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Good point - "Not necessarily a bad thing" to me means "Looks bad but really isn't." Only thing that fits is that PFS was worse for DCVAX group due to pseudoprogression (so it was an FDA safety issue), they showed the FDA data to indicate that this was not real progression, so the FDA let the trial continue because there were not real safety issues. If pseudoprogression was the issue, we may see in the DCVAX group either no PFS-OS association (atypical for most cancer trials), or even an inverse association (early "progressors" actually live longer). FWIW - I fully expect PFS to fail due to this, but OS to succeed.
This is a direct result of absence of in person promotion (dinner talks and reps in offices). Most medical clinics have closed their offices to any non-staff individuals except patients, and CME presentations are all via Zoom if held at all. So, the stagnant numbers since March are to be expected. Once a vaccine or more effective COVID treatment comes out, script increases should resume. I read an interview with the head of COVID vaccine development for NIH, who said that doses of the Moderna vaccine are already being prodcued and will be available for distribution by around the end of this year, assuming their promising vaccine proves effective in the phase 2 and 3 trials that are expected to be completed by then (which is a very fast track for clinical trials). Multiple other vaccine trials are also ongoing around the world.
Just occurred to me that this sign-off process is probably not easy for the CRO. This trial is 10 years old, and there has surely been a great deal of turnover at every site (both research coordinators and investigators). The CRO is probably having to track people down at new institutions to get all of these sign offs.
Sorry - the other was just slides.. I think this is the full video link:
https://www.facebook.com/RSDSA/videos/280136189779218/
Probably boring to you (not Amarin related) but here it is:
https://bit.ly/3fAoj2C
I recently gave a large talk on Facebook live, and one question I got was whether patients with this particular pain condition known to be associated with elevated proinflammatory cytokines were at greater risk for a fatal cytokine storm. I did a lit review and here is what I found. It seems that V may in theory be able to reduce cytokine storm in COVID, with some specific benefits on the crucial nfKappa B inflammatory pathway and by alterating response to lipopolysaccharide (which is the trigger for fatal inflammation and organ failure in severe sepsis, such as in severe burns). Below are some abstracts of relevant articles related to this issue. My take on this is that the ongoing V trial in COVID patients has a good likelihood of showing benefits of V for cytokine storm in COVID19. You can judge for yourself though:
1) Eicosapentaenoic Acid Prevents LPS-Induced TNF-a Expression by Preventing NF?B Activation
Yan Zhao et al.
Abstract
Background: Many studies have shown that fish oil supplementation inhibits tumor necrosis factor-a (TNF-a) production in mice and human subjects; however, the mechanisms remain unclear. Nuclear factor-?B (NF-?B) is a transcription factor that plays an important role in controlling the expression of pro-inflammatory genes including TNF-a. Activation of NF-?B has been shown to mediate the maximal expression of TNF-a in human monocytes. NF-?B is kept in an inactive form in the cytoplasm by I?B, the inhibitory subunit of NF-?B complex. Phosphorylation and subsequent degradation of I?B lead to NF-?B activation.
Objectives: The effect of eicosapentaenoic acid (EPA), a major n-3 fatty acid in fish oil, on the lipopolysaccharide (LPS)-induced expression of TNF-a and activation of NF-?B were investigated. The mechanism underlying EPA modulation of NF-?B activation was also studied.
Methods: Human monocytic THP-1 cells were pre-incubated with EPA and stimulated with LPS. The levels of secreted TNF-a were determined by ELISA. The DNA binding activity of NF-?B was analyzed by EMSA. The degradation and phosphorylation of I?B-a were examined by Western blot analysis.
Results: TNF-a production and expression induced by LPS were significantly decreased in cells pre-incubated with EPA. LPS-induced NF-?B activation, translocation of p65 subunit to the nucleus, phosphorylation and degradation of I?B-a were partially prevented by EPA.
Conclusions: The results suggest that suppression of the TNF-a expression by EPA is partly attributed to its inhibitory effect on NF-?B activation. EPA appears to prevent NF-?B activation by preventing the phosphorylationn of I?B-a.
2) Eicosapentaenoic Acid Potentiates the Therapeutic Effects of Adipose Tissue-Derived Mesenchymal Stromal Cells on Lung and Distal Organ Injury in Experimental Sepsis
Johnatas D Silva et al.
Abstract
Background: Even though mesenchymal stromal cells (MSCs) mitigate lung and distal organ damage in experimental polymicrobial sepsis, mortality remains high. We investigated whether preconditioning with eicosapentaenoic acid (EPA) would potentiate MSC actions in experimental sepsis by further decreasing lung and distal organ injury, thereby improving survival.
Methods: In C57BL/6 mice, sepsis was induced by cecal hligation and puncture (CLP); sham-operated animals were used as control. Twenty-four hours after surgery, CLP mice were further randomized to receive saline, adipose tissue-derived (AD)-MSCs (105, nonpreconditioned), or AD-MSCs preconditioned with EPA for 6 h (105, EPA-preconditioned MSCs) intravenously. After 24 h, survival rate, sepsis severity score, lung mechanics and histology, protein level of selected biomarkers in lung tissue, cellularity in blood, distal organ damage, and MSC distribution (by technetium-99m tagging) were analyzed. Additionally, the effects of EPA on the secretion of resolvin-D1 (RvD1), prostaglandin E2 (PGE2), interleukin (IL)-10, and transforming growth factor (TGF)-ß1 by MSCs were evaluated in vitro.
Results: Nonpreconditioned and EPA-preconditioned AD-MSCs exhibited similar viability and differentiation capacity, accumulated mainly in the lungs and kidneys following systemic administration. Compared to nonpreconditioned AD-MSCs, EPA-preconditioned AD-MSCs further reduced static lung elastance, alveolar collapse, interstitial edema, alveolar septal inflammation, collagen fiber content, neutrophil cell count as well as protein levels of interleukin-1ß and keratinocyte chemoattractant in lung tissue, and morphological abnormalities in the heart (cardiac myocyte architecture), liver (hepatocyte disarrangement and Kupffer cell hyperplasia), kidney (acute tubular necrosis), spleen (increased number of megakaryocytes and lymphocytes), and small bowel (villi architecture disorganization). EPA preconditioning of MSCs resulted in increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-ß).
Conclusions: Compared to nonpreconditioned cells, EPA-preconditioned AD-MSCs yielded further reductions in the lung and distal organ injury, resulting in greater improvement in sepsis severity score and higher survival rate in CLP-induced experimental sepsis. This may be a promising therapeutic approach to improve outcome in septic patients.
3) Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma
Soraia Carvalho Abreu et al.
Abstract
Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D1 (RvD1), prostaglandin E2 (PGE2), interleukin (IL)-10, and transforming growth factor (TGF)-ß1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-ß), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects.
4) Novel n-3 PUFA Monoacylglycerides of Pharmacological and Medicinal Interest: Anti-inflammatory and Anti-Proliferative Effects
Rayan Khaddaj-Mallat et al
Abstract
Newly-synthesized, eicosapentaenoic acid monoacylglyceride (MAG-EPA), docosahexaenoic acid monoacylglyceride (MAG-DHA) and docosapentaenoic acid monoacylglyceride (MAG-DPA) have been demonstrated to display beneficial effects in several disorders including chronic airway inflammatory diseases, pulmonary hypertension, rheumatoid arthritis, and lung and colorectal adenocarcinoma. Recent evidence reveals that omega-3 polyunsaturated fatty acid (n-3 PUFA) precursors provide a window to explore the pathobiology of inflammatory disease as well as structural templates for the design of novel pro-resolving precursors that are well absorbed by the gastrointestinal (GI) tract and metabolized into bioactive metabolites. These metabolites are found in blood circulation and tissues thereby mediating numerous immuno-modulatory effects through the activation of specific receptors. Bioactive metabolites regulate cell membrane functions, lipid signaling and gene expressions encoding for enzymes responsible for lipid storage and fatty acid metabolism. This review highlights recent experimental findings regarding n-3 PUFA monoacylglyceride research, as well as the pharmacological and medicinal relevance of these stereospecific derivatives in the resolution of chronic inflammatory diseases.
5) DHA- And EPA-derived Resolvins, Protectins, and Maresins in Airway Inflammation
Melody G Duvall 1 , Bruce D Levy 2
Abstract
Essential fatty acids can serve as important regulators of inflammation. A new window into mechanisms for the resolution of inflammation was opened with the identification and structural elucidation of mediators derived from these fatty acids with pro-resolving capacity. Inflammation is necessary to ensure the continued health of the organism after an insult or injury; however, unrestrained inflammation can lead to injury "from within" and chronic changes that may prove both morbid and fatal. The resolution phase of inflammation, once thought to be a passive event, is now known to be a highly regulated, active, and complex program that terminates the inflammatory response once the threat has been contained. Specialized pro-resolving mediators (SPMs) are biosynthesized from omega-3 essential fatty acids to resolvins, protectins, and maresins and from omega-6 fatty acids to lipoxins. Through cell-specific actions mediated through select receptors, these SPMs are potent regulators of neutrophil infiltration, cytokine and chemokine production, and clearance of apoptotic neutrophils by macrophages, promoting a return to tissue homeostasis. This process appears to be defective in several common human lung diseases, such as asthma and COPD, which are characterized by chronic unrestrained inflammation and significant associated morbidity. Here, we highlight translational research in animal models of disease and with human subjects that sheds light on this rapidly evolving area of science and review the molecular and cellular components of the resolution of lung inflammation.
6) Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: a randomized, controlled study
Alai Tan et al.
Abstract
Background
High levels of circulating proinflammatory cytokines are characteristic of inflammaging, a term coined to describe age-related chronic systemic inflammation involved in the etiology of many age-related disorders including nonhealing wounds. Some studies have shown that supplementing diets with n-3 polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) lowers systemic levels of key proinflammatory cytokines associated with inflammaging. However, findings from the few studies that have focused exclusively on older adults are inconclusive. As such, the objective of this randomized controlled study was to test the effects of EPA+DHA therapy on circulating levels of proinflammatory cytokines in adults in middle to late adulthood.
Methods
Plasma levels of fatty acids and interleukin (IL)-6, IL-1ß and tumor necrosis factor-a (TNF-a) were measured in 35 participants with chronic venous leg ulcers (mean age: 60.6 years) randomnly assigned to 8 weeks of EPA+DHA therapy (2.5 g/d) or placebo therapy.
Results
EPA+DHA therapy had a significant lowering effect on levels of IL-6, IL-1ß and TNF-a after 4 weeks of therapy and an even greater lowering effect after 8 weeks of therapy. Further, after adjusting for baseline difference, the treatment group had significantly lower levels of IL-6 (p = .008), IL-1ß (p < .001), and TNF-a (p < .001) at Week 4 and at Week 8 [IL-6 (p = .007), IL-1ß (p < .001), and TNF-a (p < .001)] compared to the control group.
Conclusion
Adults in middle to late adulthood receiving EPA+DHA therapy demonstrated significantly greater reductions in circulating levels of proinflammatory cytokines compared with those receiving placebo therapy. EPA+DHA therapy may be an effective low-risk dietary intervention for assuaging the harmful effects of inflammaging.
7) Eicosapentaenoic Acid Modifies Cytokine Activity and Inhibits Cell Proliferation in an Oesophageal Cancer Cell Line
Hisako Kubota et al.
Background/Aim: The present study investigated the effect of eicosapentaenoic acid (EPA) on nuclear factor-kappa B (NF-?B) activation, inflammatory interleukin-6 (IL-6) production, and cell proliferation in a human oesophageal carcinoma cell line (TE-1). Lipopolysaccharide (LPS)-induced IL-6 production in TE-1 cells in the presence or absence of EPA was determined using enzyme-linked immunosorbent assay (ELISA). The proliferation of TE-1 cells was determined by the WST-1 assay. TE-1 cells were stained with Hoechst 33342 and propidium iodide to observe apoptosis. Immunohistochemical staining of NF-?B in TE-1 cells was performed. LPS increased IL-6 production in TE-1 cells, and EPA treatment prevented this effect. EPA treatment inhibited NF-?B activation and induced apoptosis of TE-1 cells. EPA inhibits NF-?B activation and IL-6 production in oesophageal cancer cells, their inducing apoptosis. These effects of EPA may be of benefit in improving the outcome of cancer surgery.
8) Comparative effects of eicosapentaenoic acid and docosahexaenoic acid on proliferation, cytokine production, and pleiotropic gene expression in Jurkat cells
RenataGorjãomat et el
Abstract
Comparative effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) acid on Jurkat T cells were investigated. The following parameters were evaluated: concanavalin A (Con A) induced proliferation, production of interleukin-2 (IL-2), IL-4, IL-10, and interferon-? (INF-?), and expression of pleiotropic genes by macroarray technique (83 genes in total). DHA inhibiting effect on Con A–induced proliferation was more pronounced than that of EPA. The decrease in IL-2 and INF-? production was observed for both fatty acids, whereas the production of IL-10 was decreased by EPA only. The expression of a significant proportion of genes was altered by the fatty acids; 30% for DHA (25 genes) and 26.5% for EPA (22 genes). DHA and EPA markedly affected the expression of genes clustered as cytokines and related receptors, signal transduction pathways, transcription factors, cell cycle, defense and repair, apoptosis, DNA synthesis, cell adhesion, cytoskeleton, and hormone receptors. Therefore, the effect of fatty acids on T-lymphocyte function involves regulation of expression of important genes. Marked differences were observed between the effects of EPA and DHA, indicating that it is an over-simplification to generalize the effects of n-3 fatty acids.
9) Inhibitory effects of eicosapentaenoic acid on lipopolysaccharide-induced activation in BV2 microglia
Abstract
Upon activation, microglia release proinflammatory mediators that play important roles in eliciting neuroinflammatory responses associated with neurodegenerative diseases. The anti-inflammatory properties of eicosapentaenoic acid (EPA) have been known, however, the effects responsible for lipopolysaccharide (LPS)-induced activation remain poorly understood in microglia. In the present study, we investigated the effects of EPA on the expression of proinflammatory mediators in LPS-stimulated BV2 microglia. EPA significantly inhibited the release of nitric oxide (NO), prostaglandin E2 (PGE2) and proinflammatory cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-a in a dose-dependent manner. EPA also attenuated the production of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and proinflammatory cytokines at mRNA and/or protein levels. Moreover, EPA suppressed NF-?B activation by blocking I?B degradation, and also blocked the mitogen-activated protein kinases (MAPKs) such as ERK, p38 and JNK, and the Akt pathway. The anti-inflammatory properties of EPA may be useful for ameliorating neurodegenerative diseases as well as suppressing LPS-induced shock.
10) Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory condition characterised by arthritis, cutaneous rash, vasculitis, and involvement of central nervous system, renal and cardiopulmonary manifestations. Abnormalities in the cytokine network is believed to be involved in the pathobiology of this condition. The n-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can suppress T-cell proliferation and the production of interleukin-1, interleukin-2, and tumor necrosis factor by these cells both in vitro and in vivo. Oral supplementation of EPA and DHA induced prolonged remission of SLE in 10 consecutive patients without any side-effects. These results suggest that n-3 fatty acids, EPA and DHA, are useful in the management of SLE and possibly, other similar collagen vascular diseases.
11) Effects of the Addition of Eicosapentaenoic Acid to Strong Statin Therapy on Inflammatory Cytokines and Coronary Plaque Components Assessed by Integrated Backscatter Intravascular Ultrasound
Toshiyuki Niki et al.
Background:The effects of eicosapentaenoic acid (EPA) on coronary artery disease have been previously reported; however, those of the addition of EPA to strong statins on coronary plaque components and local inflammatory cytokines are not known.Methods and Results:A total of 95 patients who had been treated with strong statin for at least 6 months were randomized into 2 groups: an EPA group (additional treatment with EPA at 1,800 mg/day, n=48) or a control group (no additional treatment, n=47), for 6 months. The tissue characteristics of target coronary plaque in each patient were analyzed using IB-IVUS before and after treatment. We also measured plasma levels of inflammatory cytokines sampled in the coronary sinus (CS) and peripheral vein.A significant reduction in lipid volume (18.5±1.3 to 15.0±1.5 mm3, P=0.007) and a significant increase in fibrous volume (22.9±0.8 to 25.6±1.1 mm3, P=0.01) were observed in IB-IVUS image analyses in the EPA group, but no significant changes in the plaque components in the control group. CS levels of pentraxin 3 and monocyte chemoattractant protein-1 were lower after than before treatment with EPA (3.3±2.1 to 2.6±1.2 ng/ml, 120.4±26.2 to 110.2±26.8 pg/ml, P=0.015 and P=0.008, respectively); however, there were no significant changes in those inflammatory cytokines between pre- and post-treatment in the control group.Conclusions:The addition of EPA was associated with reduced lipid volume in coronary plaques and decreased inflammatory cytokines.
12) Dietary eicosapentaenoic acid and docosahexaenoic acid equally incorporate as decosahexaenoic acid but differ in inflammatory effects
SaletaSierra et al
Abstract
Objective
The ?-3 polyunsaturated fatty acids are involved in the modulation of the immune response. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) produced from dietary precursors may not be sufficient to match nutritional requirements and thus should be included in our diet. In this sense, the administration of higher amounts of DHA than of EPA in infant formulations is recommended. The aims of this work were to demonstrate that dietary administration of EPA or DHA to mice allows reaching similar tissue DHA levels and to compare their anti-inflammatory effects and mechanisms of action.
Methods
Balb/c mice were fed diets enriched with EPA or DHA for 3 wk. Twelve hours before sacrifice, a contact dermatitis was induced in the ears of the animals. Tissue fatty acid contents were determined. Cytokine and immunoglobulin concentrations were measured by enzyme-linked immunosorbent assay, and ears were collected to analyze local inflammatory effects.
Results
The DHA concentrations attained in tissues were similar to the two diets, whereas the EPA concentration increased only when the diet was enriched with this polyunsaturated fatty acid. Although EPA and DHA reduced ear inflammation, EPA reduced neutrophil infiltration in the ears more efficiently. EPA was associated with a greater reduction in the systemic macrophage inflammatory response and T-helper type 2 response and with increased interleukin-10 production.
Conclusion
Similar levels of DHA in tissues are reached in mice fed an EPA- or a DHA-enriched diet. Dietary EPA and DHA show anti-inflammatory properties, but EPA appears to be more potent.
13)Nutrition intervention using an eicosapentaenoic acid (EPA)-containing supplement in patients with advanced colorectal cancer. Effects on nutritional and inflammatory status: a phase II trial
Jane A. Read et al
Abstract
Goals
The aim of the study was to assess the impact of an eicosapentanoic acid-containing protein and energy dense oral nutritional supplement (EPA-ONS) on nutritional and inflammatory status, quality of life (QOL), plasma phospholipids (PPL) and cytokine profile, tolerance of irinotecan-containing chemotherapy and EPA-ONS in patients with advanced colorectal cancer (CRC) receiving chemotherapy.
Materials and methods
Patients with advanced CRC having one prior chemotherapy regimen received 480 ml of EPA-ONS daily for 3 weeks before commencing chemotherapy with folinic acid, 5-fluorouracil, irinotecan (FOLFIRI), and continued for 3 cycles of treatment (9 weeks). All assessments including weight, body composition, C-reactive protein (CRP), QOL, dietary intake, PPL and cytokine analyses were performed at baseline, 3 and 9 weeks.
Results
Twenty-three patients were enrolled, 20 completed 3 weeks, and 15 completed 9 weeks. The mean EPA-ONS intake was 1.7 tetrapaks (408 ml) daily. There was a significant increase in mean weight (2.5 kg) at 3 weeks (p?=?0.03). Lean body mass (LBM) was maintained. Protein and energy intake significantly decreased after the commencement of chemotherapy (protein p?=?0.003, energy p?=?0.02). There was a significant increase in energy levels (p?=?0.03), whilst all other QOL measures were maintained. PPL EPA levels increased significantly over the first 3 weeks. Mean CRP increased by 14.9 mg/L over the first 3 weeks (p?=?0.004), but decreased to baseline levels by the end of the trial. There was a significant correlation between plasma IL-6 and IL-10 concentrations and survival, and between IL-12 and toxicity.
Conclusion
Dietary counseling and the provision of EPA-ONS may result in maintenance of nutritional status and QOL, however randomized trials are required to evaluate the impact of EPA on toxicity from chemotherapy.
14) Chapter 13 - Health Benefits of n-3 Polyunsaturated Fatty Acids: Eicosapentaenoic Acid and Docosahexaenoic Acid
NalinSiriwardhana et al, *†
Abstract
Marine-based fish and fish oil are the most popular and well-known sources of n-3 polyunsaturated fatty acids (PUFAs), namely, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These n-3 PUFAs are known to have variety of health benefits against cardiovascular diseases (CVDs) including well-established hypotriglyceridemic and anti-inflammatory effects. Also, various studies indicate promising antihypertensive, anticancer, antioxidant, antidepression, antiaging, and antiarthritis effects. Moreover, recent studies also indicate anti-inflammatory and insulin-sensitizing effects of these fatty acids in metabolic disorders. Classically, n-3 PUFAs mediate some of these effects by antagonizing n-6 PUFA (arachidonic acid)-induced proinflammatory prostaglandin E2 (PGE2) formation. Another well-known mechanism by which n-3 PUFAs impart their anti-inflammatory effects is via reduction of nuclear factor-?B activation. This transcription factor is a potent inducer of proinflammatory cytokine production, including interleukin 6 and tumor necrosis factor-a, both of which are decreased by EPA and DHA. Other evidence also demonstrates that n-3 PUFAs repress lipogenesis and increase resolvins and protectin generation, ultimately leading to reduced inflammation. Finally, beneficial effects of EPA and DHA in insulin resistance include their ability to increase secretion of adiponectin, an anti-inflammatory adipokine. In summary, n-3 PUFAs have multiple health benefits mediated at least in part by their anti-inflammatory actions; thus their consumption, especially from dietary sources, should be encouraged.
15) Fatty acids and cytokine mRNA expression in human osteoblastic cells: a specific effect of arachidonic acid
G. PRIANTE et al.
Epidemiological, clinical and experimental evidence suggests that fatty acids have a modulatory effect on bone metabolism in animals and humans. To investigate this hypothesis, we evaluated the effects of three different fatty acids, arachidonic acid (AA), eicosapentaenoic acid (EPA) and oleic acid (OA), on the expression of cytokines involved in bone remodelling. Cytokine mRNAs in the human osteoblast-like cell line MG-63 were quantified by reverse transcription-PCR. AA induced increased expression of interleukin-1a, interleukin-1ß, tumour necrosis factor-a and macrophage colony-stimulating factor mRNAs in a time- and dose-dependent manner. EPA and OA had no stimulatory effects, but instead caused a significant inhibition of AA-induced cytokine mRNA expression. Cell treatment with calphostin C, an inhibitor of protein kinase C (PKC), and cellular PKC down-regulation experiments independently resulted in significant inhibition of AA-induced cytokine expression, suggesting that a PKC-dependent mechanism accounts for the effects of AA on cytokine production. In conclusion, our study demonstrates specific effects of fatty acids on cytokine gene expression in human osteoblast-like cells. The clinical relevance of our findings requires further investigation.
16) Docosahexaenoic and Eicosapentaenoic Acids Inhibit in Vitro Human Endothelial Cell Production of interleukin-6
B Khalfoun et al
Abstract
The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a key step in the inflammatory process. Interleukin-6 (IL-6) a pleiotropic cytokine in its effects, seems to be an early indicator of acute systemic inflammation. In this study, we have examined the effects of polyunsaturated fatty acids (PUFAs) on the production of IL-6 by human unstimulated EC or EC stimulated with TNF-alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic peripheral blood lymphocytes (PBL). Twenty-four hour culture supernatants of immunoreactive IL-6 were measured by Sandwich ELISA. We have shown that the production of IL-6 was potentiated when EC were stimulated with TNF-alpha; IL-4; LPS; or monocyte-depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFAs in culture medium (100 ug/ml DHA or EPA) significantly reduces the production of IL-6 by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS or depleted PBL respectively for DHA and EPA, whereas the n-6 PUFAs (Arachidonic acid), even used at the highest concentration, was ineffective. This inhibitory effect is PUFA dose dependent but is more potent with EPA than DHA. Regardless of the mode of action, since IL-6 is known to be involved in hematopoiesis, in the regulation of the immune response and in the inflammatory reaction, these results suggest that n-3 PUFAs may play a role in suppressing inflammation. Further studies are needed to elucidate the mechanism involved and the choice between the two fatty acids for clinical and therapeutic purposes.
17) Modulation of Inflammatory Cytokines by Omega-3 Fatty Acids
Jing X. Kang and Karsten H. Weylandt
Abstract
Many human diseases have been linked to inflammation, which is mediated by a number of chemical molecules including lipid mediators and cytokines. Polyunsaturated fatty acids (omega-6 and omega-3 fatty acids) are the precursors of the lipid mediators and play an important role in regulation of inflammation. Generally, omega-6 fatty acids (e.g. arachidonic acid) promote inflammation whereas omega-3 fatty acids (e.g. eicosapentaenoic acid and docosahexaenoic acid) have anti-inflammatory properties. Omega-3 fatty acids dampen inflammation through multiple pathways. On the one hand, omega-3 fatty acids inhibit the formation of omega-6 fatty acids-derived pro-inflammatory eicosanoids (e.g. PGE2 and LTB4), and on the other hand these fatty acids can form several potent anti-inflammatory lipid mediators (e.g. resolvins and protectins). These together directly or indirectly suppress the activity of nuclear transcription factors, such as NF?B, and reduce the production of pro-inflammatory enzymes and cytokines, including COX-2, tumor necrosis factor (TNF)-a, and interleukin (IL)-1ß. This chapter focuses on the evidence from recent studies using new experimental models.
18) Effects of soybean oil emulsion and eicosapentaenoic acid on stress response and immune function after a severely stressful operation.
K Furukawa et al.
Abstract
OBJECTIVE: To investigate the effects of soybean oil emulsion and oral or enteral administration of eicosapentaenoic acid (EPA) on stress response, cytokine production, protein metabolism, and immune function after surgery for esophageal cancer. SUMMARY BACKGROUND DATA: It has been reported that safflower oil, rich in n-6 polyunsaturated fatty acid (n-6 PUFA), affects the survival rate of septic animals and decreases the immune function. It has also been reported that the administration of fish oil, in contrast, reduces these stress responses and stress-induced immunosuppression. In humans, the effects of soybean oil emulsion and the administration of EPA on stress response and immune function after surgery have not been established. METHODS: Patients who underwent esophagectomy with thoracotomy were divided into three groups. Seven patients were fed by total parenteral nutrition (TPN) with soybean oil emulsion, which accounted for 20% of total calories. Seven patients were given oral or enteral administration of 1.8 g/day EPA, in addition to TPN with soybean oil emulsion. Nine patients served as the control group; these patients received fat-free TPN. Serum interleukin-6 (IL-6), C-reactive protein, concanavalin A (con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation, natural killer cell activity, and stress hormones were measured. RESULTS: The postoperative level of serum IL-6 was significantly higher in the group receiving soybean oil emulsion than in the fat-free group. Oral or enteral supplementation of EPA with soybean oil emulsion significantly reduced the level of serum IL-6 compared with the patients receiving soybean oil emulsion. Con A- or PHA-stimulated lymphocyte proliferation decreased significantly on postoperative day 7 in all groups of patients. The supplementation of EPA with soybean oil emulsion significantly improved the lymphocyte proliferation and natural killer cell activity on postoperative day 21 compared with the group receiving soybean oil emulsion. CONCLUSIONS: Soybean oil emulsion amplifies, and the supplementation of EPA reduces, the stress response and stress-induced immunosuppression.
19) Down-Regulation of the Acute-Phase Response in Patients with Pancreatic Cancer Cachexia Receiving Oral Eicosapentaenoic Acid is Mediated via Suppression of Interleukin-6
Stephen J. Wigmore et al.
1. Weight loss in pancreatic cancer is associated with persistent elevation of the acute-phase protein response. The effect of oral administration of eicosapentaenoic acid on the regulation of the acute-phase response in weight-losing patients with pancreatic cancer was investigated in vitro and in vivo.
2. Oral supplementation with eicosapentaenoic acid, in patients with cancer cachexia, resulted in a significant reduction in the serum concentration of the acute-phase protein C-reactive protein (11.0 ± 4.8 mg/l before eicosapentaenoic acid compared with 0.8 ± 0.8 mg/l after 4 weeks of eicosapentaenoic acid, P < 0.05), but no significant reduction in the serum concentration of the hepatocyte-stimulating cytokine interleukin-6. Production of interleukin-6 by peripheral blood mononuclear cells isolated from patients was significantly reduced after supplementation with eicosapentaenoic acid (interleukin-6 production by peripheral blood mononuclear cells exposed to 10 µg of lipopolysaccharide/ml: 10.2 ± 2.1 ng/ml before supplementation with eicosapentaenoic acid compared with 3.5 ± 1.7 ng/ml after supplementation, P < 0.05) and supernatants from these cells had reduced potential to stimulate C-reactive protein production by isolated human hepatocytes (hepatocyte C-reactive protein production in response to supernatants from peripheral blood mononuclear cell cultures exposed to 10 µg of lipopolysaccharide/ml: 150.4 ± 18.6 ng/ml before eicosapentaenoic acid versus 118 ± 14.9 ng/ml after 4 weeks of eicosapentaenoic acid, P < 0.05). The potential of lipopolysaccharide-stimulated peripheral blood mononuclear cell supernatants to stimulate C-reactive protein production by hepatocytes could be attenuated by neutralizing anti-interleukin-6 antibody in control subjects and in patients before, but not after, treatment with eicosapentaenoic acid.
3. In conclusion, eicosapentaenoic acid can down-regulate the acute-phase response in patients with pancreatic cancer cachexia and this process is likely to involve suppression of interleukin-6 production.
20) ?-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes
WeiHao1 et al.
Abstract
Objective
Long-term total parenteral nutrition (TPN) in children is often complicated by parental nutrition–associated liver disease and may even lead to liver failure. Recently, the addition of ?-3 fatty acids to TPN has been shown to reduce the risk of parental nutrition–associated liver disease. The purpose of this study was to explore the anti-inflammatory effects of ?-3 fatty acids (eicosapentaenoic acid [EPA]) to demonstrate the protection of the liver against hepatic steatosis and damage.
Materials and Methods
Lipopolysaccharide (LPS) and prostaglandin E2 (PGE2) were used to stimulate human macrophages and hepatocytes (THLE-3) to induce in vitro inflammatory condition. The cells were then incubated with either ?-3 (EPA) or ?-6 (arachidonic acid) fatty acids. Supernatants were collected at different time points for the measurement of tumor necrosis factor a (TNF-a), interleukin 6 (IL-6), and interleukin 10 (IL-10) using enzyme-linked immunosorbent assay. Furthermore, pretreated macrophages by LPS stimulation and after incubation with EPA were added to prestimulated hepatocytes for the subsequent measurement of cytokine response.
Results
Eicosapentaenoic acid effectively reduced LPS-induced or PGE2-induced TNF-a and IL-6 expression, and increased IL-10 expression significantly when compared with arachidonic acid. Furthermore, supernatant collected after co-culturing EPA with macrophages also suppressed the levels of TNF-a and IL-6 in hepatocytes. This would suggest that EPA not only had an anti-inflammatory effect on macrophages and hepatocytes directly, it could indirectly reduce hepatocyte inflammation through activated macrophages.
Conclusions
The addition of ?-3 fatty acids in TPN suppresses the inflammatory response via direct and indirect routes. The findings may help explain the clinical benefits of EPA in pediatric patients receiving long-term TPN.
21) Effects of the ?-6:?-3 Fatty Acid Ratio of Fat Emulsions on the Fatty Acid Composition in Cell Membranes and the Anti-Inflammatory Action
Akifumi Hagi et al.
Abstract
Background: This study investigated the effects of parenterally administered fish oil (FO) on the fatty acid composition in rats to determine the optimal ?-6:?-3 polyunsaturated fatty acid (PUFA) ratio of fat emulsions to achieve an anti-inflammatory effect. Methods: Male Sprague-Dawley rats were infused a parenteral nutrition (PN) solution containing fat emulsions with different ?-6:?-3 PUFA ratios. The fatty acid content of phospholipids in the membranes of splenocytes was analyzed by gas chromatography (experiment 1). In addition, the amounts of leukotriene (LT) B4 and LTB5 released from peritoneal polymorphonuclear leukocytes (PMNs) were measured by high-performance liquid chromatography (experiment 2). Results: In experiment 1, after infusion of the fat emulsion containing FO, the ?-3 PUFA content in cell membranes rose to 70% of the peak value on day 1 and nearly reached a plateau on day 3. The highest ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) was achieved by administrating a PN solution with the smallest ?-6:?-3 PUFA ratio. In experiment 2, a larger amount of LTB5 was released from Ca-ionophore-stimulated PMNs taken from rats given a larger quantity of FO. The ratio of LTB5:LTB4 released from PMNs correlated positively with the EPA:AA ratio in the membranous phospholipid and in serum. Conclusions: The ?-3 PUFAs were readily incorporated into the cell membrane within 3 days of infusion with the fat emulsion. The EPA:AA ratio in membranous phospholipid in PMNs was positively correlated with the LTB5:LTB4 production ratio and was a good indicator of anti-inflammatory effects.
22) The omega-3 fatty acid, eicosapentaenoic acid (EPA), prevents the damaging effects of tumour necrosis factor (TNF)-alpha during murine skeletal muscle cell differentiation
Peter Magee et al.
Abstract
Background
Eicosapentaenoic acid (EPA) is a ?-3 polyunsaturated fatty acid with anti-inflammatory and anti-cachetic properties that may have potential benefits with regards to skeletal muscle atrophy conditions where inflammation is present. It is also reported that pathologic levels of the pro-inflammatory cytokine tumour necrosis factor (TNF)-a are associated with muscle wasting, exerted through inhibition of myogenic differentiation and enhanced apoptosis. These findings led us to hypothesize that EPA may have a protective effect against skeletal muscle damage induced by the actions of TNF-a.
Results
The deleterious effects of TNF-a on C2C12 myogenesis were completely inhibited by co-treatment with EPA. Thus, EPA prevented the TNF-mediated loss of MyHC expression and significantly increased myogenic fusion (p < 0.05) and myotube diameter (p < 0.05) indices back to control levels. EPA protective activity was associated with blocking cell death pathways as EPA completely attenuated TNF-mediated increases in caspase-8 activity (p < 0.05) and cellular necrosis (p < 0.05) back to their respective control levels. EPA alone significantly reduced spontaneous apoptosis and necrosis of differentiating myotubes (p < 0.001 and p < 0.05, respectively). A 2 hour pre-treatment with EPA, prior to treatment with TNF alone, gave similar results.
Conclusion
In conclusion, EPA has a protective action against the damaging effects of TNF-a on C2C12 myogenesis. These findings support further investigations of EPA as a potential therapeutic agent during skeletal muscle regeneration following injury.
I think this is all very encouragng for the V COVID study, and might llead to a but of a price bump. hey couild also easily do an RWE study usig insurance data kkiung at CIVID consequences between those that are abd are not usig V.
Ex - The missing genetic data (IDH) are seemingly for posthoc subgroup analyses, which are not critical to topline data based on the ITT population, so no problem.
I agree that missing MRIs are a different issue. These only affect PFS (primary) but not the secondary OS outcome (and OS may be a co-primary at this point based on FDA discussions). Full topline analyses of OS would be possible starting in a week or so as soon as all sites have signed off on the data, but PFS data may be delayed until the MRI issues are resolved. Not obvious whether the company would announce "topline" OS outcomes in the absence of final primary PFS outcomes, but I would not totally rule it out (NWBO does things differently).
Key inform from today's 10-Q:
Raf - Sorry this is late:
Reverse:40
Affirm:30
Remand:15
Settle: 15
Biosect - We are on the same page. I never denied that NWBO could change the SAP, and am very happy that they have an SAP that reflects evolving research standards (which is totally appropriate). I was responding previously to comments stating that NWBO did not have any SAP until recently, which is not the case.
I want NWBO to succeed and am all for NWBO being able to change their SAP. Not trying to argue, but they clearly had some SAP in mind at the trial outset. That analytic approach would determine the parameters for their power analysis and sample size determination. A company investing so much money in a trial without thought in advance to how the data would be analyzed would just be incredibly sloppy (and hopefully not the case for NWBO). Companies I have worked with for FDA trial design all had a statistician working on the team and had a clear analytic plan before the trial started (and discussed the plan with the FDA). Maybe this is semantics - was the analytic plan they developed ever formalized as a "SAP" they were locked into with the FDA? I don't know.
Not sure they used an adaptive design (e.g., enriching the trial for responders in mid-stream) - it seemed like a pretty traditional trial.
That rumor is not possible - Every clinical trial conducted for FDA approval is going to have a written SAP before the trial starts to make sure that analysis of the trial data is not biased by knowing what the results are. This is a key part of the trial design process. NWBO's late update of the SAP is very unusual, but at least has some legitimate rationale due to changes in knowledge of how immune therapies work and the unexpected (not planned when the trial started) availability of extremely long follow-up. They are trying to turn something bad into something good.
BSB - I think it is pretty clear that dragging the trial out was intentional for exactly the issues raised. Won't be an accident if it turns out to be crucial for approvable results.
Yep - I was one of them.
Thanks Jammy. So unless they have something really funky in the new SAP, the only unbiased K-M analysis they can do would be comparing initially assigned groups. Based on what you said, mixing non-crossovers with crossovers will reduce mean OS for that whole group, so the question really comes down to how much less effective is DCVAX in patients with active real progression?
Marz - I think the soft lock would simply mean that the complete data that are available would be passed to the statisticians. There will be no results announced until topline. Any data missing at the softlock could be reported in an actual follow-up publication.
Thanks Jammy. Conceptually, I was thinking about testing (a priori) Group X Intervention Timing interaction effects on OS (coding non-crossovers as 0, late treatment as 1, and early treatment as 2). If significant, that would be consistent with stairstep MOA expectations like those I suuggested. I don't do K-M analyses so was not sure if interactions can be included when setting up the model.
There is one thing I have not seen discussed specifically regarding crossover issues, although maybe because it is too obvious. While most agree that PFS is going to be confounded, it seems that many expect OS to be complicated to interpret as well because crossovers might do just as well as those initially assigned DCVAX. If a patient originally getting DCVAX progresses, this could reflect either real tumor progression or pseudoprogression. In either case, they continue getting DCVAX in a blinded manner. If there is any real efficacy, pseudoprogression should dominate the PFS events, and these people should have relatively long OS as the early PFS would not predict poor outcomes. If an original placebo patient progresses, we know that ALL of these are real tumor progression, so the DCVAX they cross over to is always fighting an actively progressing tumor. Even if DCVAX is somewhat effective, it is hard to see how the crossovers could do equally well compared to those getting DCVAX initially. I would expect stairstep OS outcomes, with initial DCVAX the longest OS, placebo non-crossovers the shortest OS, and crossovers in between. This pattern would be easy to tease out statistically, so I do not think there will end up being much of an issue of crossover confounding of OS. PFS is another matter....
Ex - No way to know for sure. The other big piece of the dataset we KNOW was missing (until recently) is the new proposed IDH (?) genetic analyses, which can take a while. That is another plausible reason to soft lock to expedite looking at main outcomes, and possibly add these genetic data later for subgroup analyses. I agree that this is all speculation though.
Abeta- Regarding your #2, it is possible but no way to know. If you are correct, this would create a messy situation, because if they did find even one of these missing people, that would change their topline results (and I doubt they would want that to occur). So, my hunch is that the information they lack is secondary data. That is just a guess though. I think at any point they can just decide to call the lost to followup cases truly lost and not to pursue this issue further. That way they get closure.
Eight - To conduct any clinical trial, there are numerous administrative steps that have to take place before actual patient enrollment can begin. Once the study design is completed and a detailed protocol is written, this has to be approved by an institutional review board (IRB) at the site where the study will be conducted to insure compliance with regulations regarding the informed consent process, and to maximize patient safety/reduce potential harms. Normally getting IRB approval is at least a 4-6 week iterative process after all of the written IRB application materials have been submitted. Most trials are also required to be listed on clinicaltrials.gov before starting enrollment, and this submission process is iterative and takes some time as well. Finally, all the nuts and bolts of setting up accounts for payment of study costs (and completing contracts with study corporate funders like Amarin), hiring/training staff, and working out optimal recruitment and data collection workflow before starting also take some time. For urgent COVID related studies, I imagine that 6-8 weeks from announcement of plans to do the study to actually starting enrollment would be possible, but it all depends on the effort and efficiency of the investigators and their staff. Research grants typically allow for up to 6 months to do all of these study start-up activities, but given the COVID focus, I assume they will be rushing to get this done ASAP.
Hank - Yes. That is my take on it based on everything that has been reported.
Consider the possibility that NWBO might have all PFS and OS data ready for hard data lock within two weeks, but might still be missing (for example) quality of life scores for a few patients. Calling a "soft lock" at that point would allow them to proceed on time with the key data analyses we all care about the most (and then publicly announce these results more quickly) rather than being held hostage to delays in obtaining non-critical data points. I think that makes perfect sense. People on the board bitching and moaning about not getting exact dates for things obviously have never run a large clinical trial (I have). It is complicated with a lot of unpredictable things, especially given the chaos now in healthcare institutions due to Covid-19 (for example, until very recently, most faculty and staff in my instition were prohibited from coming in to work and no elective surgeries or non-emergent in-person outpatient visits were allowed). Many companies avoid ambiguous data lock timing issues simply by not announcing when data lock occurs (e.g., Amarin), but NWBO in this case is communicating openly on this issue (a nice change of pace) and providing the most specific information they can at this point. The should get credit for trying, and topline results will be announced soon enough.
Blue - Thanks for sharing! Sounds really good.
Thanks STS - For my own sanity since the ridiculous court decision, I have just been checking the board occasionally to see if there is any major news. Just seems like a holding pattern now. I suspect the only real news we will get over the next few months will be announcement of definitive Europe plans, and the timing of that will probably be out of the blue. I am hoping Europe can help us recover at least some of the lost share value, but I am also waiting impatiently for an appeals court miracle (as is everyone here).
Eight - This Phase-2 study link seems to be the originally planned study they announced previously based on the methods that are described, and it has not yet started recruiting. So, I don't think there are any study results yet, and certainly no second study. I couldn't read the full WSJ article so not sure what information they reported regarding Vascepa. Can anyone who read the full article indicate if any COVID-19 trial results for V were mentioned. TIA.
If I were Amarin, once Hikma/DRL generic version of V hits the pharmacies, I would sample them regularly for purity and turn them into the FDA ASAP if any irregularities are found.
FWIW - Fidelity research on NWBO indicates that Columbine Capital Services upgraded NWBO to "Outperform" on 5/5/20. That is the only firm listed as covering NWBO on Fidelity.
Marzan - I wanted to let you know that you are the sole reason I bought NWBO several years ago (I saw your posts about it on the AMRN board). I will owe you big if this pans out the way I suspect it will, and it will offset the profits I have lost with the recent bad AMRN news. So, a tentative thanks to you for posting about NWBO way back when!
AMRN and NWBO have interesting parallels. I was able to use publicly announced event rate data from AMRN's then-ongoing clinical trial to calculate that chances of their success were very high under every plausible clinical scenario, even though most investors discounted this. Similarly, NWBO has publicly announced blinded OS data in the JTM article and at SNO, and these look terrific under all rational clinical scenarios. For the interim blinded DCVax trial data to indicate ultimate failure regarding OS requires one to assume that that they somehow managed to enroll the most healthy, lucky, and long-lived GBM patients in any trial ever conducted. That is WAY less likely than DCVax actually working. Admittedly it is hard to tell if PFS will succeed, but I do not feel this surrogate measure is as important as actual (not K-M estimated) long-term clinical survival data, and strongly suspect the FDA would agree. I know many make fun of how long this trial has taken, but the flip side is that our trial has outcome data (real not surrogate or estimated) unlike any other cancer trial, and we will be treated differently (i.e., approval even if the primary PFS outcome fails) as a result.
I now have 150,000+ NWBO shares at a cost basis of $0.19. Love seeing this action today, and IIRC it is the biggest one day PPS increase I can recall in the last couple of years. Definitely feels different this time, reflecting a news-driven increase based on data lock timeline announced previously rather than yet more dilutive financing someone knows about and trades on before the rest of us.
I am looking forward to the excitement of the next month as we wait for data lock announcement and then TLD. GLTA!
Hamoa - Great job. Please forward to the company for use in the appeal ((in case they missed it).
That is a terrific summary! Thanks for posting.
Good point, but no idea. Hopefully this is a one off surge in costs that will not affect V coverage (which would likely not start until mid-2021). From both the risk and cost reduction perspective, providing optimal cardio disease treatment (including V) might reduce adverse events and hospitalization costs for older patients who develop Covid, so prioritizing V coverage is not out of the realm of possibility if triage is occurring. Also, private insurance is used by many people even in the countries with state-funded healthcare, and they may be less affected by budget issues.
LBL - I hope you are right. I would be ok with GIA if the PPS increases substantially short-mid term, so I could sell as needed to pay for kids' school without missing out too much on the price increase. I do not have the luxury of waiting 3 years to hit a nice price target that could be reached in 3 months with a BO, which is the only reason I am in favor of a BO.
LBL - I have heard the same rumor, but I have a hard time believing they would ever get close to that much as an offer. Might just be their bargaining position. $100 ($40 billion I think) would be one of (or THE) most expensive acquisitions by a BP for a single drug company. Lack of Europe partner deal tells me they are still looking at BO as an option, and I would be pleasantly surprised if we even got $60.
Raf -
A) Minimum $40 (because I am getting tired of waiting)
B) Minimum $20 (because of Europe value)
Rose - Cool - Thanks for sharing.
WAY too much political name calling on this board right now. COVID can strike everyone, no one can predict the future, and no one really knows what in retrospect will turn out to be the right way to handle it. I would appreciate more Amarin talk.
First quarter script growth is slow every year due to needing to meet deductibles to get V covered for some.
I recall seeing somewhere that Amarin's patent at issue was initially denied by the patent office, because decreasing TGs without raising LDL was obvious. The patent was only awarded after the specification that V would also lower ApoB made it clear that the combination of expected changes with V (lower TG and ApoB without raising LDL) when taken together, was non-obvious. I am going to assume that Amarin's attorneys did their job and made clear this issue in the trial. Based on what's posted about yesterday's call, I have to wonder how knowledgeable the lawyer was on the specifics of the patent. He may have overlooked that key ApoB issue and have been unaware of the patent history. Can't blame him for not giving great odds just based on TG and LDL effects - the patent office agreed. Given the issues above, I find it very hard to believe that a judge could find clear and convincing evidence that combined TG/LDL/ApoB effects were ALL obvious based on prior art at the time of the patent approval.