Variation of Plasma Damage-Associated Molecular Patterns in Patients with Advanced Solid Tumors after Standard of Care Systemic Treatment.

BACKGROUND: Immunogenic cell death (ICD) is known for releasing damage-associated molecular patterns (DAMPs) from tumor cells. We aimed to find ICD signals by assessing the variation of plasmatic DAMPs (HMGB1, S100A8) before-after standard of care (SoC) systemic treatment in patients with advanced solid tumors. METHODS: Patients scheduled to start a new line of systemic treatment were included. Plasmatic concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. RESULTS: Fifty-two patients were included. Forty-four patients (85%) had metastases, and 8 (15%) were treated for stage III tumors. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment in the first-line setting. Thirty-six patients (69%) were treated chemotherapy (CT) alone, ten (19%) CT plus targeted therapy, two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Median plasmatic concentration of S100A8 was significantly higher before than after treatment in the whole population (3.78 vs. 2.91 ng/mL; p = 0.011) and more markedly in the subgroups of patients who experienced RECIST-assessed tumor response (5.70 vs. 2.63 ng/mL; p = 0.002). Median plasmatic concentration of HMGB1was not significantly different before and after treatment (10.23 vs. 11.85 ng/mL; p = 0.382) and did not differ depending on tumor response. Median PFS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (8.0 vs. 10.6 months; p = 0.29) after treatment. Median PFS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (12 vs. 4.7 months; p < 0.001). Median OS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (13.1 vs. 14.7 months; p = 0.46) after treatment. Median OS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (16.7 vs. 9.0 months; p < 0.001). CONCLUSIONS: Signals of ICD were not observed. S100A8 behaves as an inflammatory marker with decreased concentration after treatment, mostly in RECIST-responders. PFS and OS were significantly prolonged in those patients who experienced a decrease of S100A8 compared with those patients who experienced increase of plasma S100A8 at three months.

Clinical outcomes and safety of passive leg raising in out-of-hospital cardiac arrest: a randomized controlled trial.

BACKGROUND: There are data suggesting that passive leg raising (PLR) improves hemodynamics during cardiopulmonary resuscitation (CPR). This trial aimed to determine the effectiveness and safety of PLR during CPR in out-of-hospital cardiac arrest (OHCA). METHODS: We conducted a randomized controlled trial with blinded assessment of the outcomes that assigned adults OHCA to be treated with PLR or in the flat position. The trial was conducted in the Camp de Tarragona region. The main end point was survival to hospital discharge with good neurological outcome defined as cerebral performance category (CPC 1-2). To study possible adverse effects, we assessed the presence of pulmonary complications on the first chest X-rays, brain edema on the computerized tomography (CT) in survivors and brain and lungs weights from autopsies in non-survivors. RESULTS: In total, 588 randomized cases were included, 301 were treated with PLR and 287 were controls. Overall, 67.8% were men and the median age was 72 (IQR 60-82) years. At hospital discharge, 3.3% in the PLR group and 3.5% in the control group were alive with CPC 1-2 (OR 0.9; 95% CI 0.4-2.3, p = 0.91). No significant differences in survival at hospital admission were found in all patients (OR 1.0; 95% CI 0.7-1.6, p = 0.95) and among patients with an initial shockable rhythm (OR 1.7; 95% CI 0.8-3.4, p = 0.15). There were no differences in pulmonary complication rates in chest X-rays [7 (25.9%) vs 5 (17.9%), p = 0.47] and brain edema on CT [5 (29.4%) vs 10 (32.6%), p = 0.84]. There were no differences in lung weight [1223 mg (IQR 909-1500) vs 1239 mg (IQR 900-1507), p = 0.82] or brain weight [1352 mg (IQR 1227-1457) vs 1380 mg (IQR 1255-1470), p = 0.43] among the 106 autopsies performed. CONCLUSION: In this trial, PLR during CPR did not improve survival to hospital discharge with CPC 1-2. No evidence of adverse effects has been found. Clinical trial registration ClinicalTrials.gov: NCT01952197, registration date: September 27, 2013, https://clinicaltrials.gov/ct2/show/NCT01952197 .

A possible role for CCR5 in the progression of atherosclerosis in HIV-infected patients: a cross-sectional study.

BACKGROUND: Chemokines can block viral entry by interfering with HIV co-receptors and are recognised mediators of atherosclerosis development. A number of experimental drugs that inhibit HIV entry arrest the development of atherosclerosis in animal models. We hypothesised that the expression of chemokine receptors in circulating leukocytes is associated with the rate of atherosclerosis progression in HIV-infected patients. METHODS: The increase in intima-media thickness during a 2-year follow-up was used to classify HIV-infected patients (n = 178) as progressors (n = 142) or non-progressors (n = 36) with respect to atherosclerosis. Logistic regression was used to assess variables associated with atherosclerosis progression. Mutations in the CCR5Δ32, CCR2 64I, and CX3CR1 (T280M and V249I) co-receptors as well as the levels of CCR5, CXCR4, CX3CR1, and CCR2 mRNA expression in circulating leukocytes were analysed as independent variables. RESULTS: Among the baseline variables, only genetic variants explained the dichotomous outcome. The expression of CCR2 and CXCR4 did not discriminate between progressors and non-progressors. Conversely, CCR5 and CX3CR1 expression was higher in not only progressors but also patients with detectable viral load. The logistic regression, however, demonstrated a significant role for CCR5 expression as a predictor of atherosclerosis progression (B = 2.1, OR = 8.1, p = 0.04) and a negligible effect for CXC3R1 and CCR2 expression. CONCLUSIONS: Available CCR5 antagonists should be investigated for their potential to delay the course of atherosclerosis in HIV-infected patients.

The deleterious influence of tenofovir-based therapies on the progression of atherosclerosis in HIV-infected patients.

We investigated the potential differential effects of antiretroviral therapies on unbalanced chemokine homeostasis and on the progression of atherosclerosis in HIV-infected patients. A two-year prospective study was performed in 67 consecutive HIV-infected patients initiating antiretroviral therapy with abacavir/lamivudine or tenofovir/emtricitabine. Circulating levels of inflammatory biomarkers, progression of subclinical atherosclerosis and expression levels of selected chemokines genes in circulating leukocytes were assessed. Control subjects showed significantly lower plasma concentrations of CRP, tPA, IL-6, and MCP-1 than HIV-infected patients at a baseline. After two years of followup, the observed decreases in plasma inflammatory biomarker levels were only significant for MCP-1, tPA, and IL-6. The decrease in plasma MCP-1 concentration was associated with the progression of atherosclerosis, and this effect was negligible only in patients receiving TDF-based therapy. Multivariate analysis confirmed that treatment with TDF was positively and significantly associated with a higher likelihood of subclinical atherosclerosis progression. However, the expression levels of selected genes in blood cells only showed associations with the viral load and total and HDL-cholesterol levels. Current antiretroviral treatments may partially attenuate the influence of HIV infection on certain inflammatory pathways, though patients receiving TDF therapy must be carefully monitored with respect to the presence and/or progression of atherosclerosis.

Serum paraoxonase-3 concentration is associated with insulin sensitivity in peripheral artery disease and with inflammation in coronary artery disease.

OBJECTIVE: There are no data on the relationship between serum paraoxonase-3 (PON3) concentration and atherosclerosis in humans. Our aim was to investigate possible associations, using recently developed methods, in patients with peripheral artery disease (PAD) or coronary artery disease (CAD). METHODS: We studied 118 PAD and 72 CAD patients and 175 healthy volunteers. Serum PON3 was determined by in-house ELISA using polyclonal antibodies generated against a synthetic peptide with a sequence specific to PON3. Polymorphisms of the PON3 promoter were analysed by the Iplex Gold MassArray™ method. RESULTS: There was a significant increase in serum PON3 concentration in both groups of patients with respect to the control group. In PAD patients, we observed significant positive correlations between PON3, insulin levels and HOMA index. These associations were not observed in CAD. There were significant positive associations between serum PON3 and ß-2-microglobulin, CCL2 and high-sensitivity C-reactive protein in CAD patients, but not in PAD. We did not find any significant differences in PON3 gene promoter polymorphisms and their haplotypes between patients and controls, indicating that associations were not genetically determined. CONCLUSION: In both atherosclerotic phenotypes, serum PON3 concentration was increased, but this was associated with decreased insulin sensitivity in PAD and with inflammation in CAD.

Antiretroviral treatment-induced dyslipidemia in HIV-infected patients is influenced by the APOC3-related rs10892151 polymorphism.

BACKGROUND: The recently observed association between the APOC3-related rs10892151 polymorphism and serum triglyceride levels has prompted us the possibility to explore whether this genetic variant may play a major role in human immunodeficiency virus (HIV)/antiretroviral therapy-induced dyslipidemia. METHODS: We determined the rs10892151 genotype distribution and serum apolipoprotein (apo) C-III concentration in a group of HIV-infected patients (n = 208) and in a group of age and sex-matched healthy volunteers (n = 200). Circulating lipid and lipoprotein levels were followed for 12 months after antiretroviral treatment initiation in the HIV-infected group. RESULTS: There were no significant variations in the frequency of the A allele between the healthy and HIV-infected groups (7.5 vs. 8.6%, respectively; p = 0.7); additionally, the A allele was not related to serum apo C-III concentration. However, among patients receiving protease inhibitor (PI) treatment, carriers of the A allele had significantly increased serum triglyceride (5.76 ± 2.54 mmol/L) and total cholesterol (6.63 ± 2.85 mmol/L) concentrations together with depressed levels of HDL-cholesterol (0.75 ± 0.3 mmol/L) when compared with patients not carrying the allele (2.43 ± 1.32, 5.2 ± 2.17 and 1.24 ± 0.4 mmol/L, respectively) at the end of the study. This effect was only evident for HDL-cholesterol concentration when patients were treated with non-nucleoside reverse transcriptase inhibitors (1.05 ± 0.4 vs. 1.28 ± 0.4 mmol/L). CONCLUSIONS: The A allelic variant of the rs10892151 polymorphism is not associated with serum apo C-III concentration, but predisposes HIV-infected patients to less favorable lipid profile, particularly in those patients treated with PIs.

Host-pathogen interactions in the development of metabolic disturbances and atherosclerosis in HIV infection: the role of CCL2 genetic variants.

BACKGROUND: Circulating CCL2 concentration has been implicated in promoting atherosclerosis in patients infected with HIV. We evaluated whether CCL2 gene variants are associated with metabolic disturbances and plasma CCL2 levels in HIV-infected patients. METHODS AND RESULTS: CCL2 genotypes and estimated haplotypes, plasma CCL2 levels and indicators of metabolic status in HIV-infected patients were compared with a representative group of the general population. We also performed a carotid/femoral artery ultrasonography to detect sub-clinical atherosclerosis in these patients. Six haplotypes were estimated in more than the 5% of individuals, and accounted for more than 98% of the population. In HIV-infected patients, carriers of H1, H2 and H5 haplotypes had higher CCL2 concentration than carriers of H3, H4 and H6 haplotypes. However, only carriers of H1 and H5 haplotypes presented higher insulin resistance as well as higher proportion of patients affected with sub-clinical. Conversely, carriers of H2 haplotype, which also showed high plasma CCL2 concentration, were associated with less deleterious metabolic disturbances. CONCLUSIONS: Our data are consistent with the hypothesis that the genetic background of the host is involved in CCL2 production and that this chemokine is implicated in promoting metabolic disturbances and sub-clinical atherosclerosis in HIV-infected patients.

Human immunodeficiency virus-infection induces major changes in high-density lipoprotein particle size distribution and composition: the effect of antiretroviral treatment and disease severity.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with abnormal high-density lipoprotein (HDL) particles. We evaluated whether HIV infection and antiretroviral treatment promotes changes in cholesterol distribution among subpopulations of HDL particles of defined sizes. METHODS: HDL particles were isolated from 78 HIV infected patients and fractionated by gel permeation chromatography to obtain five subpopulations. Thirty-six patients were antiretroviral treatment naïve, while 42 patients were treated with efavirenz or protease inhibitors. Uninfected individuals were also included as controls. RESULTS: The distribution of cholesterol across HDL particle sizes was affected by HIV infection itself. Antiretroviral therapy reduced these alterations; only minor changes in small and very small HDL particles were observed in treated patients (p=0.01). Untreated patients with low CD4+ T cell counts had less cholesterol in medium (p=0.006), small (p=0.04) and very small (p=0.03) HDL particles. Treated patients with high CD4+ T cell counts had less cholesterol in the largest HDL particles (p=0.04), with overall particle distributions resembling those observed in uninfected participants. CONCLUSIONS: HIV infection itself may promote major changes in cholesterol distribution among HDL subpopulations that could be partially attenuated by current antiretroviral treatments. Further studies in larger populations are necessary to confirm the impact of HIV on lipoprotein composition and distribution.

Treatment of hypertriglyceridemia and HIV: fenofibrate-induced changes in the expression of chemokine genes in circulating leukocytes.

Fenofibrate changed the expression of chemokine genes in circulating leukocytes of HIV-infected patients with hypertriglyceridemia. The data suggest that fenofibrate when effective in the treatment of lipoprotein abnormalities, may act as a modulator of systemic inflammation. This particular action, therefore, may also influence the clinical course of the disease.