The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110β (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB K805R mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110β function revealed that p110β catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding (G protein)-coupled receptors as well as to sustain long term insulin signaling. In addition, PIK3CB K805R mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110β catalytic activity in diabetes and cancer, opening potential new avenues for therapeutic intervention.

Background. COVID-19 patients develop pneumonia generally associated to lymphopenia and severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK-STAT signaling pathways, which can be disabled by small molecules. Methods. A group of subjects (n = 20) was treated with baricitinib according to an offlabel use of the drug. The study was designed as an observational longitudinal trial and approved by the local ethical committee. The patients were treated with baricitinib 4 mg twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of pSTAT3 in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies anti-SARS-CoV-2. In a single treated patient, we evaluated also the alteration of myeloid cell functional activity. Results. We provided evidence that baricitinib-treated patients have a marked reduction in serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-a, a rapid recovery in circulating T and B cell frequencies, and increased antibody production against SARS-CoV-2 spike protein, which were clinically associated with a reduction in oxygen flow need and progressive increase in the P/F. Conclusion. These data suggest that Baricitinib prevented the progression towards a severe/extreme form of the viral disease by modulating the patients' immune landscape and these changes were associated with a safer and favorable clinical outcome of patients with COVID-19 pneumonia. Trial registration. The ClinicalTrials.gov identifier of this project is protocol NCT04438629.

Objective: Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia. Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism. Approach and Results: Overall, 37 patients and 28 healthy subjects were studied. Platelet-leukocyte aggregates, platelet-derived microvesicles, the expression of P-selectin, and active fibrinogen receptor on platelets were quantified by flow cytometry. The profile of 45 cytokines, chemokines, and growth factors released by platelets was defined by immunoassay. The contribution of platelets to coagulation factor activity was selectively measured. Numerous platelet-monocyte (mean±SE, 67.9±4.9%, n=17 versus 19.4±3.0%, n=22; P <0.0001) and platelet-granulocyte conjugates (34.2±4.04% versus 8.6±0.7%; P <0.0001) were detected in patients. Resting patient platelets had similar levels of P-selectin (10.9±2.6%, n=12) to collagen-activated control platelets (8.7±1.5%), which was not further increased by collagen activation on patient platelets (12.4±2.5%, P =nonsignificant). The agonist-stimulated expression of the active fibrinogen receptor was reduced by 60% in patients ( P <0.0001 versus controls). Cytokines (IL [interleukin]-1α, IL-1β, IL-1RA, IL-4, IL-10, IL-13, IL, 17, IL-27, IFN [interferon]-α, and IFN-γ), chemokines (MCP-1/CCL2), and growth factors (VEGF [vascular endothelial growth factor]-A/D) were released in significantly larger amounts upon stimulation of COVID-19 platelets. Platelets contributed to increased fibrinogen, VWF (von Willebrand factor), and factor XII in COVID-19 patients. Patients (28.5±0.7 s, n=32), unlike controls (31.6±0.5 s, n=28; P <0.001), showed accelerated factor XII–dependent coagulation. Conclusions: Platelets in COVID-19 pneumonia are primed to spread proinflammatory and procoagulant activities in systemic circulation.

Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumorbearing hosts, increased the number and function of tumorantigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I͞II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.arginase ͉ immunosuppression ͉ myeloid cells ͉ nitric oxide ͉ immunotherapy I dentifying effective treatments for cancer is a clinical priority.Despite the plethora of evidence in preclinical models, the most advanced immunotherapy, either active or passive, has had limited success in human clinical trials (1). Basis for this conclusion appears to involve at least in part the progressive accumulation of myeloid cells, which exert a powerful inhibitory activity on antitumor lymphocytes as a function of tumor growth. In tumor-bearing hosts, for example, tumor progression is often associated with altered hematopoiesis, which leads to the accumulation of myeloid cells at the tumor site and in blood, secondary lymphoid organs, and bone marrow (2-4).Mouse myeloid cells express the CD11b and Gr-1 markers, have a mixed mature-immature myeloid phenotype, and are responsible for the induction of tumor-specific and nonspecific T cell dysfunctions, which are frequently observed not only in transplantable tumors but also in tumors spontaneously arising with transgenic expression of tissue-restricted oncogenes (2, 5). These cells have been termed myeloid suppressor cells (MSCs) and arise from bone marrow and other hematopoietic organs exposed to systemically released factors acting on myelomonocytic precursors (reviewed in refs. 2, 3, and 6). Moreover, MSCs are the final effectors of a circuit that negatively affects tumor immunity and that requires participation of natural killer T cells. Cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance was recently shown to be down-regulated by TGF-␤ released by CD11b ϩ ͞Gr-1 ϩ cells, an event driven by cytokine IL-13 release from CD1d-restricted natural killer T cells (7). This circuit is activated very early in tumor progression and ...

It is unknown whether zoledronic acid (ZA) at clinically relevant doses is active against tumours not located in bone. Mice transgenic for the activated ErbB-2 oncogene were treated with a cumulative number of doses equivalent to that recommended in human beings. A significant increase in tumour-free and overall survival was observed in mice treated with ZA. At clinically compatible concentrations, ZA modulated the mevalonate pathway and affected protein prenylation in both tumour cells and macrophages. A marked reduction in the number of tumour-associated macrophages was paralleled by a significant decrease in tumour vascularization. The local production of vascular endothelial growth factor and interleukin-10 was drastically down-regulated in favour of interferon-γ production. Peritoneal macrophages and tumour-associated macrophages of ZA-treated mice recovered a full M1 antitumoral phenotype, as shown by nuclear translocation of nuclear factor kB, inducible nitric oxide synthase expression and nitric oxide production. These data indicate that clinically achievable doses of ZA inhibit spontaneous mammary cancerogenesis by targeting the local microenvironment, as shown by a decreased tumour vascularization, a reduced number of tumour-associated macrophages and their reverted polarization from M2 to M1 phenotype.