scholarly journals Zebrafish Avatars towards Personalized Medicine—A Comparative Review between Avatar Models

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 293 ◽  
Author(s):  
Bruna Costa ◽  
Marta F. Estrada ◽  
Raquel V. Mendes ◽  
Rita Fior
Keyword(s):  
Predictive Power ◽  
Dynamic Interactions ◽  
Fast Analysis ◽  
In Vivo Models ◽  
The Past ◽  
Comparative Review ◽  
Drug Treatments ◽  
Patient Responses

Cancer frequency and prevalence have been increasing in the past decades, with devastating impacts on patients and their families. Despite the great advances in targeted approaches, there is still a lack of methods to predict individual patient responses, and therefore treatments are tailored according to average response rates. “Omics” approaches are used for patient stratification and choice of therapeutic options towards a more precise medicine. These methods, however, do not consider all genetic and non-genetic dynamic interactions that occur upon drug treatment. Therefore, the need to directly challenge patient cells in a personalized manner remains. The present review addresses the state of the art of patient-derived in vitro and in vivo models, from organoids to mouse and zebrafish Avatars. The predictive power of each model based on the retrospective correlation with the patient clinical outcome will be considered. Finally, the review is focused on the emerging zebrafish Avatars and their unique characteristics allowing a fast analysis of local and systemic effects of drug treatments at the single-cell level. We also address the technical challenges that the field has yet to overcome.

scholarly journals In Vitro and In Vivo Models to Study the Zoonotic Mosquito-Borne Usutu Virus

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1116
Author(s):  
Emna Benzarti ◽  
Mutien Garigliany
Keyword(s):  
Animal Health ◽  
Neurological Complications ◽  
Lessons Learned ◽  
In Vivo Models ◽  
Usutu Virus ◽  
The Past ◽  
Experimental Systems ◽  
Human Infections

Usutu virus (USUV), a mosquito-borne zoonotic flavivirus discovered in South Africa in 1959, has spread to many European countries over the last 20 years. The virus is currently a major concern for animal health due to its expanding host range and the growing number of avian mass mortality events. Although human infections with USUV are often asymptomatic, they are occasionally accompanied by neurological complications reminiscent of those due to West Nile virus (another flavivirus closely related to USUV). Whilst USUV actually appears less threatening than some other emergent arboviruses, the lessons learned from Chikungunya, Dengue, and Zika viruses during the past few years should not be ignored. Further, it would not be surprising if, with time, USUV disperses further eastwards towards Asia and possibly westwards to the Americas, which may result in more pathogenic USUV strains to humans and/or animals. These observations, inviting the scientific community to be more vigilant about the spread and genetic evolution of USUV, have prompted the use of experimental systems to understand USUV pathogenesis and to boost the development of vaccines and antivirals. This review is the first to provide comprehensive coverage of existing in vitro and in vivo models for USUV infection and to discuss their contribution in advancing data concerning this neurotropic virus. We believe that this paper is a helpful tool for scientists to identify gaps in the knowledge about USUV and to design their future experiments to study the virus.

scholarly journals Induction of Fetal Hemoglobin By FTX6058, a Novel Small Molecule Development Candidate

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Peter Rahl ◽  
Ivan Efremov ◽  
Billy Stuart ◽  
Keqiang Xie ◽  
Mark Roth ◽  
...  
Keyword(s):  
Small Molecule ◽  
Plasma Concentrations ◽  
Fetal Hemoglobin ◽  
Target Engagement ◽  
Publicly Traded ◽  
In Vivo Models ◽  
Α Subunit ◽  
The Past

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α-subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ)occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule with desirable DMPK properties suitable for clinical testing. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to 30% absolute HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed. Disclosures Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie:Fulcrum Therapeutics: Current Employment. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Peters:Fulcrum Therapeutics: Current Employment. Li:Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski:Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno:Fulcrum Therapeutics: Current Employment. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

Lipoxins: endogenous regulators of inflammation

2004 ◽  
Vol 286 (2) ◽  
pp. F189-F201 ◽  
Author(s):  
Blaithin McMahon ◽  
Catherine Godson
Keyword(s):  
Inflammatory Diseases ◽  
In Vivo Models ◽  
The Past ◽  
Endogenous Regulators ◽  
Anti Inflammatory ◽  
And Migration ◽  
Metalloproteinase Activity ◽  
Proliferation And Migration

Over the past decade, compelling in vivo and in vitro studies have highlighted lipoxins (LXs) and aspirin-triggered LXs (ATLs) as endogenously produced anti-inflammatory eicosanoids. LXs and ATLs elicit distinct anti-inflammatory and proresolution bioactions that include inhibition of leukocyte-mediated injury, stimulation of macrophage clearance of apoptotic neutrophils, repression of proinflammatory cytokine production, modulation of cytokine-stimulated metalloproteinase activity, and inhibition of cell proliferation and migration. An overview of recent advances in LX physiology is provided, with particular emphasis on the cellular and molecular processes involved. These data coupled with in vivo models of inflammatory diseases suggest that LX bioactions may be amenable to pharmacological mimicry for therapeutic gain.

scholarly journals Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 107
Author(s):  
Filipa Lopes-Coelho ◽  
Fernanda Silva ◽  
Sofia Gouveia-Fernandes ◽  
Carmo Martins ◽  
Nuno Lopes ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Cancer Progression ◽  
Oxygen Species ◽  
Endothelial Progenitor ◽  
In Vivo Models ◽  
The Past ◽  
Scavenging Capacity

Bone marrow contains endothelial progenitor cells (EPCs) that, upon pro-angiogenic stimuli, migrate and differentiate into endothelial cells (ECs) and contribute to re-endothelialization and neo-vascularization. There are currently no reliable markers to characterize EPCs, leading to their inaccurate identification. In the past, we showed that, in a panel of tumors, some cells on the vessel wall co-expressed CD14 (monocytic marker) and CD31 (EC marker), indicating a putative differentiation route of monocytes into ECs. Herein, we disclosed monocytes as potential EPCs, using in vitro and in vivo models, and also addressed the cancer context. Monocytes acquired the capacity to express ECs markers and were able to be incorporated into blood vessels, contributing to cancer progression, by being incorporated in tumor neo-vasculature. Reactive oxygen species (ROS) push monocytes to EC differentiation, and this phenotype is reverted by cysteine (a scavenger and precursor of glutathione), which indicates that angiogenesis is controlled by the interplay between the oxidative stress and the scavenging capacity of the tumor microenvironment.

Computational and bioengineered lungs as alternatives to whole animal, isolated organ, and cell-based lung models

2012 ◽  
Vol 303 (9) ◽  
pp. L733-L747 ◽  
Author(s):  
Brijeshkumar Patel ◽  
Robert Gauvin ◽  
Shahriar Absar ◽  
Vivek Gupta ◽  
Nilesh Gupta ◽  
...  
Keyword(s):  
In Silico ◽  
In Vitro Models ◽  
In Vivo Models ◽  
The Past ◽  
Complex Anatomy ◽  
Human Lungs ◽  
Conventional Cell ◽  
In Silico Models

Development of lung models for testing a drug substance or delivery system has been an intensive area of research. However, a model that mimics physiological and anatomical features of human lungs is yet to be established. Although in vitro lung models, developed and fine-tuned over the past few decades, were instrumental for the development of many commercially available drugs, they are suboptimal in reproducing the physiological microenvironment and complex anatomy of human lungs. Similarly, intersubject variability and high costs have been major limitations of using animals in the development and discovery of drugs used in the treatment of respiratory disorders. To address the complexity and limitations associated with in vivo and in vitro models, attempts have been made to develop in silico and tissue-engineered lung models that allow incorporation of various mechanical and biological factors that are otherwise difficult to reproduce in conventional cell or organ-based systems. The in silico models utilize the information obtained from in vitro and in vivo models and apply computational algorithms to incorporate multiple physiological parameters that can affect drug deposition, distribution, and disposition upon administration via the lungs. Bioengineered lungs, on the other hand, exhibit significant promise due to recent advances in stem or progenitor cell technologies. However, bioengineered approaches have met with limited success in terms of development of various components of the human respiratory system. In this review, we summarize the approaches used and advancements made toward the development of in silico and tissue-engineered lung models and discuss potential challenges associated with the development and efficacy of these models.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

Current Challenges in the Development of Vaccines and Drugs Against Emerging Vector-borne Diseases

2019 ◽  
Vol 26 (16) ◽  
pp. 2974-2986 ◽  
Author(s):  
Kwang-sun Kim
Keyword(s):  
New Host ◽  
In Vivo Models ◽  
Vector Borne Diseases ◽  
Novel Drugs ◽  
Huge Impact ◽  
Tick Borne Disease ◽  
Vector Borne ◽  
Living Organisms

Vectors are living organisms that transmit infectious diseases from an infected animal to humans or another animal. Biological vectors such as mosquitoes, ticks, and sand flies carry pathogens that multiply within their bodies prior to delivery to a new host. The increased prevalence of Vector-Borne Diseases (VBDs) such as Aedes-borne dengue, Chikungunya (CHIKV), Zika (ZIKV), malaria, Tick-Borne Disease (TBD), and scrub typhus has a huge impact on the health of both humans and livestock worldwide. In particular, zoonotic diseases transmitted by mosquitoes and ticks place a considerable burden on public health. Vaccines, drugs, and vector control methods have been developed to prevent and treat VBDs and have prevented millions of deaths. However, development of such strategies is falling behind the rapid emergence of VBDs. Therefore, a comprehensive approach to fighting VBDs must be considered immediately. In this review, I focus on the challenges posed by emerging outbreaks of VBDs and discuss available drugs and vaccines designed to overcome this burden. Research into promising drugs needs to be upgraded and fast-tracked, and novel drugs or vaccines being tested in in vitro and in vivo models need to be moved into human clinical trials. Active preventive tactics, as well as new and upgraded diagnostics, surveillance, treatments, and vaccination strategies, need to be monitored constantly if we are to manage VBDs of medical importance.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

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