagnosed with end-stage heart failure considered for HTx at our institution, who were also eligible for LVAD therapy as a bridge to transplant (BTT). Patients were divided into two groups: those who received an LVAD as BTT (LVAD group) and those who were listed without durable support (No-LVAD group). (3) Results: A total of 250 patients were analyzed. Of these, 70 patients (28%) were directly implanted with an LVAD as BTT, 11 (4.4%) received delayed LVAD implantation, and 169 (67%) were never assisted with an implantable device. The mean follow-up time was 36 +/- 29 months. In the multivariate analysis of survival before HTx, LVAD implantation showed a protective effect: LVAD vs. No-LVAD HR 0.01 (p < 0.01) and LVAD vs. LVAD delayed HR 0.13 (p = 0.02). Mortality and adverse events after HTx were similar between LVAD and No-LVAD (p = 0.65 and p = 0.39, respectively). The multi-state survival analysis showed a significantly higher probability of death for No-LVAD vs. LVAD patients with (p = 0.03) or without (p = 0.04) HTx. (4) Conclusions: The use of LVAD as a bridge to transplant was associated with an overall survival benefit, compared to patients listed without LVAD support.noneCarrozzini, Massimiliano; Bottio, Tomaso; Caraffa, Raphael; Bejko, Jonida; Bifulco, Olimpia; Guariento, Alvise; Lombardi, Carlo Mario; Metra, Marco; Azzolina, Danila; Gregori, Dario; Fedrigo, Marny; Castellani, Chiara; Tarzia, Vincenzo; Toscano, Giuseppe; Gambino, Antonio; Jorgji, Vjola; Ferrari, Enrico; Angelini, Annalisa; Gerosa, GinoCarrozzini, Massimiliano; Bottio, Tomaso; Caraffa, Raphael; Bejko, Jonida; Bifulco, Olimpia; Guariento, Alvise; Lombardi, Carlo Mario; Metra, Marco; Azzolina, Danila; Gregori, Dario; Fedrigo, Marny; Castellani, Chiara; Tarzia, Vincenzo; Toscano, Giuseppe; Gambino, Antonio; Jorgji, Vjola; Ferrari, Enrico; Angelini, Annalisa; Gerosa, Gin

Spatially organized multicellular immune hubs in human colorectal cancer.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks