Phase I clinical trial testing the dose escalation and expansion of Pressurized IntraThoracic Hyperthermic Aerosol Cisplatin administration (PITHAC) for the management of pleural carcinosis.

Background: Pleural carcinosis originates from various cancers. Its management consists in systemic therapies combined to dyspnea relief procedures. Prior studies have tested hyperthermic intrathoracic chemotherapy to treat pleural carcinosis with interesting patient survival results.

In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I.

We have observed that molecular constructs based on multiple apoA-I mimetic peptides attached to a branched scaffold display promising anti-atherosclerosis functions in vitro. Building on these promising results, we now describe chronic in vivo studies to assess anti-atherosclerotic efficacy of HDL-like nanoparticles assembled from a trimeric construct, administered over 10 weeks either ip or orally to LDL receptor-null mice. When dosed ip, the trimer-based nanolipids markedly reduced plasma LDL-cholesterol levels by 40%, unlike many other apoA-I mimetic peptides, and were substantially atheroprotective.

Bone marrow-derived HL mitigates bone marrow-derived CETP-mediated decreases in HDL in mice globally deficient in HL and the LDLr.

The objective of this study was to determine the combined effects of HL and cholesteryl ester transfer protein (CETP), derived exclusively from bone marrow (BM), on plasma lipids and atherosclerosis in high-fat-fed, atherosclerosis-prone mice. We transferred BM expressing these proteins into male and female double-knockout HL-deficient, LDL receptor-deficient mice (HL(-/-)LDLr(-/-)). Four BM chimeras were generated, where BM-derived cells expressed 1) HL but not CETP, 2) CETP and HL, 3) CETP but not HL, or 4) neither CETP nor HL.

Atherosclerosis induced by endogenous and exogenous toll-like receptor (TLR)1 or TLR6 agonists.

Atherosclerosis is a chronic inflammatory vascular disease. Toll-like receptors (TLRs) are major initiators of inflammation. TLR2 promotes atherosclerosis in LDL receptor (LDLr)-deficient mice fed a high-fat diet (HFD).

The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice.

Signaling through MyD88, an adaptor utilized by all TLRs except TLR3, is pro-atherogenic; however, it is unknown whether signaling through TIR-domain-containing adaptor-inducing interferon-β (TRIF), an adaptor used only by TLRs 3 and 4, is relevant to atherosclerosis. We determined that the TRIF(Lps2) lack-of-function mutation was atheroprotective in hyperlipidemic low density lipoprotein (LDL) receptor knockout (LDLr(-/-)) mice. LDLr(-/-) mice were crossed with either TRIF(Lps2) or TLR3 knockout mice.

Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites.

Through forward genetic screening in the mouse, a recessive mutation (couch potato, cpto) has been discovered that dramatically reduces plasma cholesterol levels across all lipoprotein classes. The cpto mutation altered a highly conserved residue in the Src homology domain 3 (SH3) domain of the Mia2 protein. Full-length hepatic Mia2 structurally and functionally resembled the related Mia3 protein.

Nonenzymatic glycation impairs the antiinflammatory properties of apolipoprotein A-I.

Objective: The goal of this study was to investigate the effects of nonenzymatic glycation on the antiinflammatory properties of apolipoprotein (apo) A-I.

Methods And Results: Rabbits were infused with saline, lipid-free apoA-I from normal subjects (apoA-I(N)), lipid-free apoA-I nonenzymatically glycated by incubation with methylglyoxal (apoA-I(Glyc in vitro)), nonenzymatically glycated lipid-free apoA-I from subjects with diabetes (apoA-I(Glyc in vivo)), discoidal reconstituted high-density lipoproteins (rHDL) containing phosphatidylcholine and apoA-I(N), (A-I(N))rHDL, or apoA-I(Glyc in vitro), (A-I(Glyc in vitro))rHDL. At 24 hours postinfusion, acute vascular inflammation was induced by inserting a nonocclusive, periarterial carotid collar.

Macrophage PLTP is atheroprotective in LDLr-deficient mice with systemic PLTP deficiency.

Systemic phospholipid transfer protein (PLTP) is a recognized risk factor for coronary heart disease. In apolipoprotein E-deficient mice, systemic PLTP deficiency is atheroprotective, whereas PLTP overexpression is proatherogenic. As expected, we also observed significantly smaller lesions (P < 0.

Atheroprotective potential of macrophage-derived phospholipid transfer protein in low-density lipoprotein receptor-deficient mice is overcome by apolipoprotein AI overexpression.

Objective: Using bone marrow transplantation, we assessed the impact of macrophage-derived phospholipid transfer protein (PLTP) on lesion development in hypercholesterolemic mice that expressed either normal levels of mouse apolipoprotein AI (apoAI) or elevated levels of only human apoAI.

Methods And Results: Bone marrow transplantations were performed in low-density lipoprotein receptor-deficient mice (LDLr-/-) that expressed either normal levels of mouse apoAI (msapoAI) or high levels of only human apoAI (msapoAI-/-, LDLr-/-, huapoAITg). Mice were lethally irradiated, reconstituted with either PLTP-expressing or PLTP-deficient bone marrow cells, and fed a high-fat diet over 16 weeks.

Participation of macrophages in atherosclerotic lesion morphology in LDLr-/- mice.

Lystbeige (beige) mice crossed with LDL receptor-deficient (LDLr-/-) mice had a distinct atherosclerotic lesion morphology that was not observed in LDLr-/- mice. This morphology is often associated with a stable plaque phenotype. We hypothesized that macrophage expression of the beige mutation accounted for this distinct morphology.

Apolipoprotein A-II inhibits high density lipoprotein remodeling and lipid-poor apolipoprotein A-I formation.

The high density lipoproteins (HDL) in human plasma are classified on the basis of apolipoprotein composition into those containing apolipoprotein (apo) A-I but not apoA-II, (A-I)HDL, and those containing both apoA-I and apoA-II, (A-I/A-II)HDL. Cholesteryl ester transfer protein (CETP) transfers core lipids between HDL and other lipoproteins. It also remodels (A-I)HDL into large and small particles in a process that generates lipid-poor, pre-beta-migrating apoA-I.

Evidence that phospholipids play a key role in pre-beta apoA-I formation and high-density lipoprotein remodeling.

The initial plasma acceptor of unesterified cholesterol and phospholipids from peripheral cells has been identified as pre-beta migrating, lipid-free, or lipid-poor apolipoprotein (apo) A-I (pre-beta apoA-I). Pre-beta apoA-I is formed when plasma factors, such as cholesteryl ester transfer protein (CETP), remodel high-density lipoproteins (HDL). The aim of this study is to determine how phospholipids influence pre-beta apoA-I formation during the CETP-mediated remodeling of HDL.

CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation.

CARMA1 is a lymphocyte-specific member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, which coordinate signaling pathways emanating from the plasma membrane. CARMA1 interacts with Bcl10 via its caspase-recruitment domain (CARD). Here we investigated the role of CARMA1 in T cell activation and found that T cell receptor (TCR) stimulation induced a physical association of CARMA1 with the TCR and Bcl10.