Anti-HER2 vaccines: new prospects for breast cancer therapy

Each year, breast cancer accounts for more than 400,000 new cancer cases and more than 130,000 cancer deaths in Europe. Prognosis of nonmetastatic breast cancer patients is directly related to the extent of the disease, mainly nodal spreading and tumor size, and to the molecular profile, particularly HER2 over-expression. In patients with HER2-over-expressing tumors, different studies have shown cellular and/or humoral immune responses against HER2 associated with a lower tumor development at early stages of the disease. These findings have led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-over-expressing tumor growth. Taken together with the clinical efficiency of trastuzumab-based anti-HER2 passive immunotherapy, these observations allowed to envisage various vaccine strategies against HER2. The induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be either composed of tumoral allogenic cells or autologous cells, or specific to HER2. It can be delivered by dendritic cells or in a DNA, peptidic or proteic form. Another area of research concerns the use of anti-idiotypic antibodies mimicking HER2.     

Safflower seeds in corn silage and alfalfa hay based early lactation diets: A practice within an optimum forage choice

Safflower seed (SS), Carthamus tinctorius L., has the highest concentration of linoleic acid among 80 oilseeds. It was hypothesized that an Iranian variety of SS can be effectively fed with cottonseeds (CS) to maintain feed intake, energy metabolism and productivity of early lactation cows under negative energy balance. Our objective was to determine effects of feeding diets containing 100 g whole CS with (1) no SS (SS0), (2) 75 g CS + 25 g SS (SS25), or (3) 50 g CS + 50 g SS (SS50), per kg of dietary DM, on feed intake, rumen fermentation, blood metabolites and milk production of early lactation cows fed diets based on a uniform mixtures of alfalfa hay and corn silage. Nine multiparous early lactation Holstein cows (46 ± 7 d in milk) were used in a replicated 3 × 3 Latin square design study with three 21-d periods. Each period had 14 d of adaptation and 7 d of data collection. Dietary inclusion of SS did not affect (P>0.10) DM intake, rumen pH and concentrations of ammonia and VFA, blood concentrations of insulin, non-esterified fatty acids, urea and triglycerides, and milk production. Adding SS linearly reduced blood glucose (P=0.05) and beta-hydroxybutyric acid (P<0.05), and increased blood total cholesterol (P<0.01) and low-density lipoproteins (P<0.05) concentrations. Results demonstrated that SS as an economical and rich source of essential fatty acids can be included up to 50 g/kg of dietary DM alongside CS for early lactation cows without affecting feed intake while maintaining rumen fermentation, peripheral energy supply and milk production.     

Lens antigen development in chick embryos studied in vivo and in vitro by immunofluorescence.

Lens antigens, detected by immunofluorescence using rabbit antiserum against adult chick lens, appear in the chick embryo at stage 16. When eye rudiments are cultured in vitro, antigens developed; but they did not when optic cups were cultured but for a few cases. Isolated presumptive lens ectoderm from stage 4 did not develop antigens when cultured, but such ectoderm from stages 7--9 developed lens antigens and also showed lens structures. Stage 4 ectoderm could be induced to lens antigen development by alcohol-killed cups from stages 9--13. The experimental system can be used for in vitro studies on lens induction.     

Development of a new live attenuated mumps virus vaccine in human diploid cells

A new live attenuated mumps vaccine was developed in human diploid cells. The S-12 virus was isolated from a 10-year-old girl showing typical symptoms of mumps infection, the diagnosis was confirmed by a pediatrician. The virus was isolated in green monkey kidney cells, without passage in chick embryo cavity or chick embryo fibroblasts. Attenuation of the wild virus was performed by serial passages in human diploid cells (MRC-5). The attenuated virus was characterized by identity tests, as well as by a reduction in plaque size, as marker tests. The virus was free from adventitious agents and safe for laboratory animals as well as for monkeys. The reactogenicity and immunogenicity of the S-12 virus for man was investigated by administration of a monovalent vaccine to 20 seronegative adult male volunteers and 30 children aged 1 to 5 years without history of mumps infection or vaccination. Seroconversion was obtained in 95% of the vaccinees. The new vaccine has the advantage of not requiring specific pathogen-free eggs, and being free from avian proteins and therefore can be used in sensitized patients.     

Relationships betweenin vitro andin vivo biotransformation of drugs in humans and animals: pharmaco-toxicological consequences

Given the crucial role played by hepatocytes in the detoxification/toxification processes of drugs, these cells have been increasingly used during the last decade in various pharmaco-toxicological areas. The majority of these studies have, however, dealt with animal cells, although examples of failures in the extrapolation of the data to man are frequent. This drawback, together with the ethical considerations in performingin vivo experiments, makes the application of the human hepatocyte model critical in the preclinical evaluation of new compounds. However, before making extensive use of these promising tools for prospective pharmaceutical research, one must ensure that they can generate data that correlate well with those obtainedin vivo. This is only possible through extensive studies on drugs showing a variety of phase I and phase II metabolic pathways in hepatocytes from different species, including man, and comparison within vivo data. Providing this validation step is undertaken, the use of such systems in drug research and development may greatly enhance the rational design of safe and effective drugs, allowing savings in time, cost and test materials as well as minimizing the use of animals.Abbreviations AMT 3-amino-3-deoxythymidine - AZT 3-azido-3-deoxythymidine - GAMT 5-glucuronyl-3-amino-3-deoxythymidine - GAZT 3-azido-3-deoxy-5-O--d-glucopyranuronosylthymidine - HIV human immunodeficiency virus - MAO monoamine oxidase     

A virtual model of the bench press exercise

The objective of this study was to design and validate a three degrees of freedom model in the sagittal plane for the bench press exercise. The mechanical model was based on rigid segments connected by revolute and prismatic pairs, which enabled a kinematic approach and global force estimation. The method requires only three simple measurements: (i) horizontal position of the hand (x₀); (ii) vertical displacement of the barbell (Z) and (iii) elbow angle (θ). Eight adult male throwers performed maximal concentric bench press exercises against different masses. The kinematic results showed that the vertical displacement of each segment and the global centre of mass followed the vertical displacement of the lifted mass. Consequently, the vertical velocity and acceleration of the combined centre of mass and the lifted mass were identical. Finally, for each lifted mass, there were no practical differences between forces calculated from the bench press model and those simultaneously measured with a force platform. The error was lower than 2.5%. The validity of the mechanical method was also highlighted by a standard error of the estimate (SEE) ranging from 2.0 to 6.6 N in absolute terms, a coefficient of variation (CV) ?0.8%, and a correlation between the two scores ?0.99 for all the lifts (p<0.001). The method described here, which is based on three simple parameters, allows accurate evaluation of the force developed by the upper limb muscles during bench press exercises in both field and laboratory conditions.     

MALDI-TOF mass spectrometry for the identification of freshwater snails from Senegal,including intermediate hosts of schistosomes

Freshwater snails of the genera Biomphalaria, Bulinus, and Oncomelania are intermediate hosts of schistosomes that cause human schistosomiasis, one of the most significant infectious neglected diseases in the world. Identification of freshwater snails is usually based on morphology and potentially DNA-based methods, but these have many drawbacks that hamper their use. MALDI-TOF MS has revolutionised clinical microbiology and has emerged in the medical entomology field. This study aims to evaluate MALDI-TOF MS profiling for the identification of both frozen and ethanol-stored snail species using protein extracts from different body parts. A total of 530 field specimens belonging to nine species (Biomphalaria pfeifferi, Bulinus forskalii, Bulinus senegalensis, Bulinus truncatus, Bulinus globosus, Bellamya unicolor, Cleopatra bulimoides, Lymnaea natalensis, Melanoides tuberculata) and 89 laboratory-reared specimens, including three species (Bi. pfeifferi, Bu. forskalii, Bu. truncatus) were used for this study. For frozen snails, the feet of 127 field and 74 laboratory-reared specimens were used to validate the optimised MALDI-TOF MS protocol. The spectral analysis yielded intra-species reproducibility and inter-species specificity which resulted in the correct identification of all the specimens in blind queries, with log-score values greater than 1.7. In a second step, we demonstrated that MALDI-TOF MS could also be used to identify ethanol-stored snails using proteins extracted from the foot using a specific database including a large number of ethanol preserved specimens. This study shows for the first time that MALDI-TOF MS is a reliable tool for the rapid identification of frozen and ethanol-stored freshwater snails without any malacological expertise.     

Importance of upper-limb inertia in calculating concentric bench press force

The purpose of this study was to investigate the influence of upper-limb inertia on the force-velocity relationship and maximal power during concentric bench press exercise. Reference peak force values (Fpeakp) measured with a force plate positioned below the bench were compared to those measured simultaneously with a kinematic device fixed on the barbell by taking (Fpeakt) or not taking (Fpeakb) upper-limb inertia into account. Thirteen men (27.8 +/- 4.1 years, 184.6 +/- 5.5 cm, 99.5 +/- 18.6 kg) performed all-out concentric bench press exercise against 8 loads ranging between 7 and 74 kg. The results showed that for each load, Fpeakb was significantly less than Fpeakp (P < 0.0001), whereas no significant difference was found between Fpeakp and Fpeakt. The values of maximal force (F0), maximal velocity (V0), optimal velocity (Vopt), and maximal power (Pmax), extrapolated from the force- and power-velocity relationships determined with the kinematic device, were significantly underestimated when upper-limb inertia was ignored. The results underline the importance of taking account of the total inertia of the moving system to ensure precise evaluation of upper-limb muscular characteristics in all-out concentric bench press exercise with a kinematic device. A major application of this study would be to develop precise upper-limb muscular characteristic evaluation in laboratory and field conditions by using a simple and cheap kinematic device.