Cell-based influenza vaccines: An effective vaccine option for under 60-year-olds.

Aim: Seasonal influenza poses a significant burden of disease, affecting not only older adults but also individuals under the age of 60. It carries a high economic burden, mainly driven by influenza-associated productivity losses in the working population. Conventional egg-based influenza vaccines may have reduced effectiveness due to antigen adaptation in eggs. In contrast, cell-based influenza vaccines are less likely to be affected by such antigen adaptation. This review aims to present real-world data (RWD) comparing the effectiveness of quadrivalent cell-based (QIVc) and egg-based (QIVe) influenza vaccines over three consecutive seasons. Methods: A comprehensive review was conducted, analyzing RWD from retrospective cohort and case-control studies on the relative vaccine effectiveness (rVE) of QIVc versus QIVe during the 2017/18-2019/20 seasons. Results: This study included six retrospective cohort studies and one case-control study, with a combined total of approximately 29 million participants. A cohort study involving people aged ≥4 years during the 2017/18 season showed a statistically significant rVE of QIVc compared to QIVe in preventing influenza-like illness, with a value of 36.2%. QIVc demonstrated statistically significant superiority over QIVe in preventing outpatient and inpatient medical encounters as observed in two cohort studies conducted during the 2018/19 and 2019/20 seasons. The rVE of QIVc compared to QIVe was found to be 7.6% in individuals aged ≥4 years and 9.5% in individuals aged ≥18 years. Three additional cohort studies conducted between 2017/18-2019/20 reported a statistically significant improvement in rVE (5.3-14.4%) of QIVc compared to QIVe in preventing influenza-related hospitalizations and emergency department visits due to influenza in individuals aged 4-64 years. In a case-control study across all three seasons, QIVc showed statistically significantly higher effectiveness compared to QIVe in preventing test-confirmed influenza, with rVEs of 10.0-14.8%. Conclusions: RWD from the 2017/18-2019/20 seasons demonstrated that QIVc is more effective than QIVe in preventing influenza-related outcomes in individuals aged 4-64 years. Preferential use of cell-based influenza vaccines, as opposed to conventional egg-based vaccines, could reduce the burden of influenza-related symptoms on individuals and alleviate the economic impact on the German population under 60 years of age.

[Cell-based influenza vaccines: an effective vaccine option for under 60-year-olds]. / Zellkulturbasierte Influenzaimpfstoffe: eine effektive Impfstoffoption für unter 60-Jährige.

The population < 60 years of age is also affected by a significant disease burden from seasonal influenza. It carries a high economic burden, mainly driven by influenza-associated productivity losses in the working population. Conventional egg-based influenza vaccines may experience reduced effectiveness due to antigen adaptation in eggs. In contrast, cell-based influenza vaccines are less likely to be affected by antigenic adaptations to the host system and showed better effectiveness in individuals 4-64 years old over several seasons compared to conventional egg-based influenza vaccines under real-world conditions. Preferential use of cell-based influenza vaccines, as opposed to conventional egg-based vaccines, could reduce the burden of influenza-related symptoms on individuals and alleviate the economic impact on the German population < 60 years of age.

Epidemiology of Pertussis and Pertussis-Related Complications in Adults: A German Claims Data Analysis.

INTRODUCTION: Pertussis is a highly contagious respiratory infection. It affects people of all ages, yet evidence of the impact of pertussis in adults with underlying conditions (UCs) is scarce. This study investigated the incidence and complication rate of pertussis in adult patients with and without UC. METHODS: A retrospective analysis was conducted using routinely collected German claims data between 2015 and 2019. Patients with and without different pneumological, cardiovascular, endocrinological, musculoskeletal, and psychological UCs were matched for incidence estimation. Logistic regression models were used to estimate the risk of pertussis depending on the presence of UCs. Negative binomial models were used to assess complication rates in patients with pertussis and with and without UC. RESULTS: In total, 4383 patients were diagnosed with pertussis during the study period. Patients with any UC had an increased risk for pertussis compared to matched patients without UC (odds ratio [OR] 1.72; 95% confidence interval [CI]1.60-1.84, p < 0.0001). Underlying asthma had the highest risk of pertussis (OR 2.70; 95% CI 2.50-2.91, p < 0.0001), followed by chronic obstructive pulmonary disease (OR 2.35; 95% CI 2.10-2.60, p < 0.0001) and depression (OR 2.08; 95% CI 1.95-2.22, p < 0.0001). Severe complications occurred in 10.8% of the pertussis cohort (13.4% with UC vs. 9.5% without UC). The UC-attributable effect on the risk of severe pertussis-related complications was significantly increased for any UC (incidence rate ratio [IRR] 1.29, 95% CI 1.19-1.39). The severe complication risk was also increased for patients aged 60+ (IRR 1.59, 95% CI 1.46-1.72). CONCLUSION: This study shows that adults with certain UCs have an increased risk for pertussis and are more likely to have complications. These results provide further evidence that pertussis is a relevant and impactful infectious disease in adults with and without certain UC, indicating that these patients need to be considered when developing vaccination recommendations to avoid pertussis and its associated complications. A graphical abstract is available with this article.

[Enhanced targeted influenza vaccines - New evidence shows higher effectiveness in older adults]. / Weiterentwickelte zielgruppenorientierte Influenzaimpfstoffe ­ Neue Evidenz zeigt höhere Effektivität bei älteren Erwachsenen.

Seasonal influenza causes a significant burden of disease in the German population and is associated with high societal costs. Persons aged 60 years and older are particularly at risk due to immunosenescence and chronic disease and account for a large proportion of influenza-associated hospitalizations and deaths. Adjuvanted, high-dose, recombinant and cell-based influenza vaccines have been developed to improve the effectiveness compared with conventional vaccines. Recent observational studies show better effectiveness of adjuvanted vaccine over conventional vaccines and similar effectiveness to the high-dose vaccine in older adults. Some countries have already considered the new evidence in their vaccination recommendations for the current or earlier seasons. The availability of the vaccines for older adults should also be ensured in Germany to guarantee a high level of vaccination protection.

National influenza surveillance systems in five European countries: a qualitative comparative framework based on WHO guidance.

BACKGROUND: Influenza surveillance systems vary widely between countries and there is no framework to evaluate national surveillance systems in terms of data generation and dissemination. This study aimed to develop and test a comparative framework for European influenza surveillance. METHODS: Surveillance systems were evaluated qualitatively in five European countries (France, Germany, Italy, Spain, and the United Kingdom) by a panel of influenza experts and researchers from each country. Seven surveillance sub-systems were defined: non-medically attended community surveillance, virological surveillance, community surveillance, outbreak surveillance, primary care surveillance, hospital surveillance, mortality surveillance). These covered a total of 19 comparable outcomes of increasing severity, ranging from non-medically attended cases to deaths, which were evaluated using 5 comparison criteria based on WHO guidance (granularity, timing, representativeness, sampling strategy, communication) to produce a framework to compare the five countries. RESULTS: France and the United Kingdom showed the widest range of surveillance sub-systems, particularly for hospital surveillance, followed by Germany, Spain, and Italy. In all countries, virological, primary care and hospital surveillance were well developed, but non-medically attended events, influenza cases in the community, outbreaks in closed settings and mortality estimates were not consistently reported or published. The framework also allowed the comparison of variations in data granularity, timing, representativeness, sampling strategy, and communication between countries. For data granularity, breakdown per risk condition were available in France and Spain, but not in the United Kingdom, Germany and Italy. For data communication, there were disparities in the timeliness and accessibility of surveillance data. CONCLUSIONS: This new framework can be used to compare influenza surveillance systems qualitatively between countries to allow the identification of structural differences as well as to evaluate adherence to WHO guidance. The framework may be adapted for other infectious respiratory diseases.

Burden of Herpes Zoster in Adult Patients with Underlying Conditions: Analysis of German Claims Data, 2007-2018.

INTRODUCTION: Several chronic underlying conditions (UCs) are known to be risk factors for developing herpes zoster (HZ) and to increase the severity of HZ and its risk of recurrence. The aim of this study was to investigate the incidence and recurrence of HZ in adult patients with one or multiple UCs. METHODS: A retrospective cohort study based on claims data representing 13% of the statutory health insurance population from 2007 to 2018 in Germany was performed. Patients aged ≥ 18 years were included when at least one of the following UCs was diagnosed: asthma, chronic heart failure, chronic obstructive pulmonary disease (COPD), coronary heart disease (CHD), depression, diabetes mellitus type 1 or 2, and rheumatoid arthritis (RA). Exact matching was used to account for differences in the distribution of age and sex between the case and matched control cohorts. Multi-morbidity was considered in sensitivity analyses by analyzing patients with only one UC. RESULTS: Patients with asthma, CHD, COPD, depression, and RA had, on average, a 30% increased risk of developing acute HZ compared to patients without any UC. RA was found to have the highest odds ratio among these conditions, varying from 1.37 to 1.57 for all age groups. Patients with depression also showed a high risk of developing HZ. Analysis of recurrence indicated that patients with at least one UC in the age groups 18-49 years and 50-59 years had the highest risk for a recurrent HZ. After experiencing a first recurrence, patients, regardless of age group, had a two- to threefold higher risk for a second recurrence. CONCLUSION: This study of representative claims data shows a higher HZ incidence and recurrence frequency in patients with UCs. These results provide relevant information for national health care guidelines and disease management programs.

Shingles is caused by the reactivation of the chickenpox virus and is characterized by a painful skin rash with blisters, commonly occurring on the trunk. Underlying conditions (UCs) are conditions that persist for a long time, require ongoing medical attention, and are rarely completely cured (chronic conditions). UCs can increase the severity, the risk, and the frequency of shingles. Here, data from a large German health care insurance provider was used to investigate whether patients with one or more UCs have a higher risk for getting shingles compared to healthy people. In particular, patients with asthma, chronic heart failure, chronic obstructive pulmonary disease, coronary heart disease, depression, diabetes, and rheumatoid arthritis were investigated. The study shows that patients with asthma, coronary heart disease, chronic obstructive pulmonary disease, depression, and rheumatoid arthritis have, on average, a 30% higher risk of developing shingles, regardless of their age. The risk of developing shingles two or more times is also higher for patients with at least one UC, with those aged 18­59 experiencing an even greater risk. It was found that patients with an UC are more exposed to develop shingles and that younger patients have a higher risk of a recurrent episode. The findings provide important information for the development or adaption of national health care guidelines and shingles vaccination recommendations.

Lactate concentration in breast cancer using advanced magnetic resonance spectroscopy.

BACKGROUND: Precision medicine in breast cancer demands markers sensitive to early treatment response. Aerobic glycolysis (AG) upregulates lactate dehydrogenase A (LDH-A) with elevated lactate production; however, existing approaches for lactate quantification are either invasive or impractical clinically. METHODS: Thirty female patients (age 39-78 years, 15 grade II and 15 grade III) with invasive ductal carcinoma were enrolled. Lactate concentration was quantified from freshly excised whole tumours with double quantum filtered (DQF) magnetic resonance spectroscopy (MRS), and Nottingham Prognostic Index (NPI), LDH-A and proliferative marker Ki-67 were assessed histologically. RESULTS: There was a significantly higher lactate concentration (t = 2.2224, p = 0.0349) in grade III (7.7 ± 2.9 mM) than in grade II (5.5 ± 2.4 mM). Lactate concentration was correlated with NPI (ρ = 0.3618, p = 0.0495), but not with Ki-67 (ρ = 0.3041, p = 0.1023) or tumour size (r = 0.1716, p = 0.3645). Lactate concentration was negatively correlated with LDH-A (ρ = -0.3734, p = 0.0421). CONCLUSION: Our results showed that lactate concentration in whole breast tumour from DQF MRS is sensitive to tumour grades and patient prognosis.

Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion.

The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA). Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a). Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins. Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness. Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin ß3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment. Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.

Circulating levels of angiogenesis-related growth factors in breast cancer: A study to profile proteins responsible for tubule formation.

The present study exploited a versatile in vitro endothelial cell/fibroblast co-culture cell system to investigate the association between angiogenesis and breast cancer by comparing the capacity of plasma from women with breast cancer and age-matched controls, to influence tubule formation and modulate angiogenesis in vitro, and to identify plasma circulating factors which might be responsible. Plasma from women with breast cancer (n=8) (added on day 7 after co-culture establishment) significantly increased tubule formation by 57% (P<0.01) when compared to cultures grown in culture medium lacking in vascular endothelial growth factor (VEGF) and fetal bovine serum (FBS), whereas plasma from controls (n=8) did not. Higher levels of VEGF, tumour necrosis factor-α (TNFα) and interleukin (IL)-6, but not leptin, were observed in plasma samples of the breast cancer group compared to the control group (n=20 in each group). In independent experiments, the effects of VEGF, TNFα, IL-6 and leptin were assessed and it was found that tubule formation was differentially affected whether these inflammatory cytokines or adipokines were added individually or in combination to the co-culture system. Using Proteome Profiler human angiogenesis array kits, 12 out of 55 angiogenesis-related proteins were differentially expressed in plasma from the breast cancer group compared to the control group. Pro-angiogenic proteins included: amphiregulin, artemin, coagulation factor III, fibroblast growth factor (FGF) acidic, GDNF, IL-8, macrophage inflammatory protein (MIP)-1α, platelet derived growth factor-AB/platelet derived growth factor-BB (PDGF-AB/PDGF-BB) and VEGF, whereas anti-angiogenic proteins were: angiopoietin-2, serpin F1 and serpin B5. In addition, FGF acidic was further identified as differentially expressed, with increased expression, when plasma samples from the normal and cancer groups, which induced an increase in tubule formation, were compared to one another. In conclusion, the present study identified angiogenesis-related proteins circulating in the serum of women with breast cancer that are likely to facilitate the growth and metastasis of breast cancer, in part through their influence on tubule formation, and, therefore, may be potential targets for new cancer therapies.

Cost for physician-diagnosed influenza and influenza-like illnesses on primary care level in Germany--results of a database analysis from May 2010 to April 2012.

BACKGROUND: Seasonal influenza is one of the most significant infectious diseases in Germany; epidemic outbreaks occur every winter and cause substantial morbidity and mortality. However, published data from Germany on the current economic burden of influenza and the costs per episode are lacking. METHODS: A retrospective database analysis was conducted using a longitudinal electronic medical records database (IMS Disease Analyzer). Patients with influenza, diagnosed by German office-based physicians using ICD-10 J09-11 (International Classification of Diseases, 10(th) revision), who were observable in the database from 12 months before the index (diagnosis) date until 1 month afterwards, were included. The selection window, defined to cover two influenza seasons, was May 2010 to April 2012. Direct and indirect costs were evaluated from payer, patient and societal perspectives. Published unit costs and tariffs from Germany (2012) were used for the analysis. RESULTS: A total of 21,039 influenza-attributable episodes in 17,836 adults, managed by primary care physicians (PCP) and 7,107 episodes in 6,288 children, managed by pediatricians, were eligible for analysis. The mean (±Standard Deviation (SD)) age of the adults with at least one episode was 46 (±18) years and 7 (±4) years in the children. The presence of clinical risk factors was documented for 39% episodes in adults and 24% episodes in children, with the most common being cardiovascular diseases in adults (29%) and chronic respiratory diseases in children (23%). Complications and severe symptoms accompanied the influenza-attributable episode (adults: 37%, children: 54%), bronchitis (adults: 16%, children: 19%) and acute upper respiratory infection (adults: 15%, children: 21%) being the most frequent. From a societal perspective, the total average mean cost (±SD) per episode was €514 (±609) in adults, where work days lost were the main cost driver (82%), and €105 (±224) in children. Complications and severe symptoms increased the cost per episode versus episodes without by 1.7 times in adults (€684 (±713) vs. €413 (±510)) and nearly 3 times in children (€149 (±278) vs. €55 (±116)). CONCLUSIONS: Based on a large patient sample derived from representative PCP and pediatricians panels, our results demonstrate that seasonal influenza is associated with substantial clinical and economic burden in Germany.

Leptin inhibits proliferation of breast cancer cells at supraphysiological concentrations by inhibiting mitogen-activated protein kinase signaling.

Leptin is a hormone secreted by white fat tissue and signals the amount of overall body fat to the hypothalamus. The circulating concentration of leptin correlates with the level of obesity. Breast cancer risk is higher in obese postmenopausal women compared with postmenopausal women of a normal weight, and high leptin concentrations may contribute to this risk. In the present study, SK-BR-3 and MDA-MB-231 breast cancer cell lines were treated with various concentrations (6.25-1,600 ng/ml) of recombinant leptin and changes in cell proliferation were assessed. The SK-BR-3 breast cancer cells exhibited a concentration-dependent increase in proliferation with physiological leptin concentrations (<100 ng/ml), but no further increase in proliferation at high leptin concentrations (>100 ng/ml) was observed. Cell proliferation was not affected at supraphysiological leptin concentrations (>800 ng/ml) in SK-BR-3 cells, whereas it decreased in MDA-MB-231 cells. Therefore, cell signaling and cell cycle changes were assessed at supraphysiological concentrations (1,600 ng/ml). In the two cell lines, leptin treatment decreased the mitogen-activated protein kinase (MAPK) cell signaling pathway activation. Leptin treatment did not increase Akt phosphorylation or significantly alter the cell population distribution across cell cycle stages. To the best of our knowledge, leptin-induced growth inhibition of breast cancer cells at supraphysiological concentrations has not been reported in the literature to date, and the findings of this study suggest that reduced MAPK activity may be the underlying cause. Thus, the effect of leptin on breast cancer growth warrants further investigation since leptin is considered to be one of the main mediators in the obesity-breast cancer connection.

Targeted vaccine selection in influenza vaccination.

BACKGROUND: The main target groups for influenza vaccination are the elderly, the chronically ill, infants, and toddlers. Influenza vaccines are needed that suit the immunological particularities of each of these age and risk groups. Recent years have seen the approval of influenza vaccines that are more immunogenic than before, but whose use in Germany is limited by the restriction of reimbursement to a small number of vaccines. METHODS: The Medline database was selectively searched for pertinent literature. RESULTS: The suboptimal immunogenicity of conventional influenza vaccines that contain inactivated viral cleavage products and subunits can be markedly improved by the use of squalene-based adjuvant systems, by the integration of viral antigens in virosomal particles, or by intradermal administration. The vaccination of elderly persons with a vaccine containing the adjuvant MF59 was found to lower the risk of hospitalization for influenza or pneumonia by 25% compared to vaccination with a trivalent inactivated vaccine (TIV). On the other hand, the adjuvant ASO3 was found to be associated with an up to 17-fold increase in the frequency of narcolepsy among 4- to 18-year-olds. In a prospective study, a virosomal vaccine lowered the frequency of laboratory-confirmed influenza in vaccinated children by 88% compared to unvaccinated children (2 versus 18 cases per 1000 individuals). A live, attenuated influenza vaccine lowered the rate of disease in children up to age 7 by 48% compared to a TIV (4.2% versus 8.1%). CONCLUSION: The newer vaccines possess improved efficacy when used for primary and booster immunization in certain age and risk groups, and they are superior in this respect to conventional vaccines based on viral cleavage products and subunits. The risk/benefit profiles of all currently available vaccines vary depending on the age group or risk group in which they are used.

Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators.

Cannabinoids-endocannaboids are possible preventatives of common diseases including cancers. Cannabinoid receptors (CB(½), TRPV1) are central components of the system. Many disease-ameliorating effects of cannabinoids-endocannabinoids are receptor mediated, but many are not, indicating non-CBR signaling pathways. Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic in most cancers, in vitro and in vivo in animals. They signal through p38, MAPK, JUN, PI3, AKT, ceramide, caspases, MMPs, PPARs, VEGF, NF-κB, p8, CHOP, TRB3 and pro-apoptotic oncogenes (p53,p21 waf1/cip1) to induce cell cycle arrest, autophagy, apoptosis and tumour inhibition. Paradoxically they are pro-proliferative and anti-apoptotic in some cancers. Differences in receptor expression and concentrations of cannabinoids in cancer and immune cells can elicit anti- or pro-cancer effects through different signal cascades (p38MAPK or PI3/AKT). Similarities between effects of cannabinoids-endocannabinoids, omega-3 LCPUFA and CLAs/CLnAs as anti-inflammatory, antiangiogenic, anti-invasive anti-cancer agents indicate common signaling pathways. Evidence in vivo and in vitro shows EPA and DHA can form endocannabinoids that: (i) are ligands for CB(½) receptors and possibly TRPV-1, (ii) have non-receptor mediated bioactivity, (iii) induce cell cycle arrest, (iii) increase autophagy and apoptosis, and (iv) augment chemotherapeutic actions in vitro. They can also form bioactive, eicosanoid-like products that appear to be non-CBR ligands but have effects on PPARs and NF-kB transcription factors. The use of cannabinoids in cancer treatment is currently limited to chemo- and radio-therapy-associated nausea and cancer-associated pain apart from one trial on brain tumours in patients. Further clinical studies are urgently required to determine the true potential of these intriguing, low toxicity compounds in cancer therapy. Particularly in view of their synergistic effects with chemotherapeutic agents similar to that observed for n-3 LCPUFA.

A novel role for insulin resistance in the connection between obesity and postmenopausal breast cancer.

The past two decades have seen a drastic increase in obesity rates in Western societies and emerging countries. As such, it has become increasingly important to understand the molecular mechanisms by which obesity affects the risk of developing associated co-morbidities. The present study aimed at identifying the effect of insulin on breast cancer and breast epithelial cells, reflective of obesity-associated hyperinsulinaemia, as a molecular explanation for the increased risk of oestrogen receptor-negative postmenopausal breast cancer in obese women. Both of the examined breast cancer cell lines (MDA­MB-231 and SK-BR-3) showed intact insulin signalling (insulin receptor phosphorylation and activation of phosphoinositol-3 kinase and mitogen-activated protein kinase cell signalling pathways), with MDA-MB-231 cells showing aberrantly amplified insulin signalling. Insulin did not induce a physiologically significant change in proliferation or apoptosis in either cell line. MDA-MB-231 cells showed decreased cell proliferation and increased S-phase population, while SK-BR-3 cells showed increased cyclin D and cyclin E gene expression and increased necrosis after insulin treatment. Hyperinsulinaemia may not be a universal mechanism by which obesity affects breast cancer progression. Normal breast epithelial cells (MCF-10A) showed intact insulin signalling, increased cell proliferation and reduced apoptosis after insulin treatment, suggesting cell growth and survival-promoting effects of insulin on these cells. Thus, hyperinsulinaemia may affect breast cancer aetiology rather than progression and this finding may provide a novel molecular mechanism for the role of insulin in the promotion of increased postmenopausal breast cancer risk in obese women.

Effect of increased consumption of whole-grain foods on blood pressure and other cardiovascular risk markers in healthy middle-aged persons: a randomized controlled trial.

BACKGROUND: Three daily portions of whole-grain foods could lower cardiovascular disease risk, but a comprehensive intervention trial was needed to confirm this recommendation. OBJECTIVES: We aimed to assess the effects of consumption of 3 daily portions of whole-grain foods (provided as only wheat or a mixture of wheat and oats) on markers of cardiovascular disease risk in relatively high-risk individuals. DESIGN: This was a randomized controlled dietary trial in middle-aged healthy individuals. After a 4-wk run-in period with a refined diet, we randomly allocated volunteers to a control (refined diet), wheat, or wheat + oats group for 12 wk. The primary outcome was a reduction of cardiovascular disease risk factors by dietary intervention with whole grains, which included lipid and inflammatory marker concentrations, insulin sensitivity, and blood pressure. RESULTS: We recruited a total of 233 volunteers; 24 volunteers withdrew, and 3 volunteers were excluded. Systolic blood pressure and pulse pressure were significantly reduced by 6 and 3 mm Hg, respectively, in the whole-grain foods groups compared with the control group. Systemic markers of cardiovascular disease risk remained unchanged apart from cholesterol concentrations, which decreased slightly but significantly in the refined group. CONCLUSIONS: Daily consumption of 3 portions of whole-grain foods can significantly reduce cardiovascular disease risk in middle-aged people mainly through blood pressure-lowering mechanisms. The observed decrease in systolic blood pressure could decrease the incidence of coronary artery disease and stroke by ≥15% and 25%, respectively. This trial was registered at clinicaltrials.gov as ISRCTN27657880.

Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines.

The omega-3 fatty acid ethanolamides, docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA), displayed greater anti-proliferative potency than their parent omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in LNCaP and PC3 prostate cancer cells. DHEA and EPEA activated cannabinoid CB(1) and CB(2) receptors in vitro with significant potency, suggesting that they are endocannabinoids. Both LNCaP and PC3 cells expressed CB(1) and CB(2) receptors, and the CB(1)- and CB(2)-selective antagonists, AM281 and AM630, administered separately or together, reduced the anti-proliferative potencies of EPEA and EPA but not of DHEA or DHA in PC3 cells and of EPA but not of EPEA, DHEA or DHA in LNCaP cells. Even so, EPEA and EPA may not have inhibited PC3 or LNCaP cell proliferation via cannabinoid receptors since the anti-proliferative potency of EPEA was well below the potency it displayed as a CB(1) or CB(2) receptor agonist. Indeed, these receptors may mediate a protective effect because the anti-proliferative potency of DHEA in LNCaP and PC3 cells was increased by separate or combined administration of AM281 and AM630. The anandamide-metabolizing enzyme, fatty acid amide hydrolase (FAAH), was highly expressed in LNCaP but not PC3 cells. Evidence was obtained that FAAH metabolizes EPEA and DHEA and that the anti-proliferative potencies of these ethanolamides in LNCaP cells can be enhanced by inhibiting this enzyme. Our findings suggest that the expression of cannabinoid receptors and of FAAH in some tumour cells could well influence the effectiveness of DHA and EPA or their ethanolamide derivatives as anticancer agents.

Enhancing cytotoxic therapies for breast and prostate cancers with polyunsaturated fatty acids.

The role of omega-3 and omega-6 fatty acids has been extensively studied in most of the human malignancies including breast, colon, prostate, pancreas, and stomach cancers. In particular, the role of omega-3 and omega-6 fatty acids in carcinogenesis has been extensively investigated in epidemiological, laboratory cell culture studies and studies in vivo in animal. Findings from these studies suggest that omega-3 and omega-6 fatty acids are cytotoxic in different cancers and act synergistically with cytotoxic drugs. Although experimental evidence for the potential beneficial role of polyunsaturated fatty acids (PUFAs) in enhancing the effectiveness of various chemotherapeutic agents in animal models and in cell culture studies is increasing, there are only a few reports that have shown supportive evidence for linking these natural compounds with augmentation of anticancer chemotherapeutics in human trials. This review presents evidence for a commonality in the proposed molecular mechanisms of action elicited by various PUFAs believed to be responsible for their enhancement of the effectiveness of anticancer chemotherapy, specifically in breast and prostate cancers, and reviews laboratory and animal studies and few reported human clinical trials. It concludes that sufficient evidence is available to suggest that major clinical trials with these natural compounds as adjuncts to standard therapies should be undertaken as a priority.