Productivity in Pharmaceutical Biotechnology R&D: The Role of Experience and Alliances

Using data on over 900 firms for the period 1988-2000, we estimate the effect on phase-specific biotech and pharmaceutical R&D success rates of a firm's overall experience, its experience in the relevant therapeutic category; the diversification of its experience, and alliances with large and small firms. We find that success probabilities vary substantially across therapeutic categories and are negatively correlated with mean sales by category, which is consistent with a model of dynamic, competitive entry. Returns to experience are statistically significant but economically small for the relatively straightforward phase 1 trials. We find evidence of large, positive, and diminishing returns to a firm's overall experience (across all therapeutic categories) for the larger and more complex late-stage trials that focus on a drug's efficacy. There is some evidence that a drug is more likely to complete phase 2 if developed by firms with considerable therapeutic category-specific experience and by firms whose experience is focused rather than broad (diseconomies of scope). Our results confirm that products developed in an alliance tend to have a higher probability of success, at least for the more complex phase 2 and phase 3 trials, and particularly if the licensee is a large firm.

Farming exposure and asthma phenotypes:In mice and men

Although several studies have shown that farmers and people with agricultural-related occupations have a higher risk of developing lung diseases such as nonallergic asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD), it has also been shown that exposure to the farm environment is associated with a protective effect on the development of atopy and allergic asthma.In this thesis, both effects of farm exposures on the immune system were studied: the protective effect against allergic asthma and the induction of non-allergic asthma. These studies were conducted among agricultural workers, and in mouse models of allergic and nonallergic lung disease. In addition, the presence of several macrophage phenotypes in animal models of allergic and non-allergic asthma was investigated, as well as the effects of exposure to farm dust extract on a macrophage cell line.This thesis demonstrated that occupational exposure to a farm environment and exposure to farm dust extracts in mice lead to a shift in the immune system towards non-allergic inflammation. This shift offers on the one hand protection against development of allergic diseases, such as allergic asthma, but is also associated with the risk of nonallergic asthma development. In addition, this thesis shows that, within the various phenotypes asthma, various inflammatory mediators and cells are important in the development and severity of airway hyperresponsiveness

Operational risk management: the basel II

This work shows the operational risk management and the importance of implementing an appropriate structure of risk management. In order to contextualize the issue was addressed the concept of risk and operational risk and the various risk categories and made the frame in the various Basel Accords. It focused on Basel II that has innovated dealing with operational risk, hitherto forgotten. In this context it was discussed the various risk assessment methods: basic, standard and advanced. The theme is organized so that there is a common thread that culminates in risk management presenting the guidelines of the BIS in this regard and a model of a risk management framework.N/

Role of uterine artery doppler at 18-22 weeks in the prediction of pre-eclampsia: a prospective study

Background: Pre-eclampsia is the most common pregnancy complication associated with serious maternal and fetal morbidity. Uterine artery Doppler reflects the impaired trophoblastic invasion of the uterine spiral arteries, which is involved in the aetiology of preeclampsia. Thus, uterine artery Doppler was proposed as a screening test for pre-eclampsia.Methods: A prospective cohort study of 100 singleton pregnancies was conducted in a tertiary centre and the study population were subjected to uterine artery Doppler study at 18-22 weeks gestation. Uterine artery Doppler indices of pulsatility index (PI), resistance index (RI) and persistence of diastolic notch was obtained and the outcome of pre-eclampsia was studied.Results: Out of 100 women, 14 women developed pre-eclampsia in which the resistance index showed a sensitivity of 21.4%, specificity of 91.8%, positive predictive value of 30% and negative predictive value of 87.7% and pulsatility index showed sensitivity of 35.7%, specificity of 90.6%, positive predictive value of 38.4% and negative predictive value of 89.6%. Diastolic notch had a sensitivity of 35.7%, specificity of 98.8%, positive predictive value of 83.3% and a negative predictive value of 90.4%.Conclusions: The high negative predictive values, indicated that women with normal Doppler velocimetry were unlikely to develop preeclampsia. Uterine artery Doppler, being non-invasive can be included during routine sonography to identify patients at risk of developing pre-eclampsia. Early, screening for pre-eclampsia will help in individualized antenatal surveillance and initiation of prophylactic therapy, early to reduce the adverse maternal and foetal complications of preeclampsia

Information management and exponencial learning in Society 5.0: foundations for an integrated system

Humanity uses the information to reduce discomfort, effort, and errors. With this in mind, headphones were invented, so that the music could be heard without disturbing others; home appliances were created to reduce the effort in washing dishes or clothes, and calculating machines were developed so that human distraction would not cause an accident in calculating the weight that a bridge could support. But the information has hardly changed the certainties and doubts about which university course to take, what the individual's daily life will be like in the academic path, which includes when and what to study, what to eat and what to do in their free time. Is there a hobby that the individual could enjoy, but does not know? There is greater access to information, but many times instead of navigating this information, the individual sinks in the middle of it. In addition, teachers and students remain stuck in the curriculum, with the same menu being provided for carnivores, vegetarians, or lactose intolerants. If before, students were beaten with wood in their hands and were attacked psychologically, having to learn the same as everyone else, nowadays only hands are no longer suffering from wood, at least in theory. Reducing mistakes in choosing a higher education course and the whole life that governs the academic path, can be a dream for many individuals, and software that collects enough information to learn about the individual and guide him/her on the beginning of their academic path could be an extremely useful compass. Knowing which university course to take, which discipline, among the electives, to choose, knowing the right time to get up according to the circadian cycle, what to do throughout the day, what and when to eat, are all informational outputs that utopian software could provide so as to contribute to the individual's success. But would such informational management drastically reduce the hassles, efforts, and mistakes to be made, or would it negatively affect the individual's life due to lack of experience with failure? Is the information learned from failure really necessary for success? This article starts from a brief history about information in education, analyses information management in Society 5.0, in the era of exponential technologies, and the construction of competence matrices. The goal is to start a debate about the delegation and trust in software, the management of personal information for individual success.info:eu-repo/semantics/acceptedVersio

Salt tolerant endonucleases for the removal of host cell DNA in Downstream Processing of enveloped viruses

Host cell DNA is a critical impurity in downstream processing of enveloped viruses. For vaccine applications, host cell DNA content should be below 10 ng per dose in the final product. Enveloped viruses exhibit an overall negative net charge on their surface and therefore have binding properties similar to DNA. Consequently, separation of virus from DNA can be cumbersome. In addition to DNA in its naked form, host cell DNA is present in virus preparations in form of chromatin. Chromatin (Figure 1) consists of complex and large structures which include DNA and highly positively charged histones. Therefore, different types of interactions of chromatin with chromatographic material and membranes can be observed, electrostatic interaction through negative charges of DNA and positive charges histones and hydrophobic interaction through hydrophobic patches of histones. Moreover, chromatin is often similar in size to viruses, further complicating their separation. We evaluated the performance of four different endonucleases, two salt tolerant endonucleases and two sensitive to salt, in the downstream processing of recombinant Measles virus. Endonuclease treatment was performed after clarification and followed by a purification step using flowthrough chromatography with Capto™ Core 700 resin. Nanoparticle tracking analysis (NTA) was used to determine size and particle concentration and TCID50 to determine the infectivity of the viruses. DNA and histones presence (in process and purified samples) were determined using PicoGreen™ assay and Western blot analysis using detecting anti-histone antibodies. The salt tolerant endonucleases are more efficient in the removal of chromatin and consequently in the removal of host cell DNA. A 97 % reduction of DNA could be observed. Please click Download on the upper right corner to see the full abstract

Virus-like particles adsorption in anion exchange chromatography media

Biotechnological and pharmaceutical industries have the development of modern vaccines and novel drug delivery systems as one of their main focus. At this point, Virus-Like Particles (VLPs) are key candidates once they have the ability to stimulate humoral and cellular immune responses combined with the inability to replicate or proliferate. VLPs are non-infectious self-assembled protein structures which mimic native viruses (lacking any viral genetic material). However great developments in VLPs manufacturing have already been achieved, their purification is still a complex process, usually slow and with low productivity. Accordingly, there is a demand for new purification strategies and unit operations. Anion exchange chromatography is well established and widely used in industry for the purification all sorts of biomolecules. It is already known that polymer-grafted media in form of charged hydrogels and/or chromatography beads have a very high protein binding capacity and they also bind large biomolecules such as plasmids and viruses. However, the separation mechanism of large biomolecules is still not well understood and this lack of knowledge hinders the development and optimization of the purification processes. To overcome this, our aim is to elucidate the adsorption mechanisms of VLPs, large proteins and protein superstructures into different types of anion exchange chromatography media including highly charged hydrogels and polymer-grafted media. The binding kinetics and equilibria of HIV-1 VLPs expressed in CHO cells and Influenza VLPs expressed in Baculovirus-Insect cell system have been measured for polymer grafted media to elucidate the effect of the charged polymer. Adsorption isotherms were measured in microtiter plates and kinetics in batch mode. Gerster, P., Kopecky, E.-M., Hammerschmidt, N., Klausberger, M., Krammer, F., Grabherr, R., Mersich, C., Urbas, L., Kramberger, P., Paril, T., Schreiner, M., Nöbauer, K., Razzazi-Fazeli, E., Jungbauer, A. Purification of infective baculoviruses by monoliths (2013) Journal of Chromatography A, 1290, 36-45. Jungbauer, A., Hahn, R. Polymethacrylate monoliths for preparative and industrial separation of biomolecular assemblies (2008) Journal of Chromatography A, 1184 (1-2), 62-79. Jungbauer, A. Chromatographic media for bioseparation (2005) Journal of Chromatography A, 1065 (1), 3-12

Hydrothermal processing of corn residues:process optimisation and products characterisation

Hydrothermal processing was used as pre-treatment method for the selective solubilisation of hemicellulose from corn residues (leaves and stalks). The raw material was treated at a liquidto- solid ratio of 10 g/g, under non-isothermal conditions (150-240ºC) and the effect of treatment on the composition of both liquid and solid phases was evaluated. The yields of solid residue and soluble products, e.g., oligosaccharides, monosaccharides, acetic acid and degradation compounds, such as furfural, hydroxymethylfurfural are presented and interpreted using the severity factor (log R0). The operational conditions leading to the maximum recovery of XOS (53% of initial (arabino)xylan) and for highest glucan content of the solid residue (64%) were established for log R0 of 3.75 and 4.21, respectively. Under the severest condition 95% of xylan was selectively solubilised and 90% of initial glucan was recovered on the solid residue, making it very attractive for further processing in a biorefinery framework