scholarly journals Personalized medicine for cystic fibrosis: Establishing human model systems

2015 ◽  
Vol 50 (S40) ◽  
pp. S14-S23 ◽  
Author(s):  
Hongmei Mou ◽  
Karissa Brazauskas ◽  
Jayaraj Rajagopal
Keyword(s):  
Cystic Fibrosis ◽  
Personalized Medicine ◽  
Model Systems ◽  
Human Model

scholarly journals New Endeavors of (Micro)Tissue Engineering: Cells Tissues Organs on-Chip and Communication Thereof

2021 ◽  
pp. 1-15
Author(s):  
Haysam M.M.A.M. Ahmed ◽  
Liliana S. Moreira Teixeira
Keyword(s):  
Tissue Engineering ◽  
Food Additives ◽  
Market Potential ◽  
Model Systems ◽  
Human Model ◽  
Human Stem Cells ◽  
Animal Testing ◽  
Preclinical Research ◽  
On Chip

The development of new therapies is tremendously hampered by the insufficient availability of human model systems suitable for preclinical research on disease target identification, drug efficacy, and toxicity. Thus, drug failures in clinical trials are too common and too costly. Animal models or standard 2D in vitro tissue cultures, regardless of whether they are human based, are regularly not representative of specific human responses. Approaching near human tissues and organs test systems is the key goal of organs-on-chips (OoC) technology. This technology is currently showing its potential to reduce both drug development costs and time-to-market, while critically lessening animal testing. OoC are based on human (stem) cells, potentially derived from healthy or disease-affected patients, thereby amenable to personalized therapy development. It is noteworthy that the OoC market potential goes beyond pharma, with the possibility to test cosmetics, food additives, or environmental contaminants. This (micro)tissue engineering-based technology is highly multidisciplinary, combining fields such as (developmental) biology, (bio)materials, microfluidics, sensors, and imaging. The enormous potential of OoC is currently facing an exciting new challenge: emulating cross-communication between tissues and organs, to simulate more complex systemic responses, such as in cancer, or restricted to confined environments, as occurs in osteoarthritis. This review describes key examples of multiorgan/tissue-on-chip approaches, or linked organs/tissues-on-chip, focusing on challenges and promising new avenues of this advanced model system. Additionally, major emphasis is given to the translation of established tissue engineering approaches, bottom up and top down, towards the development of more complex, robust, and representative (multi)organ/tissue-on-chip approaches.

scholarly journals Decreased calmodulin recruitment triggers PMCA4 dysfunction and pancreatic injury in cystic fibrosis

2020 ◽  
Author(s):  
Tamara Madácsy ◽  
Árpad Varga ◽  
Noémi Papp ◽  
Barnabás Deák ◽  
Bálint Tél ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Intracellular Signaling ◽  
Pancreatic Injury ◽  
Exocrine Pancreatic Function ◽  
Model Systems ◽  
Multiple Model ◽  
Calmodulin Binding ◽  
Ductal Cells ◽  
Pancreatic Damage ◽  
Intracellular Ca

ABSTRACTExocrine pancreatic damage is a common complication of cystic fibrosis (CF), which can significantly debilitate the quality of life and life expectancy of CF patients. The cystic fibrosis transmembrane conductance regulator (CFTR) has a major role in pancreatic ductal ion secretion, however, it presumably has an influence on intracellular signaling as well. Here we describe in multiple model systems, including iPSC-derived human pancreatic organoids from CF patients, that the activity of PMCA4 is impaired by the decreased expression of CFTR in ductal cells. The regulation of PMCA4, which colocalizes and physically interacts with CFTR on the apical membrane of the ductal cells, is dependent on the calmodulin binding ability of CFTR. Moreover, CFTR seems to be involved in the process of the apical recruitment of calmodulin, which enhances its role in calcium signaling and homeostasis. Sustained intracellular Ca2+ elevation in CFTR KO cells undermined the mitochondrial function and increased apoptosis. Based on these, the prevention of sustained intracellular Ca2+ overload may improve the exocrine pancreatic function and may have a potential therapeutic aspect in CF.

scholarly journals A new Era of Personalized Medicine for Cystic Fibrosis – at Last!

2015 ◽  
Vol 22 (5) ◽  
pp. 257-260 ◽  
Author(s):  
Bradley S Quon ◽  
Pearce G Wilcox
Keyword(s):  
Cystic Fibrosis ◽  
Personalized Medicine ◽  
Late Phase ◽  
Structure And Function ◽  
Clinical Development ◽  
New Era ◽  
High Throughput Drug Screening ◽  
Cftr Protein ◽  
And Function ◽  
Screening Approaches

The gene responsible for cystic fibrosis (CF) was discovered 25 years ago. This breakthrough has enabled a sophisticated understanding of how various mutations lead to specific alterations in the structure and function of the CF transmembrane regulator (CFTR) protein. Until recently, all therapies in CF were focused on ameliorating the downstream consequences of CFTR dysfunction. High-throughput drug screening approaches have yielded compounds that can modify CFTR structure and function, thus targeting the basic defect in CF. The present article describes theCFTRmutational classes, reviews mutation-specific therapies currently in late-phase clinical development, and highlights research opportunities and challenges with personalized medicine in CF.

scholarly journals Organoid Models for Cancer Research

2019 ◽  
Vol 3 (1) ◽  
pp. 223-234 ◽  
Author(s):  
Hans Clevers ◽  
David A. Tuveson
Keyword(s):  
Cancer Research ◽  
Tumor Microenvironment ◽  
Personalized Medicine ◽  
High Throughput ◽  
Stromal Cells ◽  
Transcriptome Sequencing ◽  
Cancer Biology ◽  
Three Dimensional ◽  
Model Systems ◽  
Liver Cancers

Organoid cultures have emerged as powerful model systems accelerating discoveries in cellular and cancer biology. These three-dimensional cultures are amenable to diverse techniques, including high-throughput genome and transcriptome sequencing, as well as genetic and biochemical perturbation, making these models well suited to answer a variety of questions. Recently, organoids have been generated from diverse human cancers, including breast, colon, pancreas, prostate, bladder, and liver cancers, and studies involving these models are expanding our knowledge of the etiology and characteristics of these malignancies. Co-cultures of cancer organoids with non-neoplastic stromal cells enable investigation of the tumor microenvironment. In addition, recent studies have established that organoids have a place in personalized medicine approaches. Here, we describe the application of organoid technology to cancer discovery and treatment.

The CFTR variant profile of Hispanic patients with cystic fibrosis: Impact on access to effective screening, diagnosis, and personalized medicine

2020 ◽  
Vol 29 (4) ◽  
pp. 607-615
Author(s):  
Megan N. Januska ◽  
Laura Marx ◽  
Patricia A. Walker ◽  
Maria N. Berdella ◽  
Elinor Langfelder‐Schwind
Keyword(s):  
Cystic Fibrosis ◽  
Personalized Medicine ◽  
Effective Screening ◽  
Hispanic Patients ◽  
And Personalized Medicine

scholarly journals Insights into the Light Response of Skeletonema marinoi: Involvement of Ovothiol

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 477
Author(s):  
Alfonsina Milito ◽  
Ida Orefice ◽  
Arianna Smerilli ◽  
Immacolata Castellano ◽  
Alessandra Napolitano ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Biological Activities ◽  
Model Systems ◽  
Human Model ◽  
Photon Flux ◽  
Intensity Increase ◽  
Light Conditions ◽  
Great Ability ◽  
Square Wave ◽  
Skeletonema Marinoi

Diatoms are one of the most widespread groups of microalgae on Earth. They possess extraordinary metabolic capabilities, including a great ability to adapt to different light conditions. Recently, we have discovered that the diatom Skeletonema marinoi produces the natural antioxidant ovothiol B, until then identified only in clams. In this study, we investigated the light-dependent modulation of ovothiol biosynthesis in S. marinoi. Diatoms were exposed to different light conditions, ranging from prolonged darkness to low or high light, also differing in the velocity of intensity increase (sinusoidal versus square-wave distribution). The expression of the gene encoding the key ovothiol biosynthetic enzyme, ovoA, was upregulated by high sinusoidal light mimicking natural conditions. Under this situation higher levels of reactive oxygen species and nitric oxide as well as ovothiol and glutathione increase were detected. No ovoA modulation was observed under prolonged darkness nor low sinusoidal light. Unnatural conditions such as continuous square-wave light induced a very high oxidative stress leading to a drop in cell growth, without enhancing ovoA gene expression. Only one of the inducible forms of nitric oxide synthase, nos2, was upregulated by light with consequent production of NO under sinusoidal light and darkness conditions. Our data suggest that ovothiol biosynthesis is triggered by a combined light stress caused by natural distribution and increased photon flux density, with no influence from the daily light dose. These results open new perspectives for the biotechnological production of ovothiols, which are receiving a great interest for their biological activities in human model systems.

The nephropathy of cystic fibrosis: A human model of chronic nephrotoxicity

1982 ◽  
Vol 13 (10) ◽  
pp. 934-939 ◽  
Author(s):  
Carlos R. Abramowsky ◽  
Gary L. Swinehart
Keyword(s):  
Cystic Fibrosis ◽  
Human Model

scholarly journals KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

2017 ◽  
Vol 114 (23) ◽  
pp. E4676-E4685 ◽  
Author(s):  
Luisa Quinti ◽  
Sharadha Dayalan Naidu ◽  
Ulrike Träger ◽  
Xiqun Chen ◽  
Kimberly Kegel-Gleason ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Model Systems ◽  
Human Model ◽  
Selective Activation ◽  
Primary Mouse

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.

Breaking through a roadblock in prostate cancer research: An update on human model systems

2012 ◽  
Vol 131 (3-5) ◽  
pp. 122-131 ◽  
Author(s):  
R. Toivanen ◽  
R.A. Taylor ◽  
D.W. Pook ◽  
S.J. Ellem ◽  
G.P. Risbridger
Keyword(s):  
Prostate Cancer ◽  
Cancer Research ◽  
Model Systems ◽  
Human Model ◽  
Prostate Cancer Research

scholarly journals OMAMO: orthology-based model organism selection

2021 ◽  
Author(s):  
Alina Nicheperovich ◽  
Adrian M Altenhoff ◽  
Christophe Dessimoz ◽  
Sina Majidian
Keyword(s):  
Literature Review ◽  
Biological Process ◽  
Model Organism ◽  
Complex Model ◽  
Model Systems ◽  
Human Model ◽  
Model Organisms ◽  
Human Biology ◽  
Traditional Model ◽  
Ethical Concerns

The conservation of pathways and genes across species has allowed scientists to use non-human model organisms to gain a deeper understanding of human biology. However, the use of traditional model systems such as mice, rats, and zebrafish is costly, time-consuming and increasingly raises ethical concerns, which highlights the need to search for less complex model organisms. Existing tools only focus on the few well-studied model systems, most of which are higher animals. To address these issues, we have developed Orthologous Matrix and Model Organisms, a software and a website that provide the user with the best simple organism for research into a biological process of interest based on orthologous relationships between the human and the species. The outputs provided by the database were supported by a systematic literature review.

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