Characterization of the structural modifications accompanying the loss of HBsAg particle immunogenicity

The aim of this work was to further understand the relationship between the immunogenicity and the structure of Hepatitis B surface antigen (HBsAg) particles used in Hepatitis B vaccines. To reach this aim, we compared by using a large range of techniques, the structure and properties of untreated particles with those of particles stored for 3 weeks at +60 °C, a treatment which resulted in a loss of HBsAg antigenicity (toward RF-1 mAb) and immunogenicity (in mice). While untreated particles imaged by electron microscopy and atomic force microscopy appeared as isolated nanoparticles of ∼ 20 nm, heated particles appeared as long chains of particle aggregates with a partial loss of their protein protrusions. Moreover, infrared spectroscopy and circular dichroism revealed that the secondary structure of the S proteins was significantly affected, with a loss of 10% of their α-helix content. Steady-state and time-resolved fluorescence data further revealed strong modifications of the most emitting Trp residues at the particle surface, confirming significant changes in the conformation of the S proteins. Moreover, modifications in the organization of both the lipid core and lipid membrane surface of the heated particles were evidenced by environment-sensitive 3-hydroxyflavone probes. Taken together, our data evidenced a clear relationship between the bona fide S protein structure and lipid organization notably at the particle surface and the particle immunogenicity.     

The plasminogen activator inhibitor-1 −675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH Study

Summary. Although the potential role of plasminogen activator inhibitor‐1 (PAI‐1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial. Objectives: To investigate whether plasma PAI‐1 concentrations and the ?675 4G/5G polymorphism located in the PAI‐1 gene could constitute risk markers for myocardial infarction (MI). Patients and methods: We used a European case–control study, the HIFMECH study, comparing 598 men with MI and 653 age‐matched controls. Results: Insulin resistance explained a major part of the variation in PAI‐1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI‐1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase = 1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR = 1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR = 1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI‐1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P = 0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P = 0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI‐1 antigen concentrations (P = 0.01 and 0.02 after adjustment for PAI‐1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C‐reactive protein (P = 0.01). Conclusion: This study suggests that PAI‐1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the ?675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.     

Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic acetylcholinesterase) or nonexisting (synaptic acetylcholinesterase). Here we identify a unique form of recombinant human butyrylcholinesterase that mimics the native enzyme assembly into tetramers; this form provides extended effective pharmacokinetics that is significantly enhanced by polyethylene glycol conjugation. We further demonstrate that this enzyme (but not a G117H/E197Q organophosphorus acid anhydride hydrolase catalytic variant) can prevent morbidity and mortality associated with organophosphorous nerve agent and pesticide exposure of animal subjects of two model species.     

The field of cancer research: an indicator of present transformations in biology

'Biology and cancer research have developed together. Invariably, at each stage, the characteristics of the cancer cell have been ascribed to some defect in whatever branch of biology happens at the time to be fashionable and exciting; today, it is molecular genetics'. Tremendous transformations have occurred in cancer research since these few lines were written by John Cairns: the discovery of oncogenes and anti-oncogenes, and the successful development of 'magic bullets' targeting the proteins encoded by these oncogenes. Nevertheless, Cairns' message is still valid. In 1978, he observed the first attempts to apply the tools and concepts of molecular biology to cancer; today, this research field reflects multiple and diverse efforts that go 'beyond' molecular biology by looking for explanations that have been left aside during its development, or by privileging new approaches, fully original or actively pursued in other fields of biological research. Because of this specific characteristic of cancer research, it is possible to use it as an indicator of trends in biological research in general.     

Interaction between the C-260T polymorphism of the CD14 gene and the plasma IL-6 concentration on the risk of myocardial infarction: the HIFMECH study

Experimental and clinical observations suggest that innate immunity plays a major role in the pathogenesis and progression of atherosclerosis. A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with coronary heart disease. Our objective was to evaluate the contribution of the CD14 polymorphism to the inflammatory response and to the risk of myocardial infarction (MI). We used an European case-control study, the HIFMECH study, comparing 533 men with MI and 575 sex- and age-matched controls. Associations between genotype and disease outcome, according to interleukin-6 (IL-6) and C-reactive protein (CRP) levels, were assessed using conditional logistic regression. The CD14/C-260T polymorphism was associated with plasma IL-6 levels, T/T subjects having higher plasma levels than C/C in cases but not in controls (mean+/-S.D.: 2.04+/-1.37 versus 1.70+/-1.15, p=0.01; 1.20+/-0.75 versus 1.35+/-0.88, p=0.31, respectively). Overall, the CD14/C-260T polymorphism was not associated with the risk of MI. However, in individuals with IL-6 plasma levels in the highest tertile, T allele carriers had a higher risk of MI than C/C (OR: 1.85; CI 95 1.05-3.25). IL-6 increased the risk of MI in carriers of the T allele (OR for first versus third IL-6 tertile: 4.02; CI 95 2.24-7.21), but not in C/C (OR: 0.75; CI 95 0.32-1.74, p=0.004 for interaction). The data indicate a role for CD14/C-260T in MI. The risk mediated by the polymorphism is highly dependent on IL-6 plasma levels.     

Functioning gonadotroph adenoma with severe ovarian hyperstimulation syndrome: A new emergency in pituitary adenoma surgery? Surgical considerations and literature review

The authors reported 2 cases of functioning gonadotroph pituitary adenoma (FGPA) revealed by an ovarian hyperstimulation syndrome (OHSS) in young women. In the first case, OHSS was observed after GnRH analog injection. Pelvic echography revealed multiple voluminous ovarian cysts. Dopamine agonist posology failed in estradiol hypersecretion control, which necessitated endoscopic endonasal transsphenoidal surgery. The patient experienced improvement in pelvic pain as estradiol hypersecretion decreased during the first few postoperative days. Outcome was favorable, and her menstrual cycle was normal after two months. The second case was a young girl with spontaneous pelvic pain and elevated plasma FSH and estradiol levels. FGPA was confirmed on cerebral MRI. Dopamine agonists were introduced, and surgical removal of the pituitary tumor was scheduled for 7 days later. In the meantime, the patient was admitted and underwent surgery for bilateral adnexal torsion related to OHSS. The pituitary tumor was removed one week later. Outcome was favorable, and estradiol and FSH plasma levels were normal after 3 months. The ovarian cysts were no longer visible on echography after 3 months. Given the lack of efficacy of the current standard medical therapy, surgical removal of pituitary adenomas is the reference treatment for FGPA. The authors suggest that severe OHSS related to FGPA should be considered as a relative surgical emergency and that surgery should not be unduly delayed, given the unpredictable risk of adnexal torsion, particularly in case of voluminous ovarian cysts. The authors performed a literature review on this topic.     

Antithrombotic efficacy of bivalirudin compared to unfractionated heparin during percutaneous coronary intervention for acute coronary syndrome

Bivalirudin is associated with an increased risk of acute stent thrombosis (AST) compared to unfractionated heparin (UFH) in acute coronary syndrome patients (ACS) during short-duration percutaneous coronary intervention (PCI). The mechanisms involved are unknown. We aimed to investigate the antithrombotic efficacy of bivalirudin compared to UFH during PCI. In a monocenter study, we prospectively enrolled 30 patients undergoing PCI for a non–ST elevation ACS. They were randomly assigned to a single intravenous (IV) bolus of UFH (70 IU/kg) or an IV bolus of bivalirudin 0.75 mg/kg followed by a 1.75 mg/kg/h infusion during PCI. All patients received a loading dose (LD) of 180 mg of ticagrelor at the time of PCI. The VASP index and activated partial thromboplastin time (aPTT) were used to assess the course of platelet reactivity (PR) and antithrombotic activity. The two groups were similar regarding baseline, angiographic, and interventional characteristics. There was no difference between the two groups in the course of PR following ticagrelor LD. An optimal PR inhibition was obtained 4 h after the LD of ticagrelor. The level of antithrombotic activity was significantly lower in the bivalirudin group compared to the UFH group (p < 0.001) during PCI but similar at 2 and 4 h post-PCI. We observed that, in ACS undergoing PCI, the antithrombotic efficacy of an IV bolus of bivalirudin is significantly lower than that of a 70-IU/kg UFH bolus. This could contribute to the excess in thrombotic acute events observed during short-duration PCI.