scholarly journals Animal models of MEN1

2017 ◽  
Vol 24 (10) ◽  
pp. T161-T177 ◽  
Author(s):  
Hermine Mohr ◽  
Natalia S Pellegata
Keyword(s):  
Animal Models ◽  
Therapy Response ◽  
Model Systems ◽  
Preclinical Studies ◽  
Hormonal Changes ◽  
Novel Therapies ◽  
Loss Of Function ◽  
Potential Models ◽  
Novel Drugs ◽  
Future Patient

Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the humanMEN1gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation inCdkn1b(p27) and not inMen1. BothMen1-knockout mice and MENX rats have been exploited for therapy-response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors.

scholarly journals Characteristics of in Vivo Model Systems for Ovarian Cancer Studies

Diagnostics ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 120 ◽  
Author(s):  
Tudrej ◽  
Kujawa ◽  
Cortez ◽  
Lisowska
Keyword(s):  
Ovarian Cancer ◽  
Animal Models ◽  
Xenograft Model ◽  
Cellular Migration ◽  
Model Systems ◽  
In Vivo Model ◽  
Preclinical Studies ◽  
Cell Of Origin ◽  
Mice Model ◽  
Mesenchymal Transition

An understanding of the molecular pathogenesis and heterogeneity of ovarian cancer holds promise for the development of early detection strategies and novel, efficient therapies. In this review, we discuss the advantages and limitations of animal models available for basic and preclinical studies. The fruit fly model is suitable mainly for basic research on cellular migration, invasiveness, adhesion, and the epithelial-to-mesenchymal transition. Higher-animal models allow to recapitulate the architecture and microenvironment of the tumor. We discuss a syngeneic mice model and the patient derived xenograft model (PDX), both useful for preclinical studies. Conditional knock-in and knock-out methodology allows to manipulate selected genes at a given time and in a certain tissue. Such models have built our knowledge about tumor-initiating genetic events and cell-of-origin of ovarian cancers; it has been shown that high-grade serous ovarian cancer may be initiated in both the ovarian surface and tubal epithelium. It is postulated that clawed frog models could be developed, enabling studies on tumor immunity and anticancer immune response. In laying hen, ovarian cancer develops spontaneously, which provides the opportunity to study the genetic, biochemical, and environmental risk factors, as well as tumor initiation, progression, and histological origin; this model can also be used for drug testing. The chick embryo chorioallantoic membrane is another attractive model and allows the study of drug response.

scholarly journals Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects

2021 ◽  
Vol 22 (7) ◽  
pp. 3722
Author(s):  
Mohamed Sabra ◽  
Catherine Karbasiafshar ◽  
Ahmed Aboulgheit ◽  
Sidharth Raj ◽  
M. Ruhul Abid ◽  
...  
Keyword(s):  
Vascular System ◽  
Therapeutic Angiogenesis ◽  
Clinical Findings ◽  
Preclinical Studies ◽  
Novel Therapies ◽  
Future Prospects ◽  
Surgical Interventions ◽  
Therapeutic Modalities ◽  
Advanced Stages ◽  
Coronary Angiogenesis

Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.

scholarly journals Regenerative potential of secretome from dental stem cells: a systematic review of preclinical studies

2018 ◽  
Vol 29 (3) ◽  
pp. 321-332 ◽  
Author(s):  
Suleiman Alhaji Muhammad ◽  
Norshariza Nordin ◽  
Sharida Fakurazi
Keyword(s):  
Systematic Review ◽  
Stem Cells ◽  
Stem Cell ◽  
Animal Models ◽  
Conditioned Medium ◽  
Tissue Regeneration ◽  
Therapeutic Benefit ◽  
Risk Of Bias ◽  
Preclinical Studies

AbstractInjury to tissues is a major clinical challenge due to the limited regenerative capacity of endogenous cells. Stem cell therapy is evolving rapidly as an alternative for tissue regeneration. However, increasing evidence suggests that the regenerative ability of stem cells is mainly mediated by paracrine actions of secretome that are generally secreted by the cells. We aimed to systematically evaluate the efficacy of dental stem cell (DSC)-conditioned medium inin vivoanimal models of various tissue defects. A total of 15 eligible studies was included by searching Pubmed, Scopus and Medline databases up to August 2017. The risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool. Of 15 studies, seven reported the therapeutic benefit of the conditioned medium on neurological diseases and three reported on joint/bone-related defects. Two interventions were on liver diseases, whereas the remaining three addressed myocardial infarction and reperfusion, lung injury and diabetes. Nine studies were performed using mouse models and the remaining six studies used rat models. The methodological quality of the studies was low, as most of the key elements required in reports of preclinical studies were not reported. The findings of this review suggested that conditioned medium from DSCs improved tissue regeneration and functional recovery. This current review strengthens the therapeutic benefit of cell-free product for tissue repair in animal models. A well-planned study utilizing validated outcome measures and long-term safety studies are required for possible translation to clinical trials.

Production of Adeno-Associated Virus Vectors in Cell Stacks for Preclinical Studies in Large Animal Models

10.3791/62727 ◽  
2021 ◽  
Author(s):  
Amira D. Rghei ◽  
Brenna A. Y. Stevens ◽  
Sylvia P. Thomas ◽  
Jacob G. E. Yates ◽  
Benjamin M. McLeod ◽  
...  
Keyword(s):  
Animal Models ◽  
Large Animal ◽  
Preclinical Studies ◽  
Adeno Associated Virus ◽  
Virus Vectors ◽  
Large Animal Models

scholarly journals APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

2019 ◽  
Vol 316 (1) ◽  
pp. F1-F8 ◽  
Author(s):  
Leslie A. Bruggeman ◽  
John F. O’Toole ◽  
John R. Sedor
Keyword(s):  
Kidney Disease ◽  
Human Genetics ◽  
Disease Risk ◽  
Kidney Diseases ◽  
Expression Patterns ◽  
Model Systems ◽  
Recessive Trait ◽  
Loss Of Function ◽  
Allele Expression ◽  
Basic Biology

The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

scholarly journals Mesenchymal Stem Cell Therapies for Paraplegia: Preclinical and Clinical Studies

Paraplegia ◽  
2021 ◽  
Author(s):  
Fereshteh Azedi ◽  
Kazem Mousavizadeh ◽  
Mohammad Taghi Joghataei
Keyword(s):  
Spinal Cord ◽  
Blood Clot ◽  
Spinal Column ◽  
Preclinical Studies ◽  
Loss Of Function ◽  
Stem Cell Therapies ◽  
Cell Therapies ◽  
Cord Injury ◽  
Preclinical And Clinical Studies

Paraplegia is the damage or loss of function in motor and/or sensory abilities. This insult can be observed in the thoracic, lumbar, or sacral parts of spinal column. Besides, paraplegia may be occurring because of any injuries or diseases of the lower segments or peripheral nerves or by cerebral palsy (CP). This damage can be seen as a result of a tumor or blood clot on the spinal cord. By now, there is not any curative treatment for paraplegia. Using mesenchymal stem cells (MSCs) in the treatment of spinal cord injury is a promising tested strategy because of their simplicity of isolation/preservation and their properties. Several preclinical studies in this field can be found; however, MSCs showed weak and conflicting outcomes in trials. In this chapter book, we will discuss about the therapeutic role of these cells in the treatment of paraplegia, with emphasis on their characterization, relevance, boundaries, and prospect views.

scholarly journals Using magnetic resonance imaging in animal models to guide drug development in multiple sclerosis

2013 ◽  
Vol 20 (1) ◽  
pp. 3-11 ◽  
Author(s):  
Nabeela Nathoo ◽  
V Wee Yong ◽  
Jeff F Dunn
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Magnetic Resonance ◽  
Animal Models ◽  
Mr Imaging ◽  
Preclinical Studies ◽  
Resonance Imaging ◽  
Magnetic Resonance Imaging Mri ◽  
Potential Therapeutics

Major advances are taking place in the development of therapeutics for multiple sclerosis (MS), with a move past traditional immunomodulatory/immunosuppressive therapies toward medications aimed at promoting remyelination or neuroprotection. With an increase in diversity of MS therapies comes the need to assess the effectiveness of such therapies. Magnetic resonance imaging (MRI) is one of the main tools used to evaluate the effectiveness of MS therapeutics in clinical trials. As all new therapeutics for MS are tested in animal models first, it is logical that MRI be incorporated into preclinical studies assessing therapeutics. Here, we review key papers showing how MR imaging has been combined with a range of animal models to evaluate potential therapeutics for MS. We also advise on how to maximize the potential for incorporating MRI into preclinical studies evaluating possible therapeutics for MS, which should improve the likelihood of discovering new medications for the condition.

Cellworks Omics Biology Model (CBM) to predict therapy response and identify biomarkers for all-trans retinoic acid (ATRA) benefit as addition to induction chemotherapy in adults with acute myeloid leukemia (AML).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7027-7027
Author(s):  
Scott C. Howard ◽  
Ansu Kumar ◽  
Himanshu Grover ◽  
Vivek Patil ◽  
Ashish Agrawal ◽  
...  
Keyword(s):  
Computational Modeling ◽  
A Priori ◽  
Therapy Response ◽  
Initial Therapy ◽  
Specific Protein ◽  
Loss Of Function ◽  
Monosomy 7 ◽  
All Trans Retinoic Acid ◽  
The Impact

7027 Background: ATRA combined with arsenic trioxide revolutionized the treatment of APL. Based on promising in vitro data, several clinical trials evaluated ATRA combinations in non-APL AML, in which some patients seemed to benefit from the addition. Thus, predicting response a priori is imperative to determine the optimal treatment for each patient. The CBM was used to evaluate the impact of initial therapy with ATRA combined with cytarabine, etoposide, idarubicin (ATRA-CEI) to assess the biomarkers responsible for response in adults with AML. Methods: AML patients participating in clinical trial NCT00151242 had their leukemia sequenced as part of the trial, and genomic profiles were used for computational modeling by the CBM, which uses curated data about genomic aberrations from PubMed as input to generate disease-specific protein network maps and predict drug responses. Disease biomarkers unique to each patient were identified using biosimulation. Digital drug simulations were conducted by measuring the effect of ATRA-CEI on a composite cell growth score of cell proliferation, apoptosis and other hallmarks of cancer. ATRA-CEI was mapped to the patient genome along with a mechanism of action and validated based on the genomic profile and its biological consequences. Results: Of 171 patients treated with ATRA-CEI, 107 (63%) responded (R) and 64 did not (NR). A subset of 18 patients with favorable genomic features were found to be NR and their non-response was correctly predicted by CBM in all 18 cases. Mutations of DNMT3A, EZH2, ASXL, FLT-3, and GART amplification emerged as novel biomarkers of ATRA-CEI failure (only 37 of 107 responders (35%) with these findings, compared to 70 of 107 responders (65%) without these findings (p = 0.0027)). DNMT3A, EZH2, ASXL1 loss of function mutations activate FABP5, a key mechanism of ATRA resistance, and also activate ABCC1 (PgP), which reduces the efficacy of etoposide and idarubicin by upregulating MDR1. In general, monosomy 7 is expected to confer ATRA resistance due to the presence of EZH2 and KMT2E gene deletions. Indeed, 18 of 32 patients with monosomy 7 did not respond. However, the 14 who responded had co-occurrence of deletions involving IGFBP3, PMS2, HUS1, CDK5, XRCC2/4, AKR1B10, and others that overcame ATRA resistance associated with monosomy 7 and were identified by CBM. Use of CBM helps avoid unnecessary use of ATRA in patients unlikely to respond (19% of cases) thus reducing toxicity and cost without changing efficacy, and also identifies those likely to respond, even when they have monosomy 7, where non-response is the norm. Conclusions: ATRA benefits a subset of patients with non-APL AML. CBM predicted response using computational modeling of all genetic alternations, which explains its success versus traditional one-gene-one-drug approaches.

scholarly journals Models of multiple system atrophy

2019 ◽  
Vol 51 (11) ◽  
pp. 1-10 ◽  
Author(s):  
He-Jin Lee ◽  
Diadem Ricarte ◽  
Darlene Ortiz ◽  
Seung-Jae Lee
Keyword(s):  
Animal Models ◽  
Multiple System Atrophy ◽  
Mouse Models ◽  
Clinical Manifestations ◽  
Lewy Bodies ◽  
Model Systems ◽  
Future Research ◽  
Cytoplasmic Inclusions ◽  
Cellular Models ◽  
Brain Extracts

AbstractMultiple system atrophy (MSA) is a neurodegenerative disease with diverse clinical manifestations, including parkinsonism, cerebellar syndrome, and autonomic failure. Pathologically, MSA is characterized by glial cytoplasmic inclusions in oligodendrocytes, which contain fibrillary forms of α-synuclein. MSA is categorized as one of the α-synucleinopathy, and α-synuclein aggregation is thought to be the culprit of the disease pathogenesis. Studies on MSA pathogenesis are scarce relative to studies on the pathogenesis of other synucleinopathies, such as Parkinson’s disease and dementia with Lewy bodies. However, recent developments in cellular and animal models of MSA, especially α-synuclein transgenic models, have driven advancements in research on this disease. Here, we review the currently available models of MSA, which include toxicant-induced animal models, α-synuclein-overexpressing cellular models, and mouse models that express α-synuclein specifically in oligodendrocytes through cell type-specific promoters. We will also discuss the results of studies in recently developed transmission mouse models, into which MSA brain extracts were intracerebrally injected. By reviewing the findings obtained from these model systems, we will discuss what we have learned about the disease and describe the strengths and limitations of the models, thereby ultimately providing direction for the design of better models and future research.

scholarly journals Animal model of intrahepatic metastasis of hepatocellular carcinoma: establishment and characteristic

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Xuemei Li ◽  
Jike Hu ◽  
Baohong Gu ◽  
Maswikiti Ewetse Paul ◽  
Bofang Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Animal Models ◽  
Cell Line ◽  
Cell Lines ◽  
Intrahepatic Metastasis ◽  
Model Systems ◽  
Large Tumor ◽  
Important Direction ◽  
Disease Study

Abstract One of the most important and striking characteristics of hepatocellular carcinoma (HCC) with intrahepatic metastasis, is that it results in extremely poor prognosis. Animal models have become a fundamental and very useful in research for disease study. However, some limitation has arisen from these model systems. We have therefore established a model of HCC with intrahepatic metastasis and noticed some differential appearances in different HCC cell lines. Luciferase-transfected HCC cell lines MHCC97-H and PLC/PRF/5 were inoculated into SCID mice via spleen. Observation the intrahepatic metastasis by bioluminescence imaging in vivo and comparing of the differential formation of metastatic lesions between different HCC cell lines by incorporating physical anatomy was done. Animal models for HCC intrahepatic metastasis were well established. However, there were some clearly noticed differences between MHCC97-H and PLC/PRF/5 cell lines. The group of MHCC97-H cell line readily metastasis in the liver, whereas group PLC/PRF/5 cell line developed extensive intrahepatic metastasis and formed large tumor in situ in the spleen. MHCC97-H and PLC/PRF/5 cell lines can be used to successfully establish a model of HCC intrahepatic metastasis with distinctive characteristics, which provides an important direction for the study of the mechanism of HCC intrahepatic metastasis, and may hopefully provide a basis for clinical treatment.

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