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Purpose: Angiogenesis is an essential process for solid tumor development. To interfere with angiogenesis, AdPPE3x-E1, an adenovirus that is transcriptionally targeted to replicate in angiogenic endothelial cells, was constructed, by replacing the E1 promoter with the modified preproendothelin-1 promoter, PPE-1-3x, previously shown to induce specific transcription in angiogenic endothelial cells.Experimental Design: The specificity of AdPPE3x-E1 to endothelial cells was shown by quantitative PCR and immunostaining, and its antiangiogenic effect was evaluated in Matrigel models. The in vivo efficacy of AdPPE3x-E1 was also tested in a cotton rat lung metastases model.Results: The replication rate of AdPPE3x-E1 in endothelial cells was similar to that of AdCMV-E1, a nonselective replicating adenovector, but the replication rate was reduced up to 60-fold in nonendothelial cells. Moreover, AdPPE3x-E1 reduced endothelial cell viability by 90% whereas nonendothelial cells were not affected. In in vitro and in vivo Matrigel models, endothelial cells infected with AdPPE3x-E1 did not develop capillary-like structures. The systemic administration of AdPPE3x-E1 reduced the lung metastases burden in a cotton rat model by 55%, compared with saline-treated rats, without significant evidence of toxicity. Quantitative PCR analysis showed that the viral copy number of AdPPE3x-E1 was increased 3-fold in the lung metastases but not in the liver, compared with a nonreplicating adenovector control.Conclusions: We have shown here for the first time an antimetastatic effect induced by an angiogenesis-transcriptionally targeted adenovirus following systemic administration. Because adenovirus replication is more efficient in humans than in cotton rats, we assume a significant effect for AdPPE3x-E1 treatment in fighting human solid tumors and metastases.

Supplementary Figure S1 from Systemic Administration of a Conditionally Replicating Adenovirus, Targeted to Angiogenesis, Reduced Lung Metastases Burden in Cotton Rats

We assess the immunogenicity and efficacy of Spikevax and Comirnaty as fourth dose COVID-19 vaccines. Six months post-fourth-dose, IgG levels were higher than pre-fourth dose at 1.58-fold (95% CI: 1.27–1.97) in Spikevax and 1.16-fold (95% CI: 0.98–1.37) in Comirnaty vaccinees. Nearly 60% (159/274) of vaccinees contracted SARS-CoV-2. Infection hazard ratios (HRs) for Spikevax (0.82; 95% CI: 0.62–1.09) and Comirnaty (0.86; 95% CI: 0.65–1.13) vaccinees were similar, as were substantial-disease HRs, i.e. 0.28 (95% CI: 0.13–0.62) and 0.51 (95% CI: 0.27–0.96), respectively.

Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose study, comparing BNT162b2 and mRNA1273, administered four months after a third BNT162b2 dose. Waning of the immune response was evident during follow-up, with an 11% (ß=0.89, 95% CI, 0.88–0.9) and 21% (ß=0.79, 95% CI, 0.76–0.82) multiplicative decay per week of IgG and neutralizing antibodies, respectively, in the mRNA1273 group, and of 14% (ß=0.86, 95% CI, 0.86–0.87) and 26% (ß=0.74, 95% CI, 0.72–0.76), respectively, in the BNT162b2 group. Direct neutralization of Omicron variants was low relative to ancestral strains. Cumulatively over the study period, both vaccines showed little efficacy against infection but were highly efficacious against substantial disease [89% [(IRR 0.11, 95% CI, 0.02–0.37) and 71% (IRR 0.29, 95% CI, 0.13–0.57) for mRNA1273 and BNT162b2, respectively]. These results are informative for further boosting policy-making.

Objective Report final results of a phase I/II study of VB-111, a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response, in combination with paclitaxel in patients with platinum-resistant ovarian cancer. Methods Study NCT01711970 was a prospective, open label, dose escalation study assessing combination treatment of VB-111 and weekly paclitaxel. In the Phase I part of the study, patients were treated with escalating doses of intravenous VB-111 and paclitaxel. In Phase 2, patients were treated with therapeutic doses of VB-111 and paclitaxel 80 mg/m2. Assessments included safety, overall survival (OS), progression free survival (PFS), and tumor response (CA-125 and RECIST). Results 21 patients with recurrent platinum-resistant ovarian cancer were enrolled. 17/21 received the therapeutic dose. Patients had a median of 3 prior lines of therapy. Half of the subjects were platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and associated with mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients. The median OS was 16.6 months in patients treated with therapeutic dose compared to 5.8 months in sub-therapeutic dose (p = 0.028). Tumor specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells in regions of apoptotic cancer cells. Conclusions Treatment with VB-111 in combination with paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect.

Background and aims Mediterranean diet has been associated with decreased cardiovascular morbidity and mortality. Both fish and olive oil are key components of this diet. Therefore, we compared their effects on nonalcoholic fatty liver disease (NAFLD) and atherogenesis in a mouse model, fed a high fat diet. Methods and results Forty nine, female LDL receptor knockout (LDLR KO) mice were allocated into 3 groups and fed an atherogenic high fat (HF) diet for 9 weeks. The HF group was fed a high fat diet alone. A HF + OO group was fed a HF diet with added olive oil (60 ml/kg feed), and the third group (HF + FO) was fed a HF diet with added fish oil (60 ml/kg feed). Both additions of fish and olive oil, significantly decreased plasma cholesterol elevation compared to HF diet. Nevertheless, only fish oil addition reduced significantly atherosclerotic lesion area by 51% compared to HF group. Liver levels of eicosapentenoic (EPA) and docosahexaenoic (DHA) acids were several folds higher in HF + FO group than in HF and HF + OO groups. Liver levels of oleic acid were higher in HF + OO compared to the other groups. Moreover, Fish oil addition significantly decreased NAFLD scores related to steatosis and inflammation and lowered the expression of the inflammatory genes interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1). Conclusion These results suggest that fish oil addition on top of an atherogenic, HF diet, is beneficial, while olive oil is not, in its effect on plaque formation and NAFLD in LDLR KO mice.

BACKGROUNDFollowing the emergence of the Omicron variant of concern, we investigated immunogenicity, efficacy and safety of BNT162b2 or mRNA1273 fourth dose in an open-label, clinical intervention trial.METHODSPrimary end-points were safety and immunogenicity and secondary end-points were vaccine efficacy in preventing SARS-CoV-2 infections and COVID-19 symptomatic disease. The two intervention arms were compared to a matched control group. Eligible participants were healthcare-workers (HCW) vaccinated with three BNT162b2 doses, and whose IgG antibody levels were ≤700 BAU (40-percentile). IgG and neutralizing titers, direct neutralization of live VOCs, and T-cell activation were assessed. All participants were actively screened for SARS-CoV-2 infections on a weekly basis.RESULTSOf 1050 eligible HCW, 154 and 120 were enrolled to receive BNT162b2 and mRNA1273, respectively, and compared to 426 age-matched controls. Recipients of both vaccine types had a ∼9-10-fold increase in IgG and neutralizing titers within 2 weeks of vaccination and an 8-fold increase in live Omicron VOC neutralization, restoring titers to those measured after the third vaccine dose. Breakthrough infections were common, mostly very mild, yet, with high viral loads. Vaccine efficacy against infection was 30% (95%CI:-9% to 55%) and 11% (95%CI:-43% to +43%) for BNT162b2 and mRNA1273, respectively. Local and systemic adverse reactions were reported in 80% and 40%, respectively.CONCLUSIONSThe fourth COVID-19 mRNA dose restores antibody titers to peak post-third dose titers. Low efficacy in preventing mild or asymptomatic Omicron infections and the infectious potential of breakthrough cases raise the urgency of next generation vaccine development.Trial registration numberclicaltrials.gov: NCT05231005, NCT05230953

Background Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. Objectives The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. Methods Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, β-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). Results We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. Conclusions Multiple serum and adipose tissue carotenoids are associated with favorable metabolic traits, including insulin sensitivity in liver and adipose tissue in humans.

BackgroundStudies of longevity examined apolipoprotein E (ApoE), a gene involved in lipoprotein metabolism, which interacts with susceptibility to age-related diseases, and with mortality. We evaluated the association of ApoE isoforms with cardiovascular disease (CVD) and all-cause mortality.MethodsA prospective cohort of 949 survivors of the Israel Study of Glucose Intolerance, Obesity, and Hypertension, examined during 1999–2004, mean age 72 years, was followed for mortality until 2017. Participants were interviewed for lifestyle habits and medical history. Anthropometrics and biochemical markers were taken. Logistic regression was used to assess CVD morbidity and Cox proportional hazard model for mortality.ResultsThe most common genotype in the cohort was ApoE E3 (76.3%), with the other two almost equally distributed (ApoE E2 11.2% and ApoE E4 12.5%). In men only, ApoE E4 associated with CVD (adjusted odds ratio = 1.46, 95% confidence interval [CI] 0.76, 2.80) and with 18-year mortality (adjusted hazard ratio = 1.47, 95% CI 0.95, 2.26), adjusting for age, ethnicity, physical activity, hypertension, diabetes, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides and lipid-lowering medications. Low levels of HDL cholesterol, adjusted for ApoE and the above-mentioned variables, associated with higher prevalence of CVD (adjusted odds ratio = 1.35, 95% CI 1.00, 1.83) and all-cause mortality (adjusted hazard ratio = 1.42, 95% CI 1.14, 1.78). ApoE E3 and E2 conferred a lower 18-year mortality risk in the physically active individuals, compared to the sedentary (adjusted hazard ratio = 0.57, 95% CI 0.44, 0.74, and adjusted hazard ratio = 0.53, 95% CI 0.78, 1.02, respectively).ConclusionsIn community-dwelling older adults, sociodemographic characteristics and physical activity, blood pressure and HDL-cholesterol levels, may outweigh the impact of ApoE polymorphisms on CVD morbidity and all-cause mortality.

TPS5606 Background: Ofranergene obadenovec (Ofra-vec, VB-111) is an anti-cancer gene based immune activator and targeted vascular disruptor. The dual mechanism of action triggers a broad antiangiogenic effect and induces of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer (PROC) demonstrated that ofra-vec in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58%, a trend for improved survival and induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a pivotal phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent PROC and may have been previously treated with up to 5 prior lines of therapy (but not >2 for PROC). Patient are randomized 1:1 to receive ofra-vec (1x1013 Viral Particles) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The dual primary endpoints are OS and PFS. A pre-planned interim analysis of CA-125 response (GCIG) performed by the DSMC met the pre-defined criteria showing that CA-125 ORR in the treatment arm was at least 10% higher than in the control arm. Study is enrolling in the US, EU, Japan and Israel, with 90% enrollment to date. Completion of accrual is anticipated in Q1 2022. Clinical trial information: NCT03398655.

TPS2075 Background: Ofranergene obadenovec (ofra-vec, VB-111) is an anti-cancer gene based immune activator and targeted vascular disruptor. The dual mechanism of action triggers a broad antiangiogenic effect and induces of a tumor directed immune response. A previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with ofra-vec monotherapy, that was continued after progression in combination with bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of ofra-vec will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses. Methods: Study NCT04406272 is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy ofra-vec in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous ofra-vec prior to resection, and ofra-vec every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and ofra-vec every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care; however, ofra-vec will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is to evaluate the influence of neoadjuvant ofra-vec on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, 6mPFS and OS. Study is open for enrolment. Clinical trial information: NCT04406272.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Vitamin A deficiency (VAD) is a major health problem, especially in developing countries. In this study, we investigated the effect of VAD from weaning to adulthood in apoE-/- mice. Three-week-old male mice were allocated into four diet groups: I. VAD II. VAD+vitamin A (VA), 1500 IU retinyl-palmitate, III. VAD+&beta, carotene (BC), 6 g/kg feed, containing 50% all-trans and 50% 9-cis BC. IV. VAD with BC and VA (BC+VA). After 13 weeks, we assessed the size of atherosclerotic plaques and measured VA in tissues and BC in plasma and tissues. VAD resulted in diminished hepatic VA levels and undetectable brain VA levels compared to the other groups. BC completely replenished VA levels in the liver, and BC+VA led to a two-fold elevation of hepatic VA accumulation. In adipose tissue, mice fed BC+VA accumulated only 13% BC compared to mice fed BC alone. Atherosclerotic lesion area of BC group was 73% lower compared to VAD group (p &lt, 0.05). These results suggest that BC can be a sole source for VA and inhibits atherogenesis.

Maternal docosahexaenoic acid (DHA) is required during pregnancy to supply for normal fetal growth and development. This pilot study aimed to assess the unknown fatty acid (FA) composition in a cohort of non-pregnant and pregnant Israeli women at term and their offspring on a normal diet without n-3 FA supplementation. The fatty acid profile, analyzed using gas chromatography, showed significantly higher plasma monounsaturated (MUFA) and lower n-6 FA percent distribution with similar n-3 index, in pregnant compared to non-pregnant women. RBC exhibited significantly higher MUFA with similar n-3 index, in pregnant compared to non-pregnant women. N-3 FA significantly correlated between neonates’ plasma, with higher n-3 index, and pregnant women's DHA. Conclusion: DHA levels in non-pregnant and pregnant Israeli women at term were comparable and the DHA in pregnant women's plasma positively correlated with their neonate's level, suggesting an efficient mother-fetus FA transfer and/or fetal fatty acid metabolism to longer FA products.

Background Poor cardiovascular health (CVH) among ethnic/racial minorities, studied primarily in the USA, may reflect lower access to healthcare. We examined factors associated with minority CVH in a setting of universal access to healthcare. Methods and results CVH behaviors and factors were evaluated in a random population sample (551 Arabs, 553 Jews) stratified by sex, ethnicity and age. More Jews (10%) than Arabs (3%) had 3 ideal health behaviors. Only one participant had all four. Although ideal diet was rare (≤1.5%) across groups, Arabs were more likely to meet intake recommendations for whole grains, but less likely to meet intake recommendations for fruits/vegetables and fish. Arabs had lower odds of attaining ideal levels for body mass index and physical activity. Smoking prevalence was 57% among Arab men and 6% among Arab women. Having four ideal health factors (cholesterol, blood pressure, glucose, smoking) was observed in 2% and 8% of Arab and Jewish men, respectively, and 13% of Arab and Jewish women. Higher prevalence of ideal total-cholesterol corresponded to lower high-density lipoprotein cholesterol among Arabs. No participant met ideal levels for all 7 metrics and only 1.8% presented with 6. Accounting for age and lower socioeconomic status, Arabs were less likely to meet a greater number of metric goals (odds ratio (95% confidence interval): 0.62 (0.42–0.92) for men, and 0.73 (0.48–1.12) for women). Conclusions Ideal CVH, rare altogether, was less prevalent among the Arab minority albeit universal access to healthcare. Health behaviors were the main contributors to the CVH disparity.

TPS5599 Background: Ofranergene obadenovec (VB-111) is a targeted anti-cancer gene therapy with a dual mechanism of action that includes a broad antiangiogenic effect and induction of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer showed that VB-111 in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58% with a trend for improved survival. The favorable outcomes were associated with induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent platinum-resistant epithelial ovarian cancer with measurable disease (RECIST 1.1), and may have been previously treated with up to 5 prior lines of therapy. Patient are randomized 1:1 to receive VB-111 (1x1013 VPs) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The efficacy endpoints are OS, PFS and ORR by RECIST 1.1 and by CA-125 (GCIG criteria). A pre-planned interim analysis was performed by the DSMC in the first 60 patients evaluable for CA-125 response. The analysis met the pre-defined criteria of a CA-125 ORR (GCIG) in the treatment arm at least 10% higher than in the control arm. Study enrolment is ongoing and over 220 patients were enrolled in the US, EU, and Israel. Enrolment of the full sample size of 400 patients is expected to complete by the end of 2021. Clinical trial information: NCT03398655.

Docosahexaenoic acid (DHA) is critical for normal brain development and function. DHA is in danger of being significantly reduced in the human food supply, and the question of whether its metabolic precursor, the essential n-3 alpha linolenic acid (ALA) during pregnancy, can support fetal brain DHA levels for optimal neurodevelopment, is fundamental. Female mice were fed either ALA-enriched or Control diet during pregnancy and lactation. The direct effect of maternal dietary ALA on lipids was analyzed in liver, red blood cells, brain and brain vasculature, together with genes of fatty acid metabolism and transport in three-week-old offspring. The long-term effect of maternal dietary ALA on brain fatty acids and memory was studied in 19-week-old offspring. Three-week-old ALA offspring showed higher levels of n-3 fatty acids in liver, red blood cell, blood-brain barrier (BBB) vasculature and brain parenchyma, DHA enrichment in brain phospholipids and higher gene and protein expression of the DHA transporter, major facilitator superfamily domain containing 2a, compared to Controls. 19-week-old ALA offspring showed higher brain DHA levels and better memory performance than Controls. The increased brain DHA levels induced by maternal dietary ALA during pregnancy-lactation, together with the up-regulated levels of major facilitator superfamily domain containing 2a, may indicate a mode for greater DHA uptake with long-term impact on better memory in ALA offspring.

Hypertension, advanced age, postprandial hyperlipidemia, and insulin resistance are major risk factors for atherosclerosis. The calcium channel blocker nifedipine is reported to ameliorate insulin resistance possibly by activating PPARγ. This is expected to become accentuated in elderly individuals due to age-related insulin resistance. Insulin resistance modulates lipoprotein metabolism. Therefore, we reasoned that nifedipne offers the potential for improving postprandial lipemia in association with increasing age. We studied the effect of nifedipine on fasting lipids, postprandial lipemia, insulin sensitivity, and plasma lipolytic activity in 24 and 15 hypertensive subjects aged 70-75 years and 40-45 years, respectively. As expected, nifedipine significantly lowered systolic and diastolic blood pressure. Nifedipine decreased fasting triglyceride level (23%) and increased HDL-C (15%) in the elderly group. At baseline, postprandial triglyceride levels were remarkably elevated in elderly compared to younger patients (1 288±798 vs. 501±260 mg·dl(-1)·h, p

TPS6097 Background: Ofranergene obadenovec (VB-111) is a targeted anti-cancer gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed viral immune response. In a phase II trial in platinum resistant ovarian cancer VB-111 in combination with weekly paclitaxel showed a CA-125 response rate (RR) of 58% and median overall survival (OS) of 498 days compared to 172.5 days in the sub-therapeutic dose (p = 0.028). The combination treatment was well tolerated. Favorable outcomes were associated with induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a phase III randomized controlled trial, VB-111-701/GOG-3018 (OVAL) was initiated in collaboration with the GOG Foundation, Inc. Methods: The OVAL study, NCT03398655, is an international, randomized, double-blind, placebo-controlled, phase III study. Patients with recurrent platinum-resistant epithelial ovarian cancer, who have measurable disease (RECIST 1.1) and were previously treated with up to 5 lines are randomized 1:1 to receive VB-111 (1x1013 VPs) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. Treatment beyond asymptomatic RECIST progression may continue until progression is confirmed by follow up imaging. The primary endpoints are OS, safety and tolerability. Secondary endpoints include progression free survival, and objective RR by CA-125 (per GCIG criteria) and RECIST 1.1. The sample size calculation of 400 patients (event driven) provides 92% power to detect a difference in survival at the two-sided 5% significance level using the logrank test. A pre-planned interim analysis will take place in Q1 2020 to assess whether the CA-125 RR per GCIG criteria in the treatment arm is sufficiently larger than in the control arm and is comparable to the positive results of the phase II study. Study enrolment is ongoing and over 80 patients were enrolled in the US and Israel. Enrollment expansion to Europe is planned in 2020. Clinical trial information: NCT03398655.

Purpose Lipoxygenases (LOX) have been implicated in carcinogenesis, however both pro- and anti-carcinogenic effects have been reported in different cancer models. Using transgenic mice, which specifically overexpress human 15-lipoxygenase (ALOX15) in endothelial cells (EC), we previously demonstrated significant inhibition of tumor development. In the Lewis lung carcinoma (LLC) model, the primary tumor developed similarly in both wild type (WT) and ALOX15 overexpressing mice. However, metastases development was significantly inhibited in the transgenic mice. Here, we explored the molecular basis for the anti-metastatic effect of endothelial cell specific ALOX15 overexpression. Materials/methods We used ALOX15 overexpressing mice, and in-vitro cell model to evaluate the molecular effect of ALOX15 on EC and LLC cells. Results When LLC cells were injected in WT and ALOX15 overexpressing mice, we observed a higher degree of apoptosis and necrosis in primary and metastatic tumors of ALOX15 overexpressing animals. These anti-carcinogenic and anti-metastatic effects were paralleled by augmented expression of cyclin-dependent kinase inhibitor 1A (CDKN1A; p21) and of the peroxisome proliferators-activated receptor (PPAR)γ and by downregulation of the steady state concentrations of connexin26 mRNA. Consistent with these in vivo effects, ALOX15 overexpression in LLC and HeLa cancer cells in vitro significantly reduced cell viability in culture. In contrast, similar treatment of non-cancerous B2B epithelial cells did not impact cell viability. Conclusions Taken together, our data suggests that endothelial cell specific overexpression of ALOX15 promotes apoptosis and necrosis in primary and metastatic tumors in mice, by upregulation of P21 and PPARγ expression in adjacent cancer cells.

Klotho is a transmembrane protein, expressed mainly in the kidneys and the choroid plexus. The extracellular domain of klotho is composed of 2 internal repeats, KL1 and KL2, which can be cleaved and act as hormones. Klotho-deficient mice develop a phenotype resembling human aging. Laboratory and clinical data suggest a favorable effect of klotho on atherosclerosis, high blood pressure, and metabolic syndrome. Therefore, we aimed to study the effect of klotho treatment on atherogenesis, blood pressure, and metabolic parameters in experimental rodent models. Fructose-fed Sprague-Dawley rats (metabolic syndrome model) and apolipoprotein E (apoE -/-) knock-out mice (atherosclerosis model) were treated with either klotho or its active domain KL1. In apoE -/- mice, klotho unexpectedly elevated plasma cholesterol and triglyceride levels compared to the control group. Yet, it did not increase the aortic sinus atherosclerotic lesion area. In fructose-fed Sprague-Dawley rats, klotho treatment did not lower blood pressure or plasma triglyceride levels. Although KL1 treatment did not lower blood pressure or plasma insulin levels, it significantly reduced the elevation of total plasma triglyceride levels (from 2.3-fold to 1.6-fold, p0.05) due to lower triglyceride-rich VLDL levels. Klotho did not show any beneficial effects on atherosclerosis and components of the metabolic syndrome and was associated with increased plasma cholesterol levels. On the other hand, treatment with KL1 may lower plasma triglyceride levels independent of insulin. Additional studies are required in order to decipher the complex role of klotho and its active domains in the regulation of plasma lipid levels.

Background: Several epidemiological studies have shown that diets rich in carotenoids are associated with a reduced risk of cardiovascular disease. However, administration of synthetic all-trans -carotene was reported to have no effect on cardiovascular disease. We previously showed that the 9-cis -carotene-rich powder of the alga Dunaliella bardawil inhibits atherogenesis and reduces plasma non-HDL cholesterol levels in mice. Context and purpose of this study: We sought to study whether isolated 9-cis -carotene inhibits atherogenesis in a murine model of atherosclerosis. Results: Twelve-week-old female LDL receptor knockout mice (LDLR-/-) were pretreated for 2 weeks with regular chow diet fortified with the alga Dunaliella powder, 9-cis β-carotene isomer, all-trans β-carotene isomer, or 9-cis retinoic acid, followed by 10 weeks of a high-fat diet with the same fortifications. In contrast to Dunaliella, 9-cis β-carotene did not inhibit the high fat dietinduced elevation of plasma cholesterol. In addition, diet fortification with Dunaliella powder, β-carotene isomers, or 9-cis retinoic acid did not change the plasma retinol or retinoic acid levels.Nevertheless, 9-cis β-carotene significantly inhibited atherogenesis compared to the control mice (39% reduction). Conclusions: The results suggest that 9-cis β-carotene should be considered as an antiatherogenic agent in the human diet

Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the "cholesterol hypothesis" that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes.

Atherosclerosis and Alzheimer's disease (AD) are a major cause of morbidity and mortality in Western societies. These diseases share common risk factors, which are exhibited in old age, including hypertension, diabetes, hypercholesterolemia and apolipoprotein (Apo) e4 allele. We previously demonstrated that factor XI (FXI) deficiency in mice reduced the atherosclerotic plaque area in coronary sinuses and the aortic arch. This led us to investigate whether FXI deficiency in elderly ApoE knockout (KO) mice would decrease pathological alterations compatible with atherosclerosis and AD. The present study used ApoE/factor XI double KO (ApoE/FXI DKO) mice aged 64 weeks and age‑matched ApoE KO mice to serve as a control group. The ApoE KO mice developed an advanced atherosclerotic lesion area in the aortic arch, which was reduced by 33% in the DKO mice. However, neither atherosclerosis nor AD‑associated pathological alterations in the elderly mice brains were observed in either the DKO mice or the ApoE KO mice. The results advocate a dichotomy between the brain and peripheral blood vessels. Therefore, the ApoE KO and DKO mice cannot serve as mouse models for studying AD or pathological brain changes compatible with atherosclerosis. The mechanism by which ApoE KO protects against brain pathology should be further studied as it may prove helpful for future treatment of senile dementia.

High plasma levels of LDL-cholesterol play a causative role in atherogenesis. The first step in atherogenesis is characterized by oxidation of retained LDL particles in the arterial wall, and scavenger receptors-mediated entry of oxidized-LDL into macrophages, resulting in the accumulation of cholesterol within macrophages. Therefore, cholesterol efflux from macrophages to HDL particles is an essential process in inhibiting the formation of atherosclerotic plaques. Previous in-vitro experiments conducted in our laboratory, revealed that 9-cis β-carotene (9CBC) enhanced the efflux of radioactively labeled cholesterol from macrophages to HDL. However, the mechanism by which 9CBC enhances cholesterol efflux remained obscure. We found, in a controlled in-vitro assay, that treating macrophages both with the Dunaliella bardawil alga derived carotenoid 9CBC, and 22R-hydroxycholesterol (22-HC), two ligands of the nuclear receptors Retinoid X Receptor (RXR) and Liver X Receptor (LXR) respectively, resulted in a synergistically increase in fluorescently-labeled cholesterol efflux. Moreover, concurrent treatment of 9CBC with liarozole, which blocks the metabolism of Retinoic Acid (RA), increased cholesterol efflux from macrophages. This result strengthens our hypothesis that 9CBC activates the RXR nuclear receptor by its conversion to RA. Furthermore, cholesterol efflux was greater in macrophages isolated from alga Dunaliella-fed WT or apoE-/- mice compared to chow diet-fed mice. Our results suggest that simultaneous activation of nuclear receptors affects regulation of cellular cholesterol and may accelerate reverse cholesterol transport, by increasing cholesterol efflux from macrophages and thus, reducing the risk for atherogenesis.

VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N=24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N=124); Arm C) BV monotherapy (“Control”; Phase 3; N=120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Baseline tumor volume was prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P< 0.001, HR=1.02). In patients with smaller tumors (< 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P=0.0094, HR=0.53; median OS = 7 vs. 15mo) as well as BV alone (Arm C; P=0.025, HR=0.58; median OS=8.5 vs. 15mo). Patients with a radiographic response (>65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm (P=0.0014, HR=0.58). Responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease.

BACKGOUND Ofranergene obadenovec (VB-111) is a targeted anti-cancer viral based gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed immune response. Previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with VB-111 monotherapy that was continued upon progression with combination treatment of VB-111 and bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of VB-111 will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses. METHODS This is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy VB-111 in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous VB-111 prior to resection, and VB-111 every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and VB-111 every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care and VB-111 will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is influence of neoadjuvant VB-111 on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, tumor/microenvironment transcriptomic alteration, and PFS/OS. Study will open for enrolment in 2019.

The retinoid cycle is the enzymatic pathway that regenerates the vision chromophore, 11-cis retinal, after it is bleached during light absorption. Genetic insults to this cycle result in incurable blinding retinal dystrophies such as retinitis pigmentosa and Leber congenital amaurosis. Previous studies demonstrated that oral treatment with 9-cis-β-carotene rich Dunaliella bardawil powder significantly improved visual and retinal function in patients with fundus albipunctatus night blindness and retinitis pigmentosa. Here we examined the effect of oral treatment with the Dunaliella powder on retinal function and structure in RPE65rd12 mice, a model of a genetic defect in the retinoid cycle. Mice were fed with a control diet, vitamin A deficient diet (VAD) or VAD diet supplemented with Dunaliella powder for 13 months. Mice fed with Dunaliella presented significantly higher dark-adapted (35.7 μV ± 3.1 vs. 6.9 μV ± 2.5, p

ObjectiveWhile extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences.Research design and methodsTo induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis.ResultsAlthough total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance.ConclusionsWe demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.

Introduction: Ofranergene Obadenovec (VB-111) is a non-replicating adenovirus 5 (Ad-5, El-deleted) carrying a proapoptotic human Fas-chimera transgene that targets angiogenic blood vessels and leads to vascular disruption. Improved responses seen among patients experiencing post treatment fever suggest that VB-111’s mode of action involves induction of a tumor directed immune response. The following experiments were conducted to assess if VB-111 may alter the immunogenic profile of the tumor. Methods: Biopsies were obtained from 3 patients with recurrent platinum-resistant ovarian cancer treated with intravenous VB-111 1x1013 viral particles (VPs) every 2 months in combination with weekly paclitaxel. H&E and Immunohistochemistry (IHC) were performed for CD8 and CD4 intratumoral T-cells, and results were compared to pre-treatment specimens and to untreated controls. In parallel, in the Lewis Lung Carcinoma (LLC) model, mice were randomly treated with intravenous saline or VB-111 at doses of 1x109 or 1x1011 VPs. Upon sacrifice lungs were harvested and weighted. Tumor burden was assessed, and Immunohistochemistry with anti-CD8 antibody for the presence of infiltrating cytotoxic T-cells was performed. Results: Specimens from Ovarian Cancer taken before treatment with VB-111 showed no or minimal T-cell infiltration. One month after VB-111 treatment, metastatic lesions demonstrated increase in CD8 (up to 74 CD8+ cells/HPF) and CD4 tumor infiltrating T-cells. At 4.5 months following first drug administration (post 3rd dose) a liver lesion showed necrotic and fibrotic tissue with no viable tumor, lymphocytic aggregate, intensive staining for CD-8 and CD-4 T-cells and pigmented macrophages. In mice induced with LLC tumor and treated with saline, large tumor masses were observed in the lungs, and the calculated average tumor burden was 0.883g. Administration of VB-111 at 1x109 and 1x1011 VPs reduced tumor burden by 42% and 72% respectively. Concurrently, the number of tumor infiltrating CD8 T-cells was increased in correlation with VB-111 treatment dose. Conclusion: Pre clinical and clinical data suggest that VB-111 induces an Immunotherapeutic effect manifested locally with tumor infiltration with CD-8 T-cells, and evidence of tumor necrosis. The viral vector may promote transformation of the tumor microenvironment from immunologically "cold" to "hot", enhancing immune cell recognition and immune activation. Citation Format: Ronnie Shapira-Frommer, Tamar Rachmilewitz Minei, Iris Barshack, Itzhak Mendel, Niva Yakov, Yael C. Cohen, Eyal Breitbart, Dror Harats, Richard T. Penson. Ofranergene Obadenovec (VB-111), an anti-cancer gene therapy, induces immunologic responses in solid tumors transforming cold tumors to hot tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4979.

5542 Background: VB-111 is a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response. We report final results of a phase I/II study of VB-111 in combination with paclitaxel in patients with platinum-resistant ovarian cancer. Methods: Study NCT01711970 was a prospective, open label, dose escalating study assessing combination treatment of VB-111 Q8W and weekly Paclitaxel. In the phase I part of the study patients were treated with escalating doses of intravenous VB-111 and Paclitaxel. In phase 2 patients were treated with therapeutic doses of VB-111 1x1013 Viral Particles and paclitaxel 80mg/m2. Assessments included safety, overall survival (OS), PFS, tumor response (CA-125 and RECIST) and histopathology. Results: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled and treated in 2 US sites. Patients received a mean of 2.3 ±1.8 repeat doses of VB-111. 17/21 received the therapeutic dose. Median age was 65 (41-79) with a median of 3 (1-4) prior lines of therapy. Half of the subjects were Platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and was associated with generally mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients including durable responses, and responses in patients with platinum refractory disease and post anti-angiogenic failure . The median OS was 498 days in patients treated with Therapeutic Dose compared to 173 days in Sub-therapueutic dose (p = 0.028). Tumor Specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells and regions of apoptotic cancer cells. Conclusions: Treatment with VB-111 in combination with weekly Paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect manifested as tumor infiltration with CD-8 T cells. Encouraging results are the basis for further exploration in the ongoing, placebo controlled, pivotal OVAL study. Clinical trial information: NCT01711970.

2018 Background: VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. Methods: MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N = 24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N = 124) and Arm C) BV monotherapy (“Control”; Phase 3; N = 120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Results: Baseline tumor volume was not significantly different between patient cohorts (Kruskal-Wallis; P = 0.1482; median~20mL). Continuous measures of baseline tumor volume were prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P < 0.001, HR = 1.02). In patients with small tumors ( < 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P = 0.0094, HR = 0.5328; median OS = 7mo vs. 15mo) as well as BV alone (Arm C; P = 0.0248, HR = 0.5776; median OS = 8.5mo vs. 15mo). Patients with a radiographic response ( > 65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm ( P = 0.0014, HR = 0.5822). Notably, in responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease. Conclusions: Small recurrent tumors have a significant OS advantage when “priming” with VB-111 monotherapy prior to combination VB-111 and BV at recurrence. Patients responding to VB-111 exhibit specific imaging characteristics related to the drug mechanism of action. Clinical trial information: NCT02511405; NCT01260506.

Objective Monocytes are motile cells which sense inflammatory stimuli and subsequently migrate to sites of inflammation. Key players in host defense, monocytes have nevertheless been implicated as requisite mediators of several chronic inflammatory diseases. Inhibition of monocyte chemotaxis is therefore an attractive anti-inflammatory strategy. Oxidized phospholipids (OxPL) are native regulators of inflammation, yet their direct effect on monocyte chemotaxis is poorly defined. In this study, we investigated the direct effect of natural and synthetic phospholipids on monocyte chemotaxis. Methods Exploring various phospholipids using in vitro chemotaxis assays, we found that the natural phospholipid 1-palmitoyl-2-glutaryl phosphatidylcholine (PGPC) can decrease monocyte chemotaxis by 50%, while other tested OxPL had no effect. We generated a library of synthetic OxPL designated lecinoxoids, which was screened for anti-inflammatory properties. Results and conclusions VB-201, a small-molecule lecinoxoid, exhibited up to 90% inhibition of monocyte chemotaxis in vitro . Molecular analysis revealed that the effect of VB-201 was not restricted to a specific chemotactic ligand or receptor, and resulted from inhibition of signaling pathways required for monocyte chemotaxis. Interestingly, VB-201 did not inhibit monocyte adhesion or phagocytosis and had no effect on chemotaxis of CD4 + T-cells or neutrophils. In vivo , oral treatment with VB-201 reduced monocyte migration in a peritonitis model and inhibited atheroma development in ApoE −/− mice, without affecting cholesterol or triglyceride levels. Our findings highlight a novel role played by native and synthetic phospholipids in regulation of monocyte chemotaxis. The data strengthen the involvement of phospholipids as key signaling molecules in inflammatory settings and demonstrate their potential therapeutic applicability.

Statins are considered very effective in reducing cardiovascular morbidity and mortality in high-risk patients. However, although adherence to statins improves morbidity and mortality (1), it remains suboptimal (2). One of the most important causes of nonadherence is the so-called statin intolerance, mainly because of muscle-related symptoms. These symptoms most often consist of myalgia unaccompanied by significant creatine kinase (CK) elevations. Less often, myositis (elevated CK >10 times the upper limit of normal) or rhabdomyolysis (CK level >10,000 IU/L or accompanied by significant elevation in creatinine level) develops. In randomized controlled trials, the incidence of statin myopathy is ~1.5–5.0% (3). However, this low incidence may be misleading for several reasons. First, in most studies patients with a history of statin intolerance were excluded. Other studies had a single-blinded statin run-in phase, and patients experiencing muscle-related symptoms or CK elevations during this phase were excluded. Patients who tend to be at risk for developing muscle-related symptoms, such as women, elderly patients, and patients with significant comorbidity, who comprise a large proportion of statin-treated patients in real-life settings, are underrepresented in randomized controlled trials. Some studies have defined muscle-related effects by elevated CK levels only, disregarding myalgia. Last but not least, patients enrolled in studies might be motivated and so minimize reporting of mild myalgias, thus leading to underestimation of the magnitude of the problem. Data concerning real-life incidence of statin-related myopathy are scarce. In the Prediction of Muscular Risk in Observational Conditions (PRIMO) study (4), 7,924 patients receiving high-dosage statin therapy in an outpatient setting in France were asked about muscle-related symptoms. Overall, muscular symptoms were reported by 10.5% of the patients. A weakness of this study is that it lacked a comparison/control group not treated with statins. In a study of adults aged ≥40 years who participated in National Health and …