👤 Jacopo Guccione

The aim of the study was to identify proteomic signatures from the serum of horses affected by simple obstructive intestinal colic to characterize the pathological process and to assess potential biomarkers for early diagnosis. Seven horses with obstructive colic received venous blood samples for determination of standard hematobiochemical, inflammatory, and lipid profiles at the time of initial clinical examination and after conservative therapy upon recovery. Proteomic profiling was also performed on all samples by means of a within-group analysis (sick horses at discharge vs. sick horses at admission). A validation of expression levels was performed by the Multiple Reaction Monitoring approach. In the within-group comparison, 70 proteins showed a significant difference; The proteins involved in the immune response (C2, FC 2.41; CFB, FC 3.41; HPX, FC 7.36; LTF, FC -0.55; PSMA7, FC-0.55), blood coagulation (VWF, FC -0.54; F13A1, FC-0.54; F13B, FC-0.57; PRDX2, FC-0.41; FBLN1, FC-0.62; KNG1, FC-3.86) and lipid homeostasis (APOA4, FC -0.66; APOA5, FC -0.13; APOE, FC-0.56; LCAT FC-0.58) have changed. The study suggested the coexistence of inflammatory status, the presence of intestinal bacteria that may have triggered the immune response, and hyperlipidemia in horses with obstructive colic. Show less

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations. Show less