[Molecular Mechanisms Underlying Toxic Actions of trans-Fatty Acids and Prevention of Related Diseases].

trans-Fatty acids (TFAs), including elaidic acid and linoelaidic acid, are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. TFAs are not synthesized in the human body, but are taken into the body from various foods, which are mainly produced during industrial food manufacturing. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, such as atherosclerosis, cardiovascular diseases, allergic diseases, and dementia. However, the underlying pathogenic mechanisms of TFA-related disorders and the specific molecular targets evoking TFA toxicity are largely unknown. To elucidate the molecular mechanisms by which TFAs cause the cytotoxicity, we focused on cell death and inflammation, which are the main and common pathogenesis of the TFA-related diseases, and analyzed the effects of TFAs on cellular responses to various stimulations inducing cell death and inflammation. This review provides recent progress in our studies on the molecular mechanisms causing toxic actions of TFAs, which lead to diverse TFA-related disorders.

trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway.

trans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

Brown Fat-Activating Lipokine 12,13-diHOME in Human Milk Is Associated With Infant Adiposity.

CONTEXT: Little is known about the specific breastmilk components responsible for protective effects on infant obesity. Whether 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), an oxidized linoleic acid metabolite and activator of brown fat metabolism, is present in human milk, or linked to infant adiposity, is unknown. OBJECTIVE: To examine associations between concentrations of 12,13-diHOME in human milk and infant adiposity. DESIGN: Prospective cohort study from 2015 to 2019, following participants from birth to 6 months of age. SETTING: Academic medical centers. PARTICIPANTS: Volunteer sample of 58 exclusively breastfeeding mother-infant pairs; exclusion criteria included smoking, gestational diabetes, and health conditions with the potential to influence maternal or infant weight gain. MAIN OUTCOME MEASURES: Infant anthropometric measures including weight, length, body mass index (BMI), and body composition at birth and at 1, 3, and 6 months postpartum. RESULTS: We report for the first time that 12,13-diHOME is present in human milk. Higher milk 12,13-diHOME level was associated with increased weight-for-length Z-score at birth (ß = 0.5742, P = 0.0008), lower infant fat mass at 1 month (P = 0.021), and reduced gain in BMI Z-score from 0 to 6 months (ß = -0.3997, P = 0.025). We observed similar associations between infant adiposity and milk abundance of related oxidized linoleic acid metabolites 12,13-Epoxy-9(Z)-octadecenoic acid (12,13-epOME) and 9,10-Dihydroxy-12-octadecenoic acid (9,10-diHOME), and metabolites linked to thermogenesis including succinate and lyso-phosphatidylglycerol 18:0. Milk abundance of 12,13-diHOME was not associated with maternal BMI, but was positively associated with maternal height, milk glucose concentration, and was significantly increased after a bout of moderate exercise. CONCLUSIONS: We report novel associations between milk abundance of 12,13-diHOME and adiposity during infancy.

Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial.

Background: Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793). Methods: Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described. Results: All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations. Conclusion: Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy. Clinical Trial Registration: clinicaltrials.org, identifier NCT03042793.

Assessment of boron-containing compounds and oleoylethanolamide supplementation on the recovery trend in patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: In this study, we investigate the effect of boron-containing compounds and oleoylethanolamide supplementation on the recovery trend in patients with COVID-19. TRIAL DESIGN: The current study is a single-center, randomized, double-blind, placebo-controlled clinical trial with parallel groups. PARTICIPANTS: The inclusion criteria include male and female patients≥18 years of age, with a confirmed diagnosis of SARS-CoV-2 infection via polymerase chain reaction (PCR) and/or antibody test and with written informed consent to participate in this trial. The exclusion criteria include regular use of any other supplement, severe and critical COVID-19 pneumonia, pregnancy and breastfeeding. This study is being conducted at Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran. INTERVENTION AND COMPARATOR: Patients are randomly assigned to four groups. The first group (A) will take one capsule containing 5 mg of boron compounds twice a day for two weeks. The second group (B) will take one capsule containing 200 mg oleoylethanolamide twice a day for two weeks. The third group (C) will take one capsule containing 5 mg boron compounds with 200 mg oleoylethanolamide twice a day for two weeks, and the fourth group (D) does not receive any additional treatment other than routine treatments. Boron-containing compounds and oleoylethanolamide capsules will be synthesized at Nutrition Research Center of Tabriz University of Medical Sciences. MAIN OUTCOMES: The primary end point of this study is to investigate the recovery rate of clinical symptoms, including fever, dry cough, and fatigue, as well as preclinical features, including complete blood count (CBC), the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) profiles within two weeks of randomization. RANDOMISATION: Patients are randomized into four equal groups in a parallel design (allocation ratio 1:1). A randomized block procedure is used to divide subjects into one of four treatment blocks (A, B, C, and D) by a computer-generated allocation schedule. BLINDING (MASKING): The participants and investigators (enrolling, assessing, and analyzing) are blinded to the intervention assignments until the end of the study and data analysis. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The calculated total sample size is 40 patients, with 10 patients in each group. TRIAL STATUS: The protocol is Version 1.0, May 17, 2020. Recruitment began May 19, 2020, and is anticipated to be completed by October 19, 2020. TRIAL REGISTRATION: This clinical trial has been registered by the title of "Assessment of boron-containing compounds and oleoylethanolamide supplementation on the recovery trend in Patients with COVID-19: A double-blind randomized placebo-controlled clinical trial" in the Iranian Registry of Clinical Trials (IRCT). The registration number is " IRCT20090609002017N35 ", https://www.irct.ir/trial/48058 . The registration date is 17 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects.

10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA-10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA-10. After single and multiple ascending doses, CXA-10 demonstrated dose-proportional increases in plasma exposure. CXA-10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA-10-202, a consistent decrease from baseline was observed with CXA-10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP-1, and IL-6. In CXA-10-203, after coadministration with CXA-10, geometric mean peak plasma concentration (Cmax ) and area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC0-t ) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA-10. Adverse events (AEs) were dose-related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA-10 was safe and well-tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA-10 75-300 mg once daily.

Risk Factors for Macroscopic Haemoglobinuria After Sclerotherapy Using Ethanolamine Oleate for Venous Malformations.

OBJECTIVES: Sclerotherapy is an essential component of the treatment for venous malformations, and ethanolamine oleate (EO) is known as a useful sclerosing agent. However, macroscopic haemoglobinuria (MH) and subsequent renal impairment are severe complications after sclerotherapy using EO. The present study aimed to clarify the MH risk factors for better peri-operative management of venous malformations. METHODS: Data collected during 130 procedures involving 94 patients who were undergoing sclerotherapy using EO for venous malformation were retrospectively analysed. Pre-operative and operative variables, including sex, age, pre-operative body mass index, location, depth, type of lesion, size, number of procedures, type of drainage vein, ratio of sclerosant to air, and injected total dose of 5% EO per body weight (BW), were examined. Univariable analysis and multivariable logistic regression were performed to determine the possible risk factors for MH. RESULTS: Following sclerotherapy, MH occurred in 27.7% of patients, but no patient developed post-operative renal impairment because of aggressive hydration and haptoglobin administration. On univariable analysis, diffuse lesion, lesion size ≥50 cm2, and total injected dose of 5% EO ≥ 0.18 mL/kg were found to be the MH risk factors. Multivariable logistic regression analysis identified a total injected dose of 5% EO ≥ 0.18 mL/kg as the significant independent factor contributing to MH risk. CONCLUSIONS: Macroscopic haemoglobinuria is a reversible complication if immediate and appropriate interventions with aggressive hydration and haptoglobin administration are performed; therefore, it should be closely monitored following sclerotherapy, especially when using 5% EO ≥ 0.18 mL/kg.

Eczema alérgico de contacto por metil glucosa dioleato contenido en una crema bálsamo / Allergic Contact Dermatitis Due to Methyl Glucose Dioleate in a Balm Cream

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Development of Lobular Panniculitis Long After Completing the Personalized Peptide Vaccine Therapy.

BACKGROUND Personalized peptide vaccine therapy is regarded as a well-tolerated, safe and effective immunotherapy for patients with advanced cancers. Herein we report an exceptional case of a patient with advanced pancreatic cancer who developed delayed lobular panniculitis at sites corresponding to vaccine injections. CASE REPORT A 64-year-old Japanese female visited our clinic due to thirst and polydipsia; she was diagnosed as having type 2 diabetes. Simultaneously, she was diagnosed as having advanced pancreatic cancer; and a distal pancreatectomy and splenectomy were performed. Afterwards, she received adjuvant chemotherapy with titanium silicate-1 and personalized peptide vaccination using Montanide® ISA-51 by a subcutaneous injection to her abdomen over a total of 30 times. Thirteen months after the vaccine therapy had come to an end, lobular panniculitis appeared at the vaccination sites. At this point, corticosteroid was administered, resulting in significant improvement in the condition of the subcutaneous nodules. CONCLUSIONS This case report highlights the importance of careful patient explanation before initiation of cancer vaccine therapy about the possibilities of lobular panniculitis as an adverse event. It also highlights that it is important that physicians have a greater awareness of the possibility of panniculitis in patients with concerns regarding subcutaneous indurations even long after the end of peptide vaccine therapy.

Protective effects of bezafibrate against elaidic acid-induced accumulation of lipid droplets in monocytic cells.

Some factors related to diet, such as trans fatty acids (TFA), are known to be involved in the progression of atherosclerosis in humans. Thus, the aim of our study was (i) to evaluate the effects of three dietary free fatty acids (FFA) (elaidic (EA), oleic (OA) and palmitic acid (PA)) on U937 human monocytes, and (ii) to study the eventual benefits of bezafibrate (BZF), a pan-agonist for PPAR isoforms (α, γ and δ) in U937 cells treated with FFA. Morphologic and functional changes were investigated by microscopic and flow cytometric methods. Cellular lipid content, lipid droplets and FA composition were identified and studied. All analyses were also realized in association with or without BZF. Contrary to OA and PA, EA slightly induced both propidium iodide-positive cells and mitochondrial depolarization. In addition, in contrast to OA and PA, EA induced only a slight increase in superoxide anion production. However, EA and OA promoted cytoplasmic lipid droplets accumulation. Only EA and OA significantly increased CD36 expression. It is noteworthy that BZF had a more or less pronounced protective effect against EA-, OA- and PA-induced side effects: BZF attenuated the impaired cell viability and inflammatory response, decreased superoxide anion production and prevented the accumulation of neutral and polar lipids. The effects were less pronounced with OA and PA than with EA. Altogether, our data revealed a benefit of BZF on the side effects induced especially with EA. It may thus be of interest in preventing the early stages of atherosclerotic plaque formation.

N-Oleoylglycine-Induced Hyperphagia Is Associated with the Activation of Agouti-Related Protein (AgRP) Neuron by Cannabinoid Receptor Type 1 (CB1R).

N-Acyl amino acids (NAAAs) are conjugate products of fatty acids and amino acids, which are available in animal-derived food. We compared the effects of N-arachidonoylglycine (NAGly), N-arachidonoylserine (NASer), and N-oleoylglycine (OLGly) on in vivo food intake and in vitro [Ca2+]i of Agouti-related protein (AgRP) neurons to identify the role of these compounds in energy homeostasis. Hypothalamic neuropeptide expression and anxiety behavior in response to OLGly were also tested. To further identify the underlying mechanism of OLGly on food intake, we first detected the expression level of potential OLGly receptors. The cannabinoid receptor type 1 (CB1R) antagonist was cotreated with OLGly to analyze the activation of AgRP neuron, including [Ca2+]i, expression levels of PKA, CREB, and c-Fos, and neuropeptide secretion. Results demonstrated that only OLGly (intrapertioneal injection of 6 mg/kg) can induce hyperphagia without changing the expression of hypothalamic neuropeptides and anxiety-like behavior. Moreover, 20 µM OLGly robustly enhances [Ca2+]i, c-Fos protein expression in AgRP neuron, and AgRP content in the culture medium. OLGly-induced activation of AgRP neuron was completely abolished by the CB1R-specific antagonist, AM251. In summary, this study is the first to demonstrate the association of OLGly-induced hyperphagia with activation of the AgRP neuron by CB1R. These findings open avenues for investigation and application of OLGly to modulate energy homeostasis.

The proportion of total C18:1 trans-fatty acids in red blood cell membranes relates to carotid plaque prevalence.

Consistent evidence supports the pro-atherogenic properties of dietary trans-fatty acids (TFAs). However, there are no clinical data on TFA intake and atheroma plaque. We cross sectionally investigated whether the proportion of total C18:1 TFA in red blood cells (RBCs), which mirrors dietary TFA intake, independently relates to carotid plaque prevalence in subjects with new-onset type 2 diabetes mellitus without prior cardiovascular disease (n=101, 56% men, mean age 61 years) and age- and sex-matched controls (n=96). RBC fatty acid composition was determined by gas chromatography. Plaque (defined as carotid intima-media thickness ≥1.5 mm) was sonographically assessed at three bilateral carotid segments. In multivariate models adjusting for group (diabetes or control) and classical cardiovascular risk factors, for each 0.1% increase in RBC total C18:1 TFA isomers, plaque prevalence increased by 53% (P=.002). In contrast, for each 0.1% increase in RBC alpha-linolenic acid, the vegetable omega-3 fatty acid, plaque prevalence decreased by 43% (P<.001). We conclude that the RBC membrane proportion of total C18:1 TFA, considered a proxy of intake, directly relates to the ultrasound feature that best predicts future cardiovascular events. Our findings support current recommendations to limit TFA intake for cardiovascular health promotion.

Severe Edema After Sclerotherapy of Labial Hemangioma With Ethamolin Oleate in a Young Child.

Adverse reactions related to ethanolamine oleate (EO) include pain during injection, redness, inflammation, tissue necrosis, and allergic reaction. The authors report a patient of exuberant facial edema after the injection of EO used in sclerotherapy of lip hemangioma in a child. A 9-year-old boy was referred to authors' oral and maxillofacial surgery unit to treat a vascular lesion of the upper lip. The lesion has causing enlargement of the middle area of the upper lip, being sessile and resilient by palpation. It was decided to employ sclerotherapy aiming to reduce the size for posterior surgical excision of the residual lesion. The day after the injection, the patient presented intense edema limited to the upper lip, complaining of mild pain. Although side effects reported of EO injection are mild and with almost no clinical significance, major complications like anaphylaxis and severe edema can occur, such in the patient here presented.

Is vaccenic acid (18:1t n-7) associated with an increased incidence of hip fracture? An explanation for the calcium paradox.

High calcium intake may increase hip fracture (HF) incidence. This phenomenon, known as the calcium paradox, might be explained by vaccenic acid (18:1t n-7, VA), the highly specific trans fatty acid (TFA) present in dairy products. First, we ecologically investigated the relationship between 18:1 TFA intake and HF incidence using data from 12 to 13 European countries collected before 2000; then we measured the effects of VA and elaidic acid (18:1t n-9, EA) on osteoblasts from goldfish scales (tissues very similar to mammalian bone), with alkaline phosphatase as a marker; and finally we measured the effect of VA on mRNA expression in the scales for the major bone proteins type I collagen and osteocalcin. HF incidence was significantly correlated with 18:1 TFA intake in men (r=0.57) and women (r=0.65). Incubation with 1µmol/L VA and EA for 48h significantly decreased alkaline phosphatase activity by 25% and 21%, respectively. Incubation of scales with 10µmol/L VA for 48h significantly decreased mRNA expression for type I collagen and osteocalcin (by about 50%). In conclusion, VA may be causatively related to HF and could explain the calcium paradox. It may be prudent to reduce 18:1 TFA intake, irrespective of trans positions, to prevent HF.

Safety and tolerability evaluation of the use of Montanide ISA™51 as vaccine adjuvant: A systematic review.

Montanide ISA™51 (ISA 51) is a vaccine adjuvant which has been tested in therapeutic and prophylactic vaccine trials. The aim of this review is to present a comprehensive examination of the safety and tolerability of ISA 51 containing vaccines. A systematic literature search was conducted in PubMed, EMBASE and clinicaltrials.gov . Eligible studies were categorized into: (A) uncontrolled studies with non-healthy subjects, (B) controlled studies with non-healthy subjects, and (C) controlled studies with healthy subjects. Reported adverse events (AEs) were assessed. 91 studies were included in our review. Generally observed AEs included injection site reaction; injection site pain; myalgia; headache; gastro-intestinal disorders; fatigue and fever - regardless of the administration route and subject characteristic. Specific AEs, e.g. injection site reactions and rash, were more frequently reported from subjects receiving ISA 51-adjuvanted vaccines than from subjects receiving antigen or ISA 51 only. The reported AEs were mainly mild to moderate in intensity. Serious AEs (SAEs) were reported in 27% of the uncontrolled trials and 2 trials conducted with healthy subjects. Notably, 2 other trials conducted with healthy subjects were stopped due to unacceptable AEs. Some studies indicate that the mixing procedure of antigen and adjuvant might influence the occurrence of AEs. Reports on SAEs and premature termination of 2 trials advise caution when using ISA 51. Yet, AEs might be preventable by proper mixing of vaccine and adjuvant to a stable emulsion. Trials including an active control group are needed for a fair evaluation of adjuvant safety.

Vaccenic acid and trans fatty acid isomers from partially hydrogenated oil both adversely affect LDL cholesterol: a double-blind, randomized controlled trial.

BACKGROUND: Adverse effects of industrially produced trans fatty acids (iTFAs) on the risk of coronary artery disease are well documented in the scientific literature; however, effects of naturally occurring trans fatty acids (TFAs) from ruminant animals (rTFA), such as vaccenic acid (VA) and cis-9,trans-11 conjugated linoleic acid (c9,t11-CLA), are less clear. Although animal and cell studies suggest that VA and c9,t11-CLA may be hypocholesterolemic and antiatherogenic, epidemiologic data comparing rTFAs and iTFAs are inconsistent, and human intervention studies have been limited, underpowered, and not well controlled. OBJECTIVE: We determined the effects of VA, c9,t11-CLA, and iTFA, in the context of highly controlled diets (24 d each), on lipoprotein risk factors compared with a control diet. RESULTS: We conducted a double-blind, randomized, crossover feeding trial in 106 healthy adults [mean ± SD age: 47 ± 10.8 y; body mass index (in kg/m(2)): 28.5 ± 4.0; low-density lipoprotein (LDL) cholesterol: 3.24 ± 0.63 mmol/L]. Diets were designed to have stearic acid replaced with the following TFA isomers (percentage of energy): 0.1% mixed isomers of TFA (control), ∼3% VA, ∼3% iTFA, or 1% c9,t11-CLA. Total dietary fat (34% of energy) and other macronutrients were matched. Total cholesterol (TC), LDL cholesterol, triacylglycerol, lipoprotein(a), and apolipoprotein B were higher after VA than after iTFA; high-density lipoprotein (HDL) cholesterol and apolipoprotein AI also were higher after VA. Compared with control, VA and iTFA both increased TC, LDL cholesterol, ratio of TC to HDL cholesterol, and apolipoprotein B (2-6% change; P < 0.05); VA also increased HDL cholesterol, apolipoprotein AI, apolipoprotein B, and lipoprotein(a) (2-6% change; P < 0.05), whereas iTFA did not. c9,t11-CLA lowered triacylglycerol (P ≤ 0.01) and had no effect on other lipoprotein risk factors. CONCLUSIONS: With respect to risk of cardiovascular disease, these results are consistent with current nutrition labeling guidelines, with the requirement of VA, but not c9,t11-CLA, to be listed under TFA on the Nutrition Facts Panel. This trial was registered at clinicaltrials.gov as NCT00942656.

Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175.

BACKGROUND: A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-1(19), the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. METHOD: Healthy malaria naïve Indian male subjects aged 18-45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10 µg, 25 µg and 50 µg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. RESULTS: JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-1(19). Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. CONCLUSION: Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-1(19) construct needs to be optimised to improve its immunogenicity. TRIAL REGISTRATION: Clinical Trial Registry, India CTRI/2010/091/000301.