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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
161

Bactérias láticas produtoras de folato e riboflavina: isolamento e avaliação do seu potencial de aplicação na produção de produtos lácteos caprinos com alto teor de vitaminas / Folate and riboflavin producing lactic acid bacteria: isolation and evaluation of their potential application for production of goat dairy products with higher vitamin content.

Fabiana Fernanda Pacheco da Silva 15 October 2015 (has links)
O valor nutricional e as características físico-químicas fazem com que os produtos lácteos caprinos sejam muito apreciados e tenham um alto valor agregado. Muitas bactérias láticas (BAL) possuem a capacidade de produzir compostos com propriedades benéficas à saúde, inclusive vitaminas do grupo B, como a riboflavina (B2) e o folato (B9), que participam de importantes funções metabólicas. O presente estudo objetivou isolar e identificar BAL capazes de produzir folato e riboflavina, utilizando leite de cabra cru e de queijos de cabra como fonte, para em seguida, avaliar a produção destas vitaminas em leite de cabra UHT, para estimar uma possível aplicação na produção de derivados lácteos de cabra com teores mais altos destas vitaminas. Um total de 179 isolados de BAL, sendo 87 provenientes de leite e 92 de queijos, foram obtidas e analisados quanto à produção de folato e de riboflavina extracelular (EC) e intracelular (IC), empregando-se ensaios microbiológicos apropriados. A produção de folato em meio de cultura a 37ºC foi observada em 151 isolados (84,4%) e de riboflavina em 15 isolados (8,4%), sendo que 14 produziram as duas vitaminas concomitantemente. A média da produção folato total (EC + IC) foi 138,8 µg/L, sendo que em 77 isolados (51%) a produção estava acima da média. Houve diferença significativa entre as médias de produção de folato total pelos isolados de leite e de queijo. A média da produção de riboflavina total (EC + IC) foi 363,7 µg/L, sendo que em 9 isolados (60%) a produção foi acima da média. Com base no RAPD-PCR e sequenciamento da porção 16S do rDNA, foram obtidos 19 perfis genéticos diferentes e identificadas 7 espécies, com predominância de Streptococcus thermophilus (7 isolados), Weissella paramensenteroides (6 isolados) e Lactococcus lactis subsp. lactis (4 isolados). Oito isolados produtores de folato acima da média foram selecionados e submetidos à avaliação da produção de folato em leite de cabra UHT a 37°C, sendo 7 positivas, com média da concentração de folato total de 120,55 µg/L, variando de 12,97 a 261,91 µg/L. Os melhores produtores de folato em leite de cabra UHT foram Lc. lactis subsp. lactis FP368 e St. thermophilus FP34v, FP170v e FP268v. A concentração de folato produzido por estes isolados foi acima da média, evidenciando seu interessante potencial de aplicação na produção de novos derivados lácteos caprinos com teores aumentados desta vitamina. Por outro lado, não foi possível detectar a produção de riboflavina em leite de cabra por nenhum dos isolados testados. / Due to the high nutritional value and physicochemical characteristics, goat milk and cheeses are highly appreciated. Many strains of lactic acid bacteria (LAB) are able to produce vitamins from the B complex, such as riboflavin (B2) and folate (B9). These vitamins have important metabolic roles. The present study aimed to isolate riboflavin- and folate-producing LAB strains from goat milk and cheeses, and evaluate the potential application of those strains in the production of goat dairy products with higher content of these vitamins. A total of 179 LAB isolates were obtained from milk (87) and cheese (92) samples. The isolates were evaluated for production of extra (EC) and intracellular (IC) riboflavin and folate, applying appropriate microbiological methods. Among these isolates, 151 (84.4%) were able to produce folate, while 15 (8.4%) displayed the ability to produce riboflavin, and 14 produced both vitamins. The average production of total folate (EC + IC) was 138.8 µg/L, and the amount of folates produced by 77 isolates (51%) were above this average. The differences observed for the average production of total folate from milk and cheese isolates were statistically significant. For total riboflavin (EC+ IC), the average rate was 363.7 µg/L. Nine isolates (60%) presented production rates above the average. No significant difference was observed between the average production of total riboflafin from milk or cheese isolates (319.3 µg/L and 379.8 µg/L, respectively). Based on RAPD-PCR and 16S rDNA sequencing, 19 different genetic profiles were obtained and 7 species were identified, with predominance of Streptococcus thermophilus (7 isolates), Weissella paramensenteroides (6 isolates), and Lactococcus lactis subsp. lactis (4 isolates). Eight isolates that produced folate above the average were selected and tested for vitamins production in UHT goat milk at 37°C. Seven isolates produced an average of 120.55 µg/L of folate in the milk and concentration varied from 12.97 to 261,91 µg/L. The best folate producers were Lactococcus lactis subsp. lactis FP368, Streptococcus thermophilus FP34v, Streptococcus thermophilus FP170v and Streptococcus thermophilus FP268v. The amount of folate produced by these isolates surpassed the average, and was above the amounts described in other studies, evidencing their potential application in the production of goat dairy products with higher content of folate. None of the tested isolates was able to produce riboflavin in UHT goat milk.
162

Neural Tube Defects and Co-Occurring Anomalies in Europe, 1980-2015

Baqar, Aqeel Mohammad 22 November 2021 (has links)
Study questions: Does the proportion of neural tube defects (NTDs) in which there are co-occurring anomalies of other systems vary by geographical area and time in Europe between 1980 and 2015? Which group of factors, e.g., sex, age, family history, condition at discovery, and prenatal screening during pregnancy that potentially affect ascertainment of isolated NTD cases and co-occurring anomalies, are associated with the presence of these anomalies? Methods: Data on fetuses or births with NTDs recorded in 28 European Surveillance of Congenital Anomalies (EUROCAT) registries operating throughout or during a part of the period 1980-2015, were obtained and analysed. Information on the corresponding denominators of total births for each registry were compiled, comprising approximately 15.7 million births. We developed algorithms to classify NTDs that occurred as part of certain recognized genetic and unknown etiology syndromes, isolated NTD cases (either with no other anomaly reported or only an anomaly considered to be secondary to the NTD), and NTDs not occurring as part of recognized syndromes but with one or more co-occurring anomalies. We assessed factors that could impact ascertainment of isolated NTD cases and NTD cases with co-occurring anomalies. We also conducted a sensitivity analysis to evaluate the effect of family history and consanguinity on NTD outcomes. Lastly, we reported on the prevalence of NTDs across Eastern, Western, Northern, and Southern Europe as defined by the World Bank. Results: A total of 14,703 fetuses or births with NTDs were recorded in the EUROCAT registries. The total number of births (live and stillbirths) that occurred during the periods when the EUROCAT registries were operating was 15.7 million. The overall prevalence at birth of NTDs in Eastern Europe was 11.6 per 10,000 births, in Western Europe 11.0 per 10,000 births, in Northern Europe 10.5 cases per 10,000 births and in Southern Europe 6.7 per 10,000 births. The most prevalent genetic syndromes were chromosomal anomalies, particularly trisomy 18. The most common secondary anomaly was Arnold-Chiari syndrome which occurred mostly with spina bifida. The most prevalent associated anomalies were limb defects, followed by congenital heart defects, abdominal wall, and urinary system defects. We found anencephaly to be most prevalent in isolated NTD cases without secondary anomalies and spina bifida in secondary anomalies and most of the co-occurring anomalies. For factors that could affect ascertainment, we found that birth type, birth weight, family history, maternal and paternal age (≥30 years) were risk factors for isolated NTD cases and for co-occurring anomalies. Lastly, approximately 48% of NTDs occurred in Northern Europe, followed 29% in Western Europe, 16% in Southern Europe, and 7.6% in Eastern Europe. Conclusion: In the absence of folate fortification, isolated NTD cases showed higher prevalence than NTDs with co-occurring anomalies over the past 35 years across Europe. This research suggests that Europe should develop and implement policies and guidelines for folate fortification to help prevent simpler NTD cases. Further research and data are needed for newer EUROCAT registries to predict trends and prevalence of NTDs. Contribution and involvement: This project was done in collaboration with the experts from the School of Epidemiology and Public Health (SEPH) and dysmorphologists that provided support with regards to NTD classification. AB spearheaded the development of the research protocol and thesis manuscript with funding and support from JL and TR. Evaluation of the output of cases from the algorithm was provided to AB by JL, TR, JE, FB, AN, EB, ML, and the EUROCAT Joint Research Centre.
163

Exosomes as Potential Transport Vehicles of Tetrahydrobiopterin, 6-Pyrovyoltetrahydrobiopterin-Synthase and Tripeptidyl-Peptidase I

Lang, Kristina 30 November 2018 (has links)
No description available.
164

Development of dry powder formulations for inhalation based on nanomedicine for targeted lung cancer therapy

Rosiere, Rémi 28 June 2016 (has links) (PDF)
Le cancer du poumon est l’un des cancers les plus fréquents dans le monde et reste le plus meurtrier actuellement en terme d’incidence absolue. Les traitements employés chez les patients atteints d’un cancer du poumon consistent en une combinaison de chirurgie, de radiothérapie et de chimiothérapie. Alors qu’il y a quelques années, les guidelines de traitement étaient principalement basées sur le stade clinique de la maladie, le développement de nouvelles thérapies a mené à une classification plus appropriée des cancers du poumon. Cette nouvelle classification se base, en plus du stade clinique de la maladie, sur l’expression de différents biomarqueurs exprimés chez des sous-populations bien définies de patients. Ces biomarqueurs sont par exemple la mutation d’un gène ou l’expression d’une protéine. Au cours de ces dix dernières années, la recherche a été très active dans ce domaine avec l’arrivée de nouveaux traitements plus spécifiques pour ces sous-populations de patients. Des exemples concrets de ces nouvelles thérapies sont les chimiothérapies dites ciblées et l’immunothérapie. L’arrivée de tels traitements a parmi d’augmenter significativement le pronostic de la maladie et également de réduire considérablement les graves effets secondaires des chimiothérapies conventionnelles. Toutefois, le bénéfice en termes de survie reste modéré. Le taux de survie des patients à cinq ans est actuellement de 15%. Il y a donc toujours un besoin urgent de mettre au point de nouvelles stratégie de traitement.La chimiothérapie inhalée constitue une perspective de traitement adjuvant du cancer du poumon très intéressante, comparée à la chimiothérapie conventionnelle. En effet, elle permettrait d’administrer des doses d’anticancéreux plus importantes directement au niveau du site tumoral tout en limitant l’exposition systémique du médicament dans l’organisme, et donc, les toxicités importantes s’y rapportant. Toutefois, aucun médicament suivant cette approche n’est actuellement disponible sur le marché et ce, malgré quelques études cliniques de Phase I/II. Cela peut principalement s’expliquer par (i) l’incapacité d’administrer des doses inhalées efficaces d’agent anticancéreux avec les dispositifs d’inhalation utilisés (les nébuliseurs), (ii) les inquiétudes quant à une possible augmentation des toxicités pulmonaires des agents anticancéreux administrés par inhalation, (iii) les moyens devant être mis en place afin d’assurer la non-contamination de l’environnement et du personnel soignant lors d’une séance d’inhalation. Basée sur de nouvelles technologies pharmaceutiques (l’inhalation sous forme de poudre sèche, les nanomédecines, les thérapies ciblées, etc.) et sur une meilleure connaissance de la biologie des cancers, la stratégie scientifique que nous proposons pourrait permettre d’apporter une solution aux problématiques précitées. Ce travail décrit le développement de nouvelles formulations de poudre sèche pour inhalation (« dry powder for inhalation », DPI) à base de nanovecteurs ciblés contre le récepteur au folate (« folate receptor », FR) pour le traitement sélectif de cancers du poumon FR-positifs. Ces formulations permettraient le ciblage (i) du site tumoral par l’utilisation de l’administration pulmonaire et (ii) spécifique des cellules cancéreuses du poumon par les nanovecteurs ciblés. Trois parties constituent ce travail.Dans la première partie, deux nouveaux excipients folatés (c.à.d. sur lesquels ont été greffés des groupements folates) ont été synthétisés en trois étapes principales par une méthode de synthèse faisant appel à des dérivés de carbodiimide. Ces excipients comportent trois types de composants majeures relatifs à leur fonction :un ligand, le groupement folate, pour le ciblage des FRs ;un composé de charge, un polysaccharide, capable d’interagir avec l’agent anticancéreux ou une structure contenant celui-ci ;et un spacer, le poly(éthylène glycol), afin d’assurer une bonne flexibilité du folate et ainsi permettre une bonne interaction avec le FR. Ces nouveaux excipients folatés ont été caractérisés par RMN du proton, par spectrométrie de masse et par analyse thermique. L’excipient F-PEG-HMD (« folate-poly(ethylene glycol)-hydrophobically-modified dextran ») était capable de former des micelles caractérisées par une distribution de taille particulaire bimodale dans l’eau, avec un diamètre moyen d’environ 80 nm. F-PEG-HMD était caractérisé par une concentration micellaire critique de 4 x 10-7 M. L’excipient F-PEG-HTCC (« Folate-poly(ethylene glycol)-(N-[(2-hydroxy- 3-trimethylammonium)propyl] chitosan ») présentait des charges positives permettant de se solubiliser en milieu aqueux, indépendamment du pH.Dans la deuxième partie du travail, des formulations DPI ont été développées à base de l’agent anticancéreux témozolomide (TMZ). Celui-ci a été choisi comme premier modèle de principe actif pour son mécanisme d’action particulier qui lui confère une activité dans les cancers apopto-résistants, comme c’est le cas de beaucoup de cancers du poumon. De plus, l’administration d’une formulation de TMZ sous forme de nanovecteur permettrait de considérablement augmenter son activité en augmentant, par exemple, sa stabilité in vivo, ou encore son incorporation intracellulaire spécifique dans les cellules cancéreuses. Toutefois, le TMZ est caractérisé par des propriétés physicochimiques ne permettant que très difficilement son encapsulation dans des nanovecteurs. Le TMZ est une petite molécule, faiblement soluble dans l’eau sans toutefois être lipophile. Comme type de nanovecteur, les micelles polymériques pourraient présenter un bon profil pour encapsuler le TMZ. Des micelles composées de F-PEG-HMD et de TMZ ont été préparées par solubilisation de ces deux composés en présence. La solubilité dans l’eau du TMZ a pu ainsi être doublée en présence de F-PEG-HMD, ce qui pourrait mener à des concentrations de TMZ augmentées au sein du site tumoral. Les micelles polymériques présentaient un diamètre moyen de 50-60 nm, en fonction de la concentration en F-PEG-HMD utilisée. Les formulations DPI ont été préparées par spray-drying des micelles en présence de mannitol et de leucine. Le TMZ est resté stable durant l’étape de spray-drying, ainsi confirmé par des propriétés antiprolifératives in vitro des formulations DPI semblables à une solution de TMZ. Deux des formulations DPI développées présentaient de bonnes propriétés aérodynamiques, avec des fractions en particule fine jusqu’à 50%, et étaient capable de libérer les micelles polymériques rapidement en milieu aqueux. Toutefois, les taux d’encapsulation obtenus étaient relativement bas (inférieurs à 10%). Le travail s’est donc poursuivi avec un autre agent anticancéreux, le paclitaxel.Dans la troisième partie du travail, des formulations DPI à base de nanovecteurs chargés en paclitaxel (PTX). Le PTX a été choisi comme deuxième modèle d’agent anticancéreux car il s’agit d’une des molécules les plus couramment utilisées dans le traitement du cancer du poumon, et ce malgré les graves effets secondaires systémiques engendrés par l’administration intraveineuse de ce médicament. L’utilisation de la voie pulmonaire pourrait permettre d’optimiser les traitements à base de PTX, et ainsi, la qualité de vie des patients (réductions conséquentes des graves effets secondaires systémiques et meilleure réponse thérapeutique). Deux types de nanovecteurs ont été préparés avec des taux d’encapsulation en PTX d’approximativement 100%. Des micelles polymériques à base de F-PEG-HMD et de PTX ont été préparées par une méthode de dialyse avec un diamètre moyen de 50 nm et un potentiel zêta d’environ -4 mV dans le PBS. Des nanoparticules lipidiques solides (« solid lipid nanoparticle », SLN) chargées en PTX ont été préparées par une méthode de nanoprécipitation et les SLNs ont ensuite été enrobées par F-PEG-HTCC. La présence de l’enrobage a été confirmée par la taille et la charge des particules (diamètre moyen de 160 nm à 230 nm et potentiel zêta de -20 mV à + 30 mV, avant et après enrobage, respectivement). Les nanovecteurs étaient capables d’être incorporés, in vitro, dans les cellules HeLa et M109-HiFR, deux lignées de cellules cancéreuses exprimant le FR, et in vivo, après administration par inhalation sur un modèle orthotopique de cancer pulmonaire murin Ce modèle, le modèle M109, a été développé dans le cadre de ce travail à partir de la lignée M109-HiFR. Après administration par inhalation, les SLNs restaient enrobées dans les tissus pulmonaires et tumoraux. Les nanovecteurs ont montré une activité antiproliférative in vitro sur les deux lignées précitées. De plus, cette activité était significativement plus grande avec les SLNs enrobées chargées en PTX qu’avec la formulation commerciale contenant le paclitaxel, le Taxol®, avec des concentrations inhibitrices médianes de 60 et 340 nM, respectivement. L’activité anti-cancéreuse in vivo des SLNs enrobées, qui présentaient un meilleur profil que les micelles polymériques pour être étudiées in vivo (plus haute teneur en PTX, plus grande activité antiproliférative, et meilleure profil de libération du PTX in vitro), a été évaluée sur le modèle M109. Les SLNs enrobées, administrées par inhalation, seules ou en association avec le Taxol par intraveineuse, ont été comparées au Taxol®, administré par inhalation, par intraveineuse ou les deux, à la même dose de PTX totale. Les traitements à base des SLNs enrobées, en particulier en association avec le Taxol® en intraveineuse, ont menés un allongement significatif de la survie des souris M109, par rapport au Taxol en intraveineuse seul (survie médiane de 38 et 27 jours, respectivement). De plus, la mort de la dernière souris M109 a été observé au jour 61 pour le traitement SLN/Taxol en association, comparé au jour 33 pour le Taxol en intraveineuse, seul, à la même dose totale en PTX (10-8-8-8 mg/kg), et au jour 29 pour le contrôle négatif (c.à.d. les souris n’ayant pas reçu de traitement). Des études supplémentaires sont toutefois requises pour conclure une potentielle augmentation de l’activité anticancéreuse des SLNs inhalées par rapport au Taxol®. En effet, les doses de PTX en inhalation étaient trop grandes pour le modèle M109 menant à la mort d’une partie non négligeable des souris M109. Nous pouvons toutefois conclure que le traitement à base des SLNs inhalées en association avec le Taxol® en intraveineuse semble prometteur pour la suite du projet. Des formulations DPI ont ensuite été produites à partir des nanovecteurs chargés en PTX par spray-drying. Les formulations obtenues présentaient une large déposition in vitro dans les poumons, avec des fractions en particule fine allant jusqu’à 50% et de bonnes propriétés de libération des nanovecteurs en milieu aqueux. Quel que soit le principe actif ou le nanovecteur utilisé, les formulations DPI développées ont montré une large déposition pulmonaire in vitro dans les voies aériennes inférieures, où les adénocarcinomes pulmonaires sont le plus souvent trouvés. De plus, les formulations ne contenant que les excipients étaient bien tolérées in vivo après inhalation chez la souris saine. Cela a été vérifié par analyse des fluides bronchoalvéolaires en termes de concentration totale en protéine, de population de cellules, et de concentration en cytokines IL-1β, IL-6, and TNF-α. Ce travail montre dès lors également que les formulations DPI pourraient constituer un système de délivrance de médicament intéressant pour amener des nanovecteurs dans le tractus respiratoire où la tumeur réside. Toutefois, alors que de nombreuses caractéristiques intéressantes des formulations ont été démontrées (la tolérance des excipients, les profils de libération du PTX obtenus, l’incorporation intracellulaire des nanovecteur ainsi que leur bonne distribution dans du tissu tumoral in vivo et leur activité anticancéreuse, etc.), l’implication des FRs pour expliquer ces caractéristiques n’a pas pu être établie clairement. / Lung cancer is one of the most frequent cancers in the world, and remains the most deadly. Lung cancer therapy involves the combination of surgery, radiotherapy and chemotherapy. Whereas the treatment guidelines used to be related mainly to the stage of the disease, more recent treatments have introduced the concept of treating lung cancers according not only to the stage, but also to the specific characteristics of the tumors, i.e. a gene mutation, expression of a protein, etc. In the last decade, scientific and clinical research has been very active in this field, with recurrent introduction of new treatments, including new chemotherapies (e.g. targeted chemotherapies and immunotherapies). Many of these new treatments certainly induce better therapeutic responses and a sharp reduction in the adverse effects of conventional chemotherapies for well-defined subpopulations of patients. However, the benefit in terms of survival rates is only moderate. The five-year survival rate is currently ~15%. There is therefore no doubt that new treatment approaches and strategies are needed. One interesting approach is aerosolized chemotherapy. The pulmonary delivery of anti-cancer drugs could potentially be an interesting alternative to conventional adjuvant chemotherapy in lung cancer treatment, for many reasons. Among them, it could enhance the therapeutic ratio significantly by decreasing systemic severe toxicities and increasing anti-tumour efficacy. However, despite interesting clinical trial reports, all the strategies describing an aerosolized anti-cancer treatment have failed to bring new medicine on the market so far. The failures have been related mainly to (i) the inability to deliver proper and efficient drug doses in the lungs with the inhalation devices used in clinical trials (i.e. nebulizers), (ii) concerns about potential increase in lung toxicities engendered by these anti-cancer drug-based aerosols, and (iii) the requirement for adapted facilities to perform the inhalation procedure safely. Based on new pharmaceutical technologies (i.e. dry powder for inhalation (DPI) technology, nanomedicine, drug targeting, etc.) and on a better knowledge of cancer biology, a plausible and feasible answer to the aforementioned causes of failure was proposed. In this work, new nanomedicine-based DPI formulations were designed and developed for proposal as adjuvant chemotherapy for lung cancer treatment, especially for folate receptor (FR)-positive adenocarcinomas. These formulations would potentiate chemotherapy by means of a dual-targeting approach, i.e. the targeting of (i) lung tumor site(s) with pulmonary delivery and (ii) lung cancer cells with FR-targeted nanocarriers. To set up this approach, the work included three parts.In the first part, two new folate-grafted excipients were synthesized using carbodiimide-mediated chemistry in three main steps. These excipients consisted of three main components with a defined function: a ligand bringing selectivity, i.e. folate groups; a loading compound able to interact non-covalently with the anti-cancer drug or a drug delivery system, i.e. polysaccharides; and a spacer ensuring good flexibility of the ligand to allow its binding to the target, i.e. poly(ethylene glycol). The excipients were characterized by 1H-NMR, mass spectrometry and thermal analysis. Folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD), a new folate-grafted self-assembling copolymer, presented a critical micellar concentration in water of 4 x 10-7 M. F-PEG-HMD micelles were characterized by a trimodal particle size distribution with a Z-average diameter of about 80 nm in water. Folate-polyethylene glycol-(N-[(2-hydroxy- 3-trimethylammonium)propyl] chitosan) (F-PEG-HTCC) presented positive charges and was easily dissolved in water, regardless of the pH.In the second part, dry powders were developed with the anti-cancer drug temozolomide (TMZ). TMZ was chosen as the first anti-cancer drug model due to its interesting anti-cancer activity in poor prognosis, apopto-resistant cancers, as is the case for many lung cancers. In addition, TMZ delivery via a nanocarrier might present many advantages such as prolonged lifetime and specific improved intracellular delivery into cancer cells. However, TMZ is characterized by poor properties for encapsulation into nanocarriers. It presents poor water solubility and low lipophilicity. Because of these properties, polymeric micelles presented the best profile for entrapping TMZ. TMZ-loaded F-PEG-HMD micelles were prepared by co-dissolution of TMZ and F-PEG-HMD. TMZ solubility in water was increased in the presence of F-PEG-HMD (a two-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The TMZ-loaded F-PEG-HMD micelles were characterized by Z-average diameters in the range of 50-60 nm, depending on the F-PEG-HMD concentration used. The micelles were spray dried to produce dry powders. TMZ remained stable during all the formulation steps, confirmed by similar in vitro anti-proliferative properties for the DPI formulations and a TMZ solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD micelles quickly in aqueous media. However, as presumed, poor entrapment efficiency values were obtained (less than 10%). A second anti-cancer compound was therefore chosen to pursue in the study, the lipophilic paclitaxel.In the third part, nanocarrier-loaded dry powders were developed with the poorly water-soluble anti-cancer drug paclitaxel (PTX) and the new folate-grafted excipients. PTX was chosen as a model drug because it is an effective anti-cancer drug currently used in lung cancer therapy and it causes severe systemic toxicities when delivered by the conventional intravenous route. Pulmonary delivery of PTX might therefore optimize treatment efficacy and/or quality of life in lung cancer patients. Two types of PTX-loaded nanocarrier were prepared with an encapsulation efficiency of approximatively 100%. PTX-loaded F-PEG-HMD micelles were prepared by a dialysis method. These had a Z-average diameter of about 50 nm and a zeta potential of about -4 mV in PBS. F-PEG-HTCC-coated solid lipid nanoparticles (SLNs) loaded with PTX were prepared in two main steps. PTX-loaded SLNs were first prepared using a nanoprecipitation method and the SLNs were then coated with F-PEG-HTCC. Efficient coating was confirmed by particle size and zeta potential (Z-average diameter of 160 nm to 230 nm and zeta potential of -20 mV to +30 mV before and after F-PEG-HTCC coating, respectively). The nanocarriers were able to enter HeLa and M109-HiFR, two FR-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. This orthotopic model, i.e. the M109 model, was developed in the study. The SLNs remained coated with F-PEG-HTCC in lung tissues and tumors after inhalation. The PTX contained in the nanocarriers remained active against HeLa and M109-HiFR in vitro, as observed by means of the colorimetric MTT assays. Moreover, PTX-loaded SLNs were characterized by significantly higher anti-proliferative properties than Taxol®, with half-maximal inhibitory concentrations of 60 and 340 nM, respectively. Afterwards, the in vivo anti-cancer activity of the coated SLNs, which led to better profile than the polymeric micelles to be studied in vivo (i.e. higher PTX loading, higher anti-proliferative properties, and better release profile of PTX in vitro), was evaluated using the M109 model. The coated SLNs, administered by inhalation, alone or combined with intravenous Taxol®, were compared with Taxol®, administered by inhalation, IV or both, at the same PTX-relative doses. Interestingly, we observed much longer survivals for the SLN inhaled treatments, especially when combined with intravenous Taxol®, than for intravenous Taxol alone (median survivals of 38 and 27 days, respectively). Moreover, the last tumor-bearing mouse death occurred at day 61 for the SLN combined therapy, compared with day 33 for the intravenous therapy alone, at the same total PTX-relative dose (i.e. 10-8-8-8 mg/kg), and with day 29 for negative control (i.e. non-treated mice). However, further evaluations are needed to conclude that there is any improvement in terms of therapeutic response compared with intravenous Taxol®. Indeed, bias related to the fact that the aerosolized PTX doses were too high was included in the survival rate analysis and was revealed by unacceptable treatment-related deaths. Nevertheless, the combination of aerosolized, loaded SLNs and intravenous Taxol seemed to be an interesting strategy of treatment to follow. Dry powders embedding the PTX-loaded nanocarriers were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the nanocarriers in aqueous media.Whatever the drug or the nanocarrier adopted, the developed DPI formulations showed wide in vitro pulmonary deposition in the lower respiratory tract, where adenocarcinomas are more often found. Moreover, nanocarrier-based dry powders without drugs were well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1β, IL-6, and TNF-α concentration in bronchoalveolar lavage fluids. The present work therefore also shows that dry powders for inhalation could constitute an interesting drug delivery system able to release nanocarriers in the respiratory tract where the tumor is growing and spreading. However, in contrast to the undeniable improvements in terms of drug delivery system (e.g. safety of the excipients, drug release profile, the cell binding and uptake of the nanocarriers and their distribution into tumor in vivo, anti-cancer activity), no substantial effect linked to an implication of the FRs was observed to explain the aforesaid improvements. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished
165

An Investigation of the Demethylation of γ-Butyrobetaine and Other Methylamines by the Human Gut Symbiont Eubacterium limosum

Ellenbogen, Jared Bert January 2021 (has links)
No description available.
166

Stability of Selected B Vitamins in Thermally-Treated Pinto Beans

West, Virginia Anne 01 March 2015 (has links) (PDF)
Beans are a commonly consumed food and a staple in many regions worldwide. Pinto beans (Phaseolus vulgaris), categorized as legumes, are dried seeds from plants and are high in protein, carbohydrate and fiber, and low in fat. They are also a good source of various minerals and well as thiamin, riboflavin, niacin, vitamin B6, and folate Beans are typically soaked and thermally processed before consumption. Different processing methods can impact the composition of beans. The purpose of this study was to examine the effect of thermal treatments on vitamin concentration in pinto beans. Beans were simmered, canned, dried-flaked, or dried-extruded, and measured for thiamin, riboflavin, folate, and vitamin B6. Beans were then reheated and measured again for vitamin concentration. Vitamin loss was comparable between the most commonly consumed stages of processing: Simmered, canned reheated, dried-flaked reheated and dried-extruded reheated. The only statistically significant differences were that simmering caused the least amount of degradation of thiamin and dried-flaked product had the least amount of vitamin B6 degradation. Though dried-flaked and dried-extruded beans generally decreased in vitamin concentration, these two products were comparable to the simmered and canned reheated products. This suggests that drying is a nutritionally acceptable means of processing pinto beans, resulting in products that are more economical to transport and more convenient to prepare.
167

Novel folate amphiphile conjugates for targeted drug delivery

Bhattacharya, Shiladitya 01 January 2008 (has links) (PDF)
Cancer is not only difficult to treat but the patients also suffer from the pain associated with anticancer treatments. Targeted chemotherapeutics can reduce the adverse effects by reducing the dose required for tumor cell kill. Cancers of various origins often have characteristic marker molecules that distinguish them from the normal tissues. Folate receptors are such marker molecules present in ovarian and cervical cancers. The hypothesis for the current study is that amphiphiles constructed out of folic acid, the natural ligand for the folate receptor, can deliver paclitaxel, a chemotherapeutic compound, to folate receptor expressing cancer cells. To test this hypothesis, amphiphilic molecules were synthesized out of folic acid and fatty acids or long chain aliphatic amines. The gamma carboxylic group of folic acid was converted to an N-alkyl substituted amide. The alkyl group had various chain lengths varying from eleven methylene groups to seventeen methylene groups giving rise to a number of amphiphiles. The amphiphiles formed micelles in aqueous solutions. The critical micellization concentrations of the amphiphiles were measured by pyrene fluorescence and were found to be in the range of 10–70μM. HeLa and Caco-2 cells were taken as in vitro tumor models. Folate receptor expression was verified in HeLa and Caco-2 cells by western blot analysis. HeLa showed more than forty fold expression of the receptor when compared to Caco-2 and was chosen as receptor positive cell line while Caco-2 served as a negative control. Uptake of the folate labeled delivery system in the cell lines was tested by a fluorescent probe (aminocoumarin) labeled amphiphile. To test the specificity of the delivery system towards the receptor positive HeLa cells, the receptors were knocked down (70%) by folate receptor specific siRNA. Fluorescent amphiphile uptake in the knockdown cells was comparable to that of the negative control, Caco-2. Finally cytotoxicity studies were performed for paclitaxel formulated with the folate labeled amphiphiles and compared to free drug treatment in HeLa and Caco-2. IC50 values in HeLa for formulations with the folate labeled amphiphiles were ten folds less than those observed for free drug treatment whereas in Caco-2 no significant difference was noted.
168

Folate and Cobalamin Serum Levels in Healthy Children and Adolescents and Their Association with Age, Sex, BMI and Socioeconomic Status

Kreusler, Paulina, Vogel, Mandy, Willenberg, Anja, Baber, Ronny, Dietz, Yvonne, Körner, Antje, Ceglarek, Uta, Kiess, Wieland 05 May 2023 (has links)
This study proposes age- and sex-specific percentiles for serum cobalamin and folate, and analyzes the effects of sex, age, body mass index (BMI), and socioeconomic status (SES) on cobalamin and folate concentrations in healthy children and adolescents. In total, 4478 serum samples provided by healthy participants (2 months–18.0 years) in the LIFE (Leipzig Research Centre for Civilization Diseases) Child population-based cohort study between 2011 and 2015 were analyzed by electrochemiluminescence immunoassay (ECLIA). Continuous age-and sex-related percentiles (2.5th, 10th, 50th, 90th, 97.5th) were estimated, applying Cole’s LMS method. In both sexes, folate concentrations decreased continuously with age, whereas cobalamin concentration peaked between three and seven years of age and declined thereafter. Female sex was associated with higher concentrations of both vitamins in 13- to 18-year-olds and with higher folate levels in one- to five-year-olds. BMI was inversely correlated with concentrations of both vitamins, whilst SES positively affected folate but not cobalamin concentrations. To conclude, in the assessment of cobalamin and folate status, the age- and sex-dependent dynamic of the respective serum concentrations must be considered. While BMI is a determinant of both vitamin concentrations, SES is only associated with folate concentrations.
169

Design, Synthesis, and Application of Sensors for Biologically Relevant Molecules

Esipenko, Nina A. 14 April 2014 (has links)
No description available.
170

FOOD SAFETY AND QUALITY IN DEVELOPING COUNTRIES: THE ROLE OF LACTIC ACID BACTERIA

ANGRI, MATTEO 17 March 2016 (has links)
La sicurezza e la qualità degli alimenti sono tutt’ora un problema critico per i paesi in via di sviluppo. Le diete a basso contenuto di acido folico, per esempio, possono causare gravi problemi di salute, soprattutto nei bambini. Gravi disturbi legati al tubo neurale (DTN) nei neonati possono derivare infatti da madri che hanno insufficiente apporto di acido folico (400-600 g / giorno) durante il periodo di gravidanza. Inoltre, se non adeguatamente protetti o trattati, I prodotti alimentari possono essere vettori di funghi e batteri patogeni rappresentando una fonte potenziale di malattie per l’uomo e una perdita economica per le industrie agro-alimentari. Nella seguente tesi si è quindi quindi studiato il ruolo di batteri lattici selezionati (LAB) in grado di aumentare il valore nutrizionale del latte attraverso la produzione di acido folico durante il processo di fermentazione. Inoltre, ci si è concentrati sul loro uso come "bio-conservanti" contro funghi e batteri, attraverso la sintesi di composti antimicrobici (batteriocine) in grado di inibire la crescita di funghi filamentosi e/o batteri patogeni. / The safety and quality of food are still a critical issue in developing countries. Diets with a low content of folic acid, for example, may cause serious health problems, especially in children. Severe disorders related to neural tube (NTD) in infants may arise from mothers having inadequate intakes of folic acid (400-600 g/dia) during the mother pregnancy period. Moreover foods, when not properly protected or treated, can be vectors of pathogenic fungi and bacteria thereby representing a potential source of human diseases and an economical loss for the food industry. In the following thesis we have therefore investigated the role of selected lactic acid bacteria (LAB) in increasing the nutritional value of milk through the production of folic acid during the fermentation process. In addition, we focused on their use as “bio-preservatives” against fungal and bacterial spoilage, through the synthesis of antimicrobial compounds (bacteriocins) able to inhibit the growth of filamentous fungi and /or pathogenic bacteria.

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