Association of apolipoprotein levels with peripheral arterial disease: a meta-analysis of literature studies.

AIMS: Lower limb peripheral artery disease (PAD) is a leading cause of atherosclerotic cardiovascular disease (ASCVD). Discordant data are available on the association between apolipoprotein and PAD. We performed a meta-analyses on the association between apolipoprotein (apo)B, apoA-I, and apoB/apoA-I ratio with PAD. METHODS AND RESULTS: PubMed, Web of Science, Scopus databases were systematically searched. Studies providing data about apoB, apoA-I, apoB/apoA-I ratio in PAD subjects and non-PAD controls were included. Differences between PAD and non-PAD subjects were expressed as mean difference (MD) with pertinent 95% confidence intervals (95%CI). Twenty-two studies were included. Peripheral artery disease subjects showed higher apoB (MD: 12.5 mg/dL, 95%CI: 2.14, 22.87) and lower apoA-I levels (MD: -7.11 mg/dL, 95%CI: -11.94, -2.28) than non-PAD controls. Accordingly, ApoB/ApoA-I ratio resulted higher in PAD subjects than non-PAD controls (MD: 0.11, 95% CI: 0.00, 0.21). Non-HDL-C showed a direct association with the difference in apoB (z-value: 4.72, P < 0.001) and an inverse association with the difference of apoA-I (z-value: -2.43, P = 0.015) between PAD subjects and non-PAD controls. An increasing BMI was associated with an increasing difference in apoA-I values between PAD subjects and non-PAD controls (z-value: 1.98, P = 0.047). CONCLUSIONS: Our meta-analysis suggests that PAD subjects exhibit increased apoB and reduced apoA-I levels, accompanied by an increased apoB/apoA-I ratio as compared with non-PAD controls.

Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach.

INTRODUCTION: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. METHODS: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. RESULTS: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value < 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. CONCLUSIONS: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.

Risk Assessment and Antithrombotic Strategies in Antiphospholipid Antibody Carriers.

Antiphospholipid antibodies (aPL) are a cluster of autoantibodies directed against plasma proteins with affinity for membrane phospholipids. The most frequently tested aPL are lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), and anti-ß2-glycoprotein I antibodies (anti-ß2GPI). aPL play a key pathogenic role in the development of the antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by recurrent thrombotic and/or pregnancy complications in patients with persistent aPL. However, aPL positivity is occasionally documented in patients with no previous history of thrombotic or pregnancy morbidity. LA activity, multiple aPL positivity, high-titer aPL, and a concomitant systemic autoimmune disease are recognized risk factors for future thrombotic events in asymptomatic carriers. Moreover, an accelerated atherosclerosis with increased cardiovascular (CV) risk has also been associated with aPL positivity, thus exposing aPL carriers to fatal complications and chronic disability requiring cardiac rehabilitation. Overall, an accurate risk stratification is recommended for aPL-positive subjects in order to prevent both venous and arterial thrombotic complications. In this review, we provide an overview of the main antithrombotic and risk assessment strategies in aPL carriers.

Impact of Genetic Variations and Epigenetic Mechanisms on the Risk of Obesity.

Rare genetic obesity disorders are characterized by mutations of genes strongly involved in the central or peripheral regulation of energy balance. These mutations are effective in causing the early onset of severe obesity and insatiable hunger (hyperphagia), suggesting that the genetic component can contribute to 40-70% of obesity. However, genes' roles in the processes leading to obesity are still unclear. This review is aimed to summarize the current knowledge of the genetic causes of obesity, especially monogenic obesity, describing the role of epigenetic mechanisms in obesity and metabolic diseases. A comprehensive understanding of the underlying genetic and epigenetic mechanisms, with the metabolic processes they control, will permit adequate management and prevention of obesity.

Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors.

The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell membrane receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. Its expression is increased in many human cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and correlates with a poor prognosis and early invasion and metastasis. uPAR is able to control, through a cross-talk with tyrosine kinase receptors, the shift between tumor dormancy and proliferation, that usually precedes metastasis formation. Therefore, we investigated the role of uPAR expression in RAS mutated NSCLC and CRC cells. In this study we provided evidence, for the first time, that RAS mutational condition is functionally correlated to uPAR overexpression in NSCLC and CRC cancer cell lines and patient-derived tissue samples. Moreover, oncogenic features related to uPAR overexpression in RAS mutated NSCLC and CRC, such as adhesion, migration and metastatic process may be targeted, in vitro and in vivo, by new anti-uPAR small molecules, specific inhibitors of uPAR-vitronectin interaction. Therefore, anti-uPAR drugs could represent an effective pharmacological strategy for NSCLC and CRC patients carrying RAS mutations.

Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.

BACKGROUND: Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. METHODS: Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice. RESULTS: Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation. CONCLUSIONS: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.

Everolimus induces Met inactivation by disrupting the FKBP12/Met complex.

Inhibition of the mechanistic target of rapamycin (mTOR) is a promising treatment strategy for several cancer types. Rapamycin derivatives such as everolimus are allosteric mTOR inhibitors acting through interaction with the intracellular immunophilin FKBP12, a prolyl isomerase with different cellular functions. Although mTOR inhibitors have significantly improved survival of different cancer patients, resistance and lack of predictive factors of response remain unsolved issues. To elucidate the mechanisms of resistance to everolimus, we evaluated Met activation in everolimus-sensitive/resistant human cancer cells, in vitro and in vivo. Biochemical and computational analyses were performed. Everolimus-resistant cells were xenografted into mice (10/group) and studied for their response to everolimus and Met inhibitors. The statistical significance of the in vitro results was evaluated by Student's t test.Everolimus reduced Met phosphorylation in everolimus-sensitive cells. This event was mediated by the formation of a Met-FKBP12 complex, which in turn is disrupted by everolimus. Aberrant Met activation in everolimus-resistant cells and overexpression of wild-type/mutant Met caused everolimus resistance. Pharmacological inhibition and RNA silencing of Met are effective in condition of everolimus resistance (P<0.01). In mice xenografted with everolimus-resistant cells, the combination of everolimus with the Met inhibitor PHA665752 reduced tumor growth and induced a statistically significant survival advantage (combination vs control P=0.0005).FKBP12 binding is required for full Met activation and everolimus can inhibit Met. Persistent Met activation might sustain everolimus resistance. These results identify a novel everolimus mechanism of action and suggest the development of clinical strategies based on Met inhibitors in everolimus-resistant cancers.

Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status.

Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited. To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies. Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants. However, in live cells only saracatinib efficiently reduced EGFR activation, while dasatinib was the most effective agent in inhibiting Src TK. Consistently, a pronounced anti-proliferative effect was achieved with saracatinib, in EGFR mutant cells, or with dasatinib, in wt EGFR/Ras mutant cells, poorly dependent on EGFR and erlotinib-resistant. We then identified the most effective drug combinations to overcome resistance to EGFR inhibitors, both in vitro and in nude mice: in T790M EGFR erlotinib-resistant cells, saracatinib with the anti-EGFR mAb cetuximab; in Ras mutant erlotinib-resistant models, dasatinib with the MEK inhibitor selumetinib. Src inhibitors may act with different mechanisms in NSCLCs, depending on EGFR/Ras mutational profile, and may be integrated with EGFR or MEK inhibitors for different cohorts of NSCLCs.