Biosimilar medicines and patient registries – expectations, limitations, and opportunities

Abstract Introduction: Biology therapies in a various medical specializations and for a broad spectrum of indications were launched during last two decades. As a new in class the therapies were obliged to provide additional data re gar ding efficacy and safety after their real medical practice integration. Patient registries, databases collecting various patient data, were introduced to grant data on the treatment effectiveness, safety, and long-term on treatment survival. Satisfactory treatment effect and acceptable safety profile were confirmed after couple of years of careful observation. However, the benefits were usually offered at much higher treatment costs compared to the standard therapies. Biologically similar drugs, so-called biosimilars (B.S), are being launched after original molecule patent protection expiry during recent years. They were expected as an ideal solution to avoid distinct impact on the medical budget: comparable effect for less money. The unsubstantiated doubts about biosimilar efficacy and safety were the reason of the late launch in many markets. Since biosimilars are considered as new therapy entities, the cautiousness to certain extent should be required. Information gained from post-marketing observations and patient registries over several years, confirmed the biosimilar product comparable quality. Healthcare budget savings could secure easier therapy access for more new patients.</jats:p

Analysis of the source of heterogeneity in the osmotic response of plant membrane vesicles

Plasma membrane vesicles have been widely employed to understand the biophysics of water movements, especially when active aquaporins are present. In general, water permeability coefficients in these preparations outcome from the analysis of the osmotic response of the vesicles by means of light scattering. As from now, this is possible by following a theoretical approach that assumes that scattered light follows a single exponential function and that this behavior is the consequence of vesicle volume changes due to an osmotic challenge. However, some experimental data do not necessarily fit to single exponentials but to double ones. It is argued that the observed double exponential behavior has two possible causes: different vesicle population in terms of permeability or in terms of size distribution. As classical models cannot identify this source of heterogeneity, a mathematical modeling approach was developed based on phenomenological equations of water transport. In the three comparative models presented here, it was assumed that water moves according to an osmotic mechanism across the vesicles, and there is no solute movement across them. Interestingly, when tested in a well described plasma membrane vesicle preparation, the application of these models indicates that the source of heterogeneity in the osmotic response is vesicles having different permeability, clearly discarding the variable size effect. In conclusion, the mathematical approach presented here allows to identify the source of heterogeneity; this information being of particular interest, especially when studying gating mechanisms triggered in water channel activity.Instituto de Física de Líquidos y Sistemas Biológico

Menestykseni salaisuus : Työelämässä menestyjien syyselityksiä omalle menestykselleen

Tausta Työelämässä menestymistä käsittelevät tutkimukset ovat perinteisesti jakaneet työelämässä menestymisen käsitteen objektiivisesti koettuun menestymiseen ja subjektiivisesti koettuun menestymiseen. Objektiivinen menestyminen tarkoittaa faktapohjaisia asioita, kuten hierarkkista statusta organisaatiossa. Subjektiivinen menestyminen viittaa työtyytyväisyyden kaltaiseen koettuun asiantilaan. Tutkimus käsittelee työelämässä menestymiselle annettuja syyselityksiä eli attribuutioita. Attribuutiot muodostavat tutkimukseen teoreettisen raamin, jonka sisällä ovat menestykselle annetut selitykset. Tutkimuksen päätarkoituksena on selvittää työelämässä menestymiselle annettujen attribuutioiden sisältöä, ei niiden rakennetta. Aineisto Tutkimuksen aineisto koostuu yhdeksästä työelämässä menestymisen syitä henkilökohtaisella tasolla kartoittavasta puolistrukturoidusta teemahaastattelusta. Tutkittavat ovat omien organisaatioidensa ylintä johtoa. Heidän johtamiensa organisaatioiden vaihtelevat kooltaan kymmeniä työllistävistä aina tuhansia työllistäviin. Tutkittavat edustavat varsin erilaisia toimialoja. Iältään he ovat keskimäärin 56-vuotiaita. Haastattelut toteutettiin kesällä ja syksyllä 2010. Menetelmät Työelämässä menestymisen syyselityksiä tutkittiin laadullisesti. Menetelmä on lähinnä induktiivisesti etenevä aineistölähtöinen sisällönanalyysi. Analyysiyksikkönä on pääasiassa ajatuskokonaisuus. Aineistoa käsitellään myös erilaisilla tutkimusaiheeseen liittyvillä teorioilla. Keskeiset tulokset Lapsuudessa ja nuoruudessa vanhempien esimerkki, ei niinkään neuvot, nähtiin tärkeänä attribuutiona myöhemmälle työelämämenestykselle. Tutkittavat eivät perustele menestymistään kognitiivisilla seikoilla, kuten korkeilla älyllisillä ominaisuuksillaan. He painottavat metakognitiota, omistautumistaan työlle, ahkeruuttaan ja muita motivationaalisia tekijöitä. Tutkittavat attribuoivat työelämässä menestymistään arvojensa ja ominaisuuksiensa kohtaamisella työtehtävän ja organisaation kanssa. Tutkittavat korostavat sattuman merkitystä työelämässä menestymisensä syynä

Copper tolerance of Aegilops, Triticum, Secale and triticale seedlings and copper and iron content in their shoots

Twenty-seven different cereal accessions belonging to the Triticinae subtribe were screened for copper tolerance in hydroponic cultures. Based on the shoot dry mass reduction and the decreased value of the FJFm fluorescence induction parameter the Secale species were the most tolerant ones. Slightly tolerant and relatively sensitive common wheat cultivars were also identified. No significant correlation was found between the copper and iron concentration of the shoots and the degree of tolerance

Water and solute permeability studies and its regulatory mechanisms in Beta vulgaris

El descubrimiento en el mundo vegetal de canales para el movimiento de agua (acuaporinas) ha establecido un debate que abre las puertas a nuevas investigaciones que permitan dilucidar su papel. El objetivo de la presente tesis doctoral se centró por lo tanto en el estudio funcional y molecular del transporte de agua en la vía celular usando como modelo la membrana de la vacuola (tonoplasto) del parénquima de raíz de remolacha (Beta vulgaris). Estudios a nivel de la vacuola, muestran que el cambio de volumen a largo plazo fue reversiblemente inhibido por mercurio y acidificación externa (citoplasmática), siendo nulo a pH 6.6. Se observa además una alta permeabilidad a urea, también sensible a pH. Estudios a nivel del tonoplasto muestran un alto valor de permeabilidad al agua, inhibición por mercurio y baja energía de activación, parámetros que caracterizan la presencia acuaporinas, corroborado con anticuerpos específicos contra acuaporinas de tonoplasto (TIPs). Estudios a nivel molecular, con la sobrexpresión de una TIP en ovocitos de Xenopus mostraron actividad funcional pero no efecto de pH. Sin embargo, acuaporinas de membrana plasmática (PIPs), sobrexpresadas en el mismo sistema, fueron fuertemente inhibidas por la acidificación intracelular. Mediante mutagénesis dirigida se localizó el residuo sensor de pH, una histidina, fuertemente conservada y responsable de la sensibilidad a pH de estas acuaporinas. Este trabajo aporta por lo tanto evidencias que permiten fundamentalmente replantear el papel de la vía celular y establecer al pH como un importante mecanismo de regulación del pasaje de agua en plantas.The discovery of channels that facilitate water movement in plant cells has established a new debate that opens the possibility of new research work than can help to elucidate their role in plant water transport. The objective of this thesis work is therefore to characterize at a functional and molecular level water transport in the cellular pathway employing as a model the vacuole membrane (tonoplast) of red beet (Beta vulgaris) root parenchyma. At the cellular level, our findings showed that long term volume changes was reversibly inhibited by mercury chloride and external acidification, being abolished at pH 6.6. A high permeability to urea, also blocked by low pH was also observed. At the level of the tonoplast, our findings showed high water permeability, mercurial inhibition, low activation energy, parameters that are consistent with the presence of functional aquaporins, which were also confirmed by antibodies against tonoplast aquaporins or TIPs. At the molecular level, studies overexpressing a TIP clon in Xenopus oocytes showed functional aquaporin activity but lack of a pH response. On the other hand, overexpression of plasmalemma aquaporins or PIPs was highly sensitive to cytoplasmic acidification. Site directed mutagenesis allowed to localize the residues responsible of the pH sensing, a histidine, highly conserved in PIPs. The described work allowed us to revisit the role of the cellular pathway in water transport and that to postulate that cytoplasmic acidification is an important regulatory mechanism involved in plant water transport.Fil: Sutka, Moira Romina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Analysis of the source of heterogeneity in the osmotic response of plant membrane vesicles

Plasma membrane vesicles have been widely employed to understand the biophysics of water movements, especially when active aquaporins are present. In general, water permeability coefficients in these preparations outcomes from the analysis of the osmotic response of the vesicles by means of light scattering. As from now, this is possible by following a theoretical approach that assumes that scattered light follows a single exponential function and that this behavior is the consequence of vesicle volume changes due to an osmotic challenge. However, some experimental data do not necessarily fit to single exponentials but to double ones. It is argued that the observed double exponential behavior has two possible causes: different vesicle population in terms of permeability or in terms of size distribution. As classical models can not identify this source of heterogeneity, a mathematical modeling approach was developed based on phenomenological equations of water transport. In the three comparative models here presented, it was assumed that water moves according to an osmotic mechanism across the vesicles, and there is no solute movement across them. Interestingly, when tested in a well described plasma membrane vesicle preparation, the application of these models indicates that the source of heterogeneity in the osmotic response is vesicles having different permeability, clearly discarding the variable size effect. In conclusion, the here presented mathematical approach allows to identify the source of heterogeneity; being this information of particular interest, especially when studying gating mechanisms triggered in water channel activity.Fil: Alleva, Karina Edith. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Biomembranas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; ArgentinaFil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Sutka, Moira Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Biomembranas; ArgentinaFil: Amodeo, Gabriela. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Biomembranas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentin

The water to solute permeability ratio governs the osmotic volume dynamics in beetroot vacuoles

Plant cell vacuoles occupy up to 90% of the cell volume and, beyond their physiological function, are constantly subjected to water and solute exchange. The osmotic flow and vacuole volume dynamics relies on the vacuole membrane -the tonoplast- and its capacity to regulate its permeability to both water and solutes. The osmotic permeability coefficient (Pf) is the parameter that better characterizes the water transport when submitted to an osmotic gradient. Usually, Pf determinations are made in vitro from the initial rate of volume change, when a fast (almost instantaneous) osmolality change occurs. When aquaporins are present, it is accepted that initial volume changes are only due to water movements. However, in living cells osmotic changes are not necessarily abrupt but gradually imposed. Under these conditions, water flux might not be the only relevant driving force shaping the vacuole volume response. In this study, we quantitatively investigated volume dynamics of isolated Beta vulgaris root vacuoles under progressively applied osmotic gradients at different pH, a condition that modifies the tonoplast Pf. We followed the vacuole volume changes while simultaneously determining the external osmolality time-courses and analyzing these data with mathematical modeling. Our findings indicate that vacuole volume changes, under progressively applied osmotic gradients, would not depend on the membrane elastic properties, nor on the non-osmotic volume of the vacuole, but on water and solute fluxes across the tonoplast. We found that the volume of the vacuole at the steady state is determined by the ratio of water to solute permeabilites (Pf /Ps), which in turn is ruled by pH. The dependence of the permeability ratio on pH can be interpreted in terms of the degree of aquaporin inhibition and the consequently solute transport modulation. This is relevant in many plant organs such as root, leaves, cotyledons, or stems that perform extensive rhythmic growth movements, which very likely involve considerable cell volume changes within seconds to hours.Instituto de Física de Líquidos y Sistemas BiológicosFacultad de Ciencias Exacta

The Water to Solute Permeability Ratio Governs the Osmotic Volume Dynamics in Beetroot Vacuoles

Plant cell vacuoles occupy up to 90% of the cell volume and, beyond their physiological function, are constantly subjected to water and solute exchange. The osmotic flow and vacuole volume dynamics relies on the vacuole membrane -the tonoplast- and its capacity to regulate its permeability to both water and solutes. The osmotic permeability coefficient (Pf) is the parameter that better characterizes the water transport when submitted to an osmotic gradient. Usually, Pf determinations are made in vitro from the initial rate of volume change, when a fast (almost instantaneous) osmolality change occurs. When aquaporins are present, it is accepted that initial volume changes are only due to water movements. However, in living cells osmotic changes are not necessarily abrupt but gradually imposed. Under these conditions, water flux might not be the only relevant driving force shaping the vacuole volume response. In this study, we quantitatively investigated volume dynamics of isolated Beta vulgaris root vacuoles under progressively applied osmotic gradients at different pH, a condition that modifies the tonoplast Pf. We followed the vacuole volume changes while simultaneously determining the external osmolality time-courses and analyzing these data with mathematical modeling. Our findings indicate that vacuole volume changes, under progressively applied osmotic gradients, would not depend on the membrane elastic properties, nor on the non-osmotic volume of the vacuole, but on water and solute fluxes across the tonoplast. We found that the volume of the vacuole at the steady state is determined by the ratio of water to solute permeabilites (Pf /Ps), which in turn is ruled by pH. The dependence of the permeability ratio on pH can be interpreted in terms of the degree of aquaporin inhibition and the consequently solute transport modulation. This is relevant in many plant organs such as root, leaves, cotyledons, or stems that perform extensive rhythmic growth movements, which very likely involve considerable cell volume changes within seconds to hours.Fil: Vitali, Victoria Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Sutka, Moira Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Amodeo, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Chara, Osvaldo. Technische Universität Dresden; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Ozu, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentin

A Harmonized Nitrous Oxide (N2O) Ocean Observation Network for the 21st Century

Nitrous oxide (N2O) is an important atmospheric trace gas involved in tropospheric warming and stratospheric ozone depletion. Estimates of the global ocean contribution to N2O emissions average 21% (range: 10 to 53%). Ongoing environmental changes such as warming, deoxygenation and acidification are affecting oceanic N2O cycling and emissions to the atmosphere. International activities over the last decades aimed at improving estimates of global N2O emissions, including (i) the MarinE MethanE and NiTrous Oxide database (MEMENTO) for archiving of quality-controlled data, and (ii) a recent large-scale inter-laboratory comparison by Working Group 143 of the Scientific Committee on Ocean Research (SCOR). To reduce uncertainties in oceanic N2O emission estimates and to characterize the spatial and temporal variability in N2O distributions in a changing ocean, we propose the establishment of a harmonized N2O Observation Network (N2O-ON) combining discrete and continuous data from various platforms. The network will integrate observations obtained by calibrated techniques, using time series measurements at fixed stations and repeated hydrographic sections on voluntary observing ships and research vessels. In addition to exploiting existing oceanographic infrastructure, we propose the establishment of central calibration facilities in selected international laboratories to improve accuracy, and ensure standardization and comparability of N2O measurements. Final data products will include a harmonized global N2O concentration and emission fields for use in model validation and projections of future oceanic N2O emissions, to inform the global research community and policy makers