Metodo alternativo per modellare le metastasi epatiche

[Clark AM, Wheeler SE, Taylor DP, Pillai VC, Young CL, Prantil-Baun R, Nguyen T, Stolz DB, Borenstein JT, Lauffenburger DA, Venkataramanan R, Griffith LG, Wells A. A microphysiological system model of therapy for liver micrometastases. Exp Biol Med (Maywood). 2014 Sep;239(9):1170-9.]

Abstract:

“Metastasis accounts for almost 90% of cancer-associated mortality. The effectiveness of cancer therapeutics is limited by the protective microenvironment of the metastatic niche and consequently these disseminated tumors remain incurable. Metastatic disease progression continues to be poorly understood due to the lack of appropriate model systems. To address this gap in understanding, we propose an all-human microphysiological system that facilitates the investigation of cancer behavior in the liver metastatic niche. This existing LiverChip is a 3D-system modeling the hepatic niche; it incorporates a full complement of human parenchymal and non-parenchymal cells and effectively recapitulates micrometastases. Moreover, this system allows real-time monitoring of micrometastasis and assessment of human-specific signaling. It is being utilized to further our understanding of the efficacy of chemotherapeutics by examining the activity of established and novel agents on micrometastases under conditions replicating diurnal variations in hormones, nutrients and mild inflammatory states using programmable microdispensers. These inputs affect the cues that govern tumor cell responses. Three critical signaling groups are targeted: the glucose/insulin responses, the stress hormone cortisol and the gut microbiome in relation to inflammatory cues. Currently, the system sustains functioning hepatocytes for a minimum of 15 days; confirmed by monitoring hepatic function (urea, α-1-antitrypsin, fibrinogen, and cytochrome P450) and injury (AST and ALT). Breast cancer cell lines effectively integrate into the hepatic niche without detectable disruption to tissue, and preliminary evidence suggests growth attenuation amongst a subpopulation of breast cancer cells. xMAP technology combined with systems biology modeling are also employed to evaluate cellular crosstalk and illustrate communication networks in the early microenvironment of micrometastases. This model is anticipated to identify new therapeutic strategies for metastasis by elucidating the paracrine effects between the hepatic and metastatic cells, while concurrently evaluating agent efficacy for metastasis, metabolism and tolerability.“

Differenze tra specie in farmacocinetica e farmacodinamica

[Toutain PL, Ferran A, Bousquet-Mélou A. Species differences in pharmacokinetics and pharmacodynamics. Handb Exp Pharmacol. 2010;(199):19-48.]

Abstract:

Veterinary medicine faces the unique challenge of having to treat many types of domestic animal species, including mammals, birds, and fishes. Moreover, these species have evolved into genetically unique breeds having certain distinguishable characteristics developed by artificial selection. The main challenge for veterinarians is not to select a drug but to determine, for the selected agent, a rational dosing regimen because the dosage regimen for a drug in a given species may depend on its anatomy, biochemistry, physiology, and behaviour as well as on the nature and causes of the condition requiring treatment. Both between- and within-species differences in drug response can be explained either by variations in drug pharmacokinetics (PK) or drug pharmacodynamics (PD), the magnitude of which varies from drug to drug. This chapter highlights selected aspects of species differences in PK and PD and considers underlying physiological and patho-physiological mechanisms in the main domestic species. Particular attention was paid to aspects of animal behaviour (food behaviour, social behavior, etc.) as a determinant of interspecies differences in PK or/and PD. Modalities of drug administration are many and result not only from anatomical, physiological and/or behavioural differences across species but also from management options. The latter is the case for collective/group treatment of food-producing animals, frequently dosed by the oral route at a herd or flock level. After drug administration, the main causes of observed inter-species differences arise from species differences in the handling of drugs (absorption, distribution, metabolism, and elimination). Such differences are most common and of greatest magnitude when functions which are phylogenetically divergent between species, such as digestive functions (ruminant vs. non-ruminant, carnivore vs. herbivore, etc.), are involved in drug absorption. Interspecies differences also exist in drug action but these are generally more limited, except when a particular targeted function has evolved, as is the case for reproductive physiology (mammals vs. birds vs. fishes; annual vs. seasonal reproductive cycle in mammals; etc.). In contrast, for antimicrobial and antiparasitic drugs, interspecies differences are more limited and rather reflect those of the pathogens than of the host. Interspecies difference in drug metabolism is a major factor accounting for species differences in PK and also in PD (production or not of active metabolites). Recent and future advances in molecular biology and pharmacogenetics will enable a more comprehensive view of interspecies differences and also between breeds with existing polymorphism. Finally, the main message of this review is that differences between species are not only numerous but also often unpredictable so that no generalisations are possible, even though for several drugs allometric approaches do allow some valuable interspecies extrapolations. Instead, each drug must be investigated on a species-by-species basis to guarantee its effective and safe use, thus ensuring the well-being of animals and safeguarding of the environment and human consumption of animal products.

Organoide di timo per studi su trapianti e immunologici

[Vianello F, Poznansky MC. Generation of a tissue-engineered thymic organoid. Methods Mol Biol. 2007;380:163-70.]

Abstract:

The thymic microenvironment provides essential support for the generation of a functional and diverse population of human T cells. In particular, the three-dimensional (3D) thymic architecture contributes to critical cell-cell interactions. We report that thymic stroma, arrayed on a synthetic 3D matrix, supports the development of functional human T cells from hematopoietic precursor cells. Newly generated T cells contain T-cell receptor excision circles and are both fully mature and functional. The coculture of T-cell progenitors with thymic stroma can thus be used to generate de novo functional and diverse T-cell populations. This novel tissue engineered thymic system has biological applications for the study of T-lymphopoiesis and self-tolerance as well as potential therapeutic applications including the immune reconstitution of immunocompromised patients and the induction of tolerance in individuals receiving tissue or organ transplants.