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In this issue of Cancer Cell , Awad et al. report a phase 1b clinical trial combining a personalized vaccine NEO-PV-01 with chemotherapy and anti-PD-1 pembrolizumab in first-line metastatic non-squamous NSCLC. They demonstrate that this treatment regimen was well tolerated and induced neoantigen-specific CD4+ T cell responses with effector phenotype. [ABSTRACT FROM AUTHOR]

Background Proprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease. Objectives The objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a). Methods We measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial patients with coronary heart disease and/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels <100 mg/dL (baseline) and were subsequently randomized either to atorvastatin + torcetrapib, a cholesterol ester transfer protein inhibitor, or to atorvastatin + placebo. Results At baseline, both plasma PCSK9 and Lp(a) were dose-dependently increased with increasing atorvastatin doses. Compared with patients without T2D, those with T2D had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL, P = .0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL, P = .0005). Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ± 125.3 ng/mL [+3.7%], P = .005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL [+0.7%], P = .39). Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (−3.4 ± 10.7 mg/dL [−11.1%], P < .0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL [+0.1%], P = .92). Conclusion In patients at high cardiovascular disease risk, PCSK9 and Lp(a) are positively and dose-dependently correlated with atorvastatin dosage, whereas the presence of T2D is associated with higher PCSK9 but lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increases PCSK9 levels and decreases Lp(a) levels. [ABSTRACT FROM AUTHOR]

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 T cell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 T cells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans. [Display omitted] • Intravenous heterologous prime boost with SNP-ChAdOx1 elicits potent CD8 T cell responses • Antigen-specific T cells are necessary but insufficient for therapeutic efficacy • Intravenous ChAdOx1 promotes tumor regression through type I IFN-dependent TME remodeling • Type I IFN reduces the frequency of immunosuppressive Chil3 monocytes in the TME Ramirez-Valdez et al. describe an intravenous heterologous prime-boost vaccination strategy that effectively promotes tumor regression by eliciting high-magnitude anti-tumor CD8 T cell responses and modulating the tumor microenvironment through type I IFN signaling. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease–related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies. We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis -acting variants on 4719 blood proteins from the deCODE study (N = 35,559) and 4979 blood proteins from the Fenland study (N = 10,708). The meta-analysis identified genome-wide significant variants (P <5 × 10−8) at 5 loci (ABCG5/8 , TWIST2 , SPINK1 , PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP. This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets for AP. Graphical Abstract. Overview of the study design. Study design summary identifying cohorts and methods applied. The ultimate end point of the study is to identify new genetic variants, blood proteins, and therapeutic targets for acute pancreatitis. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Patients with coronary artery disease (CAD) are characterized by an impaired cardiometabolic risk profile including high levels of atherogenic apolipoprotein (apo) B-containing lipoprotein levels. Genetic studies have highlighted a critical role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism and CAD risk. Objective To determine whether improving dietary quality and increasing physical activity levels improve parameters of the cardiometabolic risk profile such as plasma apoB and PCSK9 levels in patients with CAD. Methods We recruited 86 men aged between 39 and 80 years (82 of them on statins) undergoing coronary artery bypass graft (CABG) surgery. These patients participated in a 1-year lifestyle modification program aiming at achieving a minimum of 150 minutes/week of physical activity and improving diet quality by following dietary guidelines. We used magnetic resonance imaging to measure visceral adipose tissue and a modified Bruce protocol to measure fitness levels before and after the intervention. Results Plasma apoB and low-density lipoprotein cholesterol levels were not modified by the intervention (−3.0%, P = .08 and 1.3%, P = .56, respectively), whereas non-HDL cholesterol decreased by 4.5% ( P = .04) and triglycerides by 13% ( P = .002). In contrast, PCSK9 levels increased by 5.2% after the intervention ( P = .05). HDL cholesterol and apolipoprotein A-I levels also increased (+12%, P < .0001 and + 6%, P < .0001, respectively). PCSK9 levels increased with improvements in fitness ( r = 0.23, P = .04) and visceral fat mobilization ( r = −0.23, P = .04). Conclusion In post-CABG patients, a lifestyle modification program lead to significant improvements in some parameters of the lipoprotein profile but unexpectedly increased plasma PCSK9 levels. [ABSTRACT FROM AUTHOR]

Lumkuia fuzzi is a small non-mammalian cynodont from the Middle Triassic of South Africa. It has traditionally been phylogenetically identified as a basal Probainognathia, but some studies place it more basally as the sister-group to Eucynodontia. Lumkuia is known from a single specimen comprising a skull and partial skeleton. Only the skull has been thoroughly described. Here we use synchrotron X-ray computed tomography to describe the dental series and postcranial skeleton of Lumkuia. The shoulder girdle, forearm, manual phalanges, partial vertebral column, and ribs are described. To assess the effect of these new observations on the phylogenetic position of Lumkuia , the scoring of this taxon is updated and new characters are added to two previous analyses, one supporting Lumkuia as a Probainognathia and the other in which the taxon is usually retrieved as a basal Eucynodontia. Our phylogenetic analyses all unambiguously support the position of Lumkuia as a basal Probainognathia. The most commonly retrieved synapomorphies shared by Lumkuia and the probainognathians are cranial (absence of an ectopterygoid and pineal foramen), postcranial (the procoracoid does not contribute to the glenoid fossa), and palaeoneurological (reduction of the external nasal ramus of the maxillary canal, presence of a cochlear canal) characters. The degree of skeletal ossification and stages of dental replacement and wear support that the specimen is a subadult. The forelimbs were adapted to sprawling and occasional scratch-digging, thus suggesting a facultative fossorial ecology for Lumkuia. [Display omitted] • The postcrania of Lumkuia fuzzi is described in detail using synchrotron imaging for the first time. • New phylogenetic analyses support that Lumkuia is a basal probainognathian. • Lumkuia was adapted for scratch-digging. • The dentition and dental replacement support that the holotype is a subadult. [ABSTRACT FROM AUTHOR]

Résumé La précarité, en constante augmentation, n’épargne pas les enfants. En France, l’accès aux soins est possible pour tous les enfants grâce à différentes structures et mesures existantes. Les modalités de prise en charge pour les patients étrangers font l’objet de textes de lois précis souvent peu connus du personnel soignant. Les services d’accueil d’urgences (SAU), par leurs locaux, leur organisation, leurs intervenants et l’affluence des patients, constituent un environnement particulier qui n’est pas toujours propice à la communication et peut favoriser des situations de maltraitance. L’urgence de la situation ne doit pas mettre la communication au second plan. La place de l’enfant dans le dialogue est souvent oubliée. Prendre en considération la relation triangulaire en respectant la parole de l’enfant et faire participer les parents lors des soins sont des garants d’une bonne alliance thérapeutique. La confidentialité et le secret médical dans les SAU pédiatriques sont régis par des lois. Cependant, l’évolution des pratiques thérapeutiques, du cadre de l’exercice médical et la multiplicité des intervenants imposent des contraintes fortes tant au niveau individuel que collectif, au détriment du secret médical. Summary Children suffer most from today's increasing precariousness. In France, access to care is available for all children through various structures and existing measures. The support for foreign children is overseen by specific legislation often unfamiliar to caregivers. Pediatric emergencies, their location, organization, actors, and patient flow are a particular environment that is not always suitable to communication and may lead to situations of abuse. Communication should not be forgotten because of the urgency of the situation. The place of the child in the dialogue is often forgotten. Considering the triangular relationship, listening to the child and involving the parents in care are the basis for a good therapeutic alliance. Privacy and medical confidentiality in pediatric emergencies are governed by law. However, changes in treatments and medical practices along with the variety of actors involved imply both individual and collective limitations, to the detriment of medical confidentiality. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this prospective study was to examine the relationship between plasma lipoprotein–associated phospholipase A2 (Lp-PLA2) activity and the progression rate of aortic stenosis (AS). Background We recently reported that Lp-PLA2 is highly expressed in stenotic aortic valves where it may contribute to the mineralization of valvular interstitial cells. Methods Patients with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. AS progression rate was assessed by annualized increase in peak aortic jet velocity (V peak ), mean gradient (MG), and aortic valve area index (AVAi). Circulating Lp-PLA2 activity was measured and dichotomized based on the median value. Results Of 183 patients included in this subanalysis of the PROGRESSA study, 70% were men and the mean age was 66 ± 13 years. Over the 2.5 ± 1.4 years of follow up, the AS progression rate tended to be higher in patients with high versus low Lp-PLA2 activity (annualized V peak = 0.17 ± 0.23 m/s vs. 0.12 ± 0.18 m/s; p = 0.14). There was a significant interaction (p < 0.05) between baseline AS severity and Lp-PLA2 activity with respect to impact on AS progression rate. In patients with mild AS (i.e., V peak <3 m/s; n = 123), increased Lp-PLA2 activity was associated with a significantly faster AS progression rate (V peak 0.16 ± 0.18 m/s vs. 0.09 ± 0.14 m/s; p = 0.01) but not in patients with moderate or severe AS (p = 0.99). After adjustment for other risk factors, increased Lp-PLA2 activity remained independently associated with faster AS progression rate (p = 0.005) in the former subset. Conclusions There was no significant association between plasma Lp-PLA2 activity or mass and stenosis progression in the whole cohort. However, increased Lp-PLA2 activity was associated with a faster stenosis progression rate in the subset of patients with mild AS. These findings provide an impetus for the elaboration of a randomized trial targeting Lp-PLA2 activity in patients with early stages of calcific aortic valve disease. [ABSTRACT FROM AUTHOR]

Objectives Studies performed in rodents have suggested a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in insulin resistance and impaired body fat distribution. Our objective was to examine the relationships between markers of adiposity and insulin resistance and plasma PCSK9 levels in humans. In addition, we explored the effect of a one-year lifestyle modification program on plasma PCSK9 levels in abdominally obese, dyslipidemic men. Methods Plasma PCSK9 levels were measured by ELISA in 175 abdominally obese, dyslipidemic sedentary men. Of these abdominally obese men, 117 non-diabetic individuals completed a one-year lifestyle modification program aiming at increasing cardiorespiratory fitness levels and improving nutritional quality. Results We found no association between plasma PCSK9 levels and body mass index, waist circumference, fat and fat-free mass, or visceral and subcutaneous adipose tissue measured by computed tomography. Compared to men with the lowest PCSK9 levels (bottom tertile), those with the highest PCSK9 levels (top tertile) had the most detrimental lipoprotein-lipid profile including lower LDL particle size (253.6 ± 4.0 vs. 251.6 ± 4.0 Å, p < 0.05) and higher apolipoprotein C-III levels (36.8 ± 10.6 vs. 32.3 ± 32.3, p < 0.05). These men were also characterized by higher HOMA-IR indices (6.78 ± 3.01 vs. 5.54 ± 2.91, p < 0.05). After one year, study participants lost on average 6.7 ± 4.6 kg ( p < 0.0001). Plasma PCSK9 decreased by 9.2 ± 53.7 ng/ml (3.8%, p = 0.07). Conclusions Plasma PCSK9 levels are not associated with body fat distribution indices, modestly associated with markers of insulin resistance and LDL particle size and are slightly affected by a lifestyle modification program in abdominally obese men. [ABSTRACT FROM AUTHOR]

Clinical trials have not provided evidence for a role of statin therapy in reducing aortic valve stenosis (AVS) severity in patients with documented AVS. However, whether statin therapy could prevent the onset of AVS is unknown. Our objectives were (1) to compare the incidence rates of AVS among patients treated with high-dose versus usual-dose statin or placebo and (2) to identify clinical risk factors associated with the development of AVS. We conducted post hoc analyses in 23,508 participants from 3 large-scale multicenter atorvastatin randomized blinded clinical trials: Treating to New Targets, the Incremental Decrease in End Points Through Aggressive Lipid Lowering, and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels. The main outcome measure was the incidence of clinical AVS over a median follow-up of 4.9 years (82 cases). Among patients who developed AVS, 39 (47.6%) were treated with atorvastatin 80 mg and 43 (52.4%) were treated with lower dose statin (atorvastatin 10 mg in Treating to New Targets, simvastatin 20 to 40 mg in Incremental Decrease in End Points Through Aggressive Lipid Lowering, or placebo in Stroke Prevention by Aggressive Reduction in Cholesterol Levels; hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.59 to 1.41, p [ 0.67). In multivariate analyses forcing treatment, sex, and race into the model, factors that were significantly associated with AVS included age (HR 2.17, 95% CI 1.61 to 2.93, p <0.0001 per 1-SD increment), diabetes (HR 1.67, 95% CI 1.00 to 2.80, p [ 0.05), vitamin K antagonist use (HR 3.25, 95% CI 2.06 to 5.16, p <0.0001), and previous statin use (HR 2.65, 95% CI 1.54 to 4.60, p [ 0.0008). In conclusion, random allocation to high-dose versus usual-dose statin therapy or placebo did not impact the incidence of AVS among patients without known AVS. Age, diabetes, vitamin K antagonists, and previous statin use were significant predictors of incident AVS in these high-risk patients. [ABSTRACT FROM AUTHOR]

Highlights: [•] CMT-causing mutants NEFLQ333P and NEFLP8R have different biochemical properties. [•] Celastrol induced different HSPs in cultured sensory neurons and motor neurons. [•] Celastrol treatment prevented NEFLQ333P-induced abnormalities only in motor neurons. [•] Celastrol treatment prevented NEFLP8R-induced abnormalities only in sensory neurons. [ABSTRACT FROM AUTHOR]

Abstract: Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. It comprises a group of diseases caused by mutations in genes involved in Schwann cells homeostasis and neuronal function that affect the peripheral nerves. So far mutations in more than 33 genes have been identified causing either the demyelinating form (CMT1) or the axonal form (CMT2). Genes involving a large variety of unrelated functions may lead to the same phenotype when mutated. Our review will focus on the common link between genes causing axonal phenotypes like MFN2, KIF1B, DYNC1H1, Rab7, TRPV4, ARSs, NEFL, HSPB1, MPZ, and HSPB8. While KIF1B and DYNC1H1, two genes coding for molecular motors, are directly linked to axonal transport, the involvement of the other CMT2-causing genes in this function is less obvious. However, the last years have seen a growing list of evidence demonstrating that intracellular trafficking and mitochondrial dynamics might be dysfunctional in CMT2, and these mechanisms might present a common link between dissimilar CMT2-causing genes. The involvement of impaired transport in the pathogenesis of other rare neurological diseases or recessive CMT2 is also discussed. [Copyright &y& Elsevier]

Abstract: Objective: Little is known about how visceral adipose tissue (VAT) influences circulating apolipoprotein B (apoB) levels, which reflect atherogenic risk. We have examined the effects of a 1-year lifestyle modification program on plasma apoB levels in viscerally obese men and compared post-intervention levels to those of a reference group of lean healthy men. Methods: Fasting plasma apoB levels were measured in 107 non-diabetic, viscerally obese men, before and after a 1-year lifestyle intervention program aiming at improving nutritional and physical activity/exercise habits. Results: After the intervention, subjects significantly decreased their volume of VAT (Δ =−26±18%, p <0.0001) measured by computed tomography and significantly, but modestly reduced their fasting apoB levels (Δ =−3±14%, p =0.04). When compared to the reference group, men in the intervention group still had higher apoB levels suggesting that they did not “normalize” their apoB concentrations to the level of the healthy non-obese reference men. To further explore the relationship between VAT and apoB, men in the intervention group were stratified according to quartiles of VAT achieved after the intervention. Only men of the lowest quartile of VAT (corresponding to 844±42cm3, similar to the value of the reference group; 809±52cm3 of VAT) showed plasma apoB levels which were similar to those of the reference group (0.98±0.21 vs. 0.99±0.24g/L, NS, for lowest VAT quartile and reference group, respectively). Conclusion: These results suggest that, in order to “normalize” apoB levels in response to a lifestyle modification program, viscerally obese dyslipidemic men need to achieve levels of VAT similar to healthy non-obese men. [Copyright &y& Elsevier]

Integrins are bidirectional signaling molecules on the cell surface that have fundamental roles in regulating cell behavior and contribute to cell migration and adhesion. Understanding of the mechanism of integrin signaling and activation has been advanced with truncated ectodomain preparations; however, the nature of conformational change in the full-length intact integrin molecule remains an active area of research. Here we used small angle x-ray scattering and electron microscopy to study detergent-solubilized, intact platelet integrin αIIbβ3. In the resting state, the intact αIIbβ3 adopted a compact, bent conformation. Upon activation with Mn2+, the average integrin extension increased. Further activation by addition of ligand led to stabilization of the extended state and opening of the headpiece. The observed extension and conformational rearrangement upon activation are consistent with the extension and headpiece opening model of integrin activation. [ABSTRACT FROM AUTHOR]

Abstract: The temporary residences for adolescents were set up in many French departments (territorial and administrative divisions) following the Family Conference 2004. They reflect a new concept in the field of child psychiatry and serve a large set of goals. First of all, they must provide better access to care, help adolescents overcome their reluctance to consult, and ensure appropriate timely responses. That mission is common to every “teenage residence”. Some residences however have therapeutic units and carry out a mission that goes beyond welcoming adolescents. They are to provide the most appropriate response to each demand, and either conduct an on-site follow-up or refer the patient to a partner service. Such decisions require to focus on the modalities of transference specific to adolescents, the nature of their disorders and the therapeutic resources available in the service. Deciding to refer an adolescent who has made it to consultation is not easy, nor is it always most appropriate. When they suggest a treatment, it is also their duty to put forward diverse healing modalities-plural and innovative. In this article, we will present our experience and our work at the Paris Maison des adolescents-Maison de Solenn, outlining more specifically the welcoming of the adolescents, the difficult task of redirecting certain demands and the therapeutic responses provided by our service. [Copyright &y& Elsevier]

Objectives: The aim of this study was to investigate the relationship between lipid and nonlipid biomarker levels achieved during statin therapy and the incidence of major cardiovascular events (MCVEs) in patients with stable coronary heart disease (CHD). Background: Several plasma nonlipid biomarkers have been shown to predict MCVEs in population studies. Methods: This is a nested case-control study in the TNT (Treating to New Targets) study population, a randomized trial that compared the efficacy of high- (80 mg) versus low-dose (10 mg) atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 nonlipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg and again 1 year after being randomized to 10 or 80 mg atorvastatin in 507 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1,020 control subjects. An MCVE was defined as CHD death; nonfatal, non–procedure-related myocardial infarction; resuscitated cardiac arrest; or fatal or nonfatal stroke. Results: Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were all predictive of recurrent MCVEs (p ≤ 0.009). Concentrations of many of the 18 nonlipid biomarkers were lowered by atorvastatin therapy (independent of dose). However, almost none of the nonlipid biomarker levels, whether measured after the 8-week run-in period or after 1 year of treatment with 10 or 80 mg atorvastatin, were predictive of recurrent MCVEs. Conclusions: In patients with stable CHD, atorvastatin improved plasma levels of an expanded panel of nonlipid biomarkers. However, independently of atorvastatin dose, the achieved levels of the vast majority of nonlipid biomarkers did not predict MCVEs. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691) [ABSTRACT FROM AUTHOR]

Abstract: Objective: Test the hypothesis that considering leisure-time and work-related physical activity habits in addition to the Framingham risk score (FRS) would result into better classification of coronary heart disease (CHD) risk than FRS alone. Methods: Prospective, population-based study of 9564 men and 12165 women aged 45–79 years followed for an average of 11.4 years. A modified FRS which takes into account physical activity (evaluated using a validated lifestyle questionnaire taking into account leisure-time and work-related physical activity) was computed. Results: During follow-up, 2191 CHD events occurred. Among 3369 men who were classified as intermediate risk (event rate of 12.4%) according to the FRS, 413 were reclassified into the low-risk category and 279 were reclassified into the high-risk category after modification of the FRS. After reclassification of these men, CHD event rate was of 5.3% and 18.6%, respectively for men classified at low and high CHD risk. Among 4766 women initially classified as intermediate risk (event rate of 8.4%), 1282 were reclassified into the low-risk category whereas 1071 women were reclassified into the high-risk category. After reclassification of these women, CHD event rate was of 6.8% and 12.2%, respectively for women classified at low and high CHD risk. Conclusions: Results of the present study suggest that asking simple questions about leisure-time and work-related physical activity which can be rapidly obtained by any physician at no cost could be helpful in the estimation of patients’ CHD risk. [Copyright &y& Elsevier]

Objectives: This study was designed to test the hypothesis that at any low-density lipoprotein cholesterol (LDL-C) level, other lipid parameters such as non–high-density lipoprotein cholesterol (HDL-C) levels, triglyceride (TG) levels, and the total cholesterol (TC)/HDL-C are still associated with an increased coronary heart disease (CHD) risk. Background: Although LDL-C is considered to be the primary target of lipid-lowering therapy, other parameters of the lipoprotein-lipid profile may more closely associated with CHD risk. Methods: In the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk prospective population study, 21,448 participants without diabetes or CHD between age 45 and 79 years were followed for 11.0 years. A total of 2,086 participants developed CHD during follow-up. Results: Among individuals with low LDL-C levels (<100 mg/dl), after adjustment for age, sex, smoking, systolic blood pressure, waist circumference, physical activity, and hormone replacement therapy (in women), those with non–HDL-C >130 mg/dl had a hazard ratio (HR) for future CHD of 1.84 (95% confidence interval [CI]: 1.12 to 3.04) when compared with those with non–HDL-C levels <130 mg/dl. In a similar model, individuals with TG levels >150 mg/dl had an HR of 1.63 (95% CI: 1.02 to 2.59) when compared with those with TG levels <150 mg/dl, and individuals with a TC/HDL-C ratio >5 had an HR of 2.19 (95% CI: 1.22 to 3.93) when compared with those with a TC/HDL-C ratio <5. Conclusions: In this prospective study, independently of their plasma LDL-C levels, participants with high non–HDL-C levels, high TG levels, or with an elevated TC/HDL-C ratio were at increased CHD risk. CHD risk assessment algorithms as well as lipid targets of lipid-lowering trials may also need to consider other easily available parameters such as non–HDL-C. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the effect of exercise training on markers of the lipoprotein-lipid profile and inflammatory markers in post-menopausal overweight/obese women with a moderately elevated systolic blood pressure. Methods: A total of 267 women [mean body mass index (BMI)=32.0±5.7kg/m2 and mean age=57.3±6.6 years] underwent a 6-month exercise intervention program. Exercise training was performed 3–4 times per week at a targeted heart rate corresponding to 50% of the maximal oxygen consumption. Results: Compared to baseline values, mean change in relative VO2 max (the primary endpoint) was of 1.18±2.25mL/minkg (p <0.0001), mean weight loss was of 1.4±3.3kg (p <0.0001), mean reduction in waist circumference was of 2.4±6.9cm (p <0.0001) and systolic blood pressure did not change significantly (−1.2±13.0mmHg, NS). No changes were observed in markers of the lipoprotein-lipid profile. No changes were observed for plasma levels of C-reactive protein, interleukin-6, tumor-necrosis factor-α and adiponectin. Changes in VO2 max were negatively associated with changes in body weight (r =−0.26, p <0.0001) and waist circumference (r =−0.16, p =0.01), but not with changes in cardiometabolic risk markers. Conclusion: Although exercise training significantly increased cardiorespiratory fitness in these sedentary, but metabolically healthy obese/overweight women with a moderately elevated systolic blood pressure, no significant improvements were observed in their cardiometabolic risk profile. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the association between HDL particle size measured by gradient gel electrophoresis and risk of incident coronary heart disease (CHD) in apparently healthy men and women. Methods: We performed a prospective case–control study nested in the EPIC-Norfolk cohort. Cases were apparently healthy men and women aged 45–79 years who developed fatal or nonfatal CHD (n =1035). They were matched to 1920 controls who remained free of CHD over the follow-up period of 6 years. Results: Participants with the smallest HDL particles had the most unfavourable cardiometabolic risk profile whereas those with the largest HDL particles had the most favourable risk profile. Plasma HDL cholesterol levels were found to be the best correlate of HDL particle size (r =0.58 and r =0.62, respectively, for men and women, p <0.001). Men in the highest quartile of HDL particle size had an unadjusted odds ratio (OR) for future CHD of 0.75 (95% CI, 0.57–0.97) compared to those in the bottom quartile. For women, the equivalent OR was 0.50 (0.35–0.71). After additional adjustment for diabetes, body mass index, systolic blood pressure, LDL and HDL cholesterol levels, the ORs were 1.43 (1.01–2.03) in men and 0.84 (0.52–1.35) in women. Conclusions: A decreased HDL particle size is associated with an adverse cardiometabolic risk profile. Small HDL particle size was also associated with an increased CHD risk, but this association was largely explained by traditional risk factors. [Copyright &y& Elsevier]

The objective of the present study was to determine the respective contributions of visceral adipose tissue (AT) accumulation and cardiorespiratory fitness to variation of inflammatory markers in men and women. Circulating levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and adiponectin were obtained with visceral AT (computed tomography) and fitness (physical working capacity test) levels in a sample of healthy men (n = 120) and women (n = 152) covering a wide range of adiposity. An inflammation score was developed based on gender-specific percentile values of each inflammatory marker (0 or 1), which yielded a score ranging from 0 (low) to 4 (high). Visceral AT was positively associated with C-reactive protein and interleukin-6 levels (r ≥0.35, p <0.0001), but negatively associated with adiponectin (r = −0.29, p ≤0.0003) after adjustment for fitness. After adjusting for visceral AT, fitness was not associated with variation in inflammatory markers in women and only with adiponectin in men (r = −0.20, p = 0.03). In participants with low visceral AT (<130 cm2 for men and <100 cm2 for women), prevalences of participants with an increased inflammation score were 23.9% and 28.0%, respectively, for participants with high and low fitness, whereas in subjects with increased visceral AT, prevalences of a high inflammation score were 60.0% and 61.7%, respectively, for participants with high and low fitness. In conclusion, these results suggest that the previously reported association between poor fitness and low-grade inflammation may be largely attributable to increased visceral AT accumulation and its associated state of insulin resistance, conditions frequently observed in subjects with poor cardiorespiratory fitness. [Copyright &y& Elsevier]

Abstract: The kinetics of ligand binding to hemoglobins has been measured for decades. Initially, these studies were confined to readily available pentacoordinate oxygen transport proteins like myoglobin, leghemoglobin, and red blood cell hemoglobin. Bimolecular ligand binding to these proteins is relatively simple, as ligand association is largely unimpeded at the heme iron. Although many techniques have been used to examine these reactions in the past, stopped-flow rapid mixing and flash photolysis are the most common ways to measure rate constants for ligand association and dissociation. Expression of recombinant proteins has allowed for examination of many newly discovered hemoglobins. The hexacoordinate hemoglobins are one such group of proteins that exhibit more complex binding kinetics than pentacoordinate hemoglobins due to reversible intramolecular coordination by a histidine side chain. Here, we describe methods for characterizing the kinetics of ligand binding to hexacoordinate hemoglobins with a focus on measurement of histidine coordination and exogenous ligand binding in both the ferrous and the ferric oxidation states. [Copyright &y& Elsevier]