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1.
The staggering cost of bringing a drug to market coupled with the extremely high failure rate of prospective compounds in early phase clinical trials due to unexpected human toxicity makes it imperative that more relevant human models be developed to better predict drug toxicity. Drug–induced nephrotoxicity remains especially difficult to predict in both pre-clinical and clinical settings and is often undetected until patient hospitalization. Current pre-clinical methods of determining renal toxicity include 2D cell cultures and animal models, both of which are incapable of fully recapitulating the in vivo human response to drugs, contributing to the high failure rate upon clinical trials. We have bioengineered a 3D kidney tissue model using immortalized human renal cortical epithelial cells with kidney functions similar to that found in vivo. These 3D tissues were compared to 2D cells in terms of both acute (3 days) and chronic (2 weeks) toxicity induced by Cisplatin, Gentamicin, and Doxorubicin using both traditional LDH secretion and the pre-clinical biomarkers Kim-1 and NGAL as assessments of toxicity. The 3D tissues were more sensitive to drug-induced toxicity and, unlike the 2D cells, were capable of being used to monitor chronic toxicity due to repeat dosing. The inclusion of this tissue model in drug testing prior to the initiation of phase I clinical trials would allow for better prediction of the nephrotoxic effects of new drugs. 相似文献
2.
JC. Brisset F. Gazeau C. Corot N. Nighoghossian Y. Berthezène E. Canet-Soulas M. Wiart 《IRBM》2018,39(2):93-102
Background
Inflammation is a share process in atherosclerosis and stroke and is thought to be a key player in the evolution of these diseases. Ten years ago, inflammation imaging with magnetic resonance imaging (MRI) was considered very promising for both pre-clinical and clinical studies of atherosclerosis and stroke.Contribution
We report here contributions to the field of inflammation imaging with USPIO-enhanced MRI. The goal was to investigate the life cycle of USPIOs in the body, and how the MRI signal has been impacted during their bio-interactions and bioprocessing. Those mechanisms were applied to pre-clinical longitudinal studies of inflammation in atherosclerosis and at the acute stage of ischemic stroke thus allowing the monitoring of treatment effects.Conclusion
This review presents the contribution of the collaborative research project under the “TecSan” grant from the French Research Agency (ANR) as well as pre-clinical and clinical perspectives of USPIO's inflammation MRI in atherosclerosis and stroke. 相似文献3.
Pfefferkorn JA Song Y Sun KL Miller SR Trivedi BK Choi C Sorenson RJ Bratton LD Unangst PC Larsen SD Poel TJ Cheng XM Lee C Erasga N Auerbach B Askew V Dillon L Hanselman JC Lin Z Lu G Robertson A Olsen K Mertz T Sekerke C Pavlovsky A Harris MS Bainbridge G Caspers N Chen H Eberstadt M 《Bioorganic & medicinal chemistry letters》2007,17(16):4538-4544
4.
Mesenchymal stromal cells (MSC) are a population of phenotypically heterogeneous cells that can be isolated from many readily accessible tissues, including bone marrow, umbilical cord, placenta and adipose tissue, where they form part of the supportive, stromal micro-environment. Extensive ex vivo and pre-clinical data suggest that subpopulations within MSC contribute to immunomodulation of the host, without provoking immunologic responses from alloreactive T cells or other effector cells, as well as contributing to tissue repair. These unique properties make MSC an ideal investigational agent for treating graft-versus-host disease (GvHD). Therapeutic trials with varied MSC dosing schedules and clinical end-points have shown mixed results. We have reviewed the biology of MSC gleaned from pre-clinical models, and summarized the results of clinical trials utilizing MSC for the treatment of acute and chronic GvHD. 相似文献
5.
During the last decade, the idea of a “translational” approach has become commonplace within the field of neuroscience. Despite the rapid adaptation of this theoretical framework, few examples of hypothesis-driven translation start with a pre-clinical finding and end with a positive clinical result and no examples of a novel medication have been developed in this way for the treatment of cognition-related disorders. Whereas instances of successful translation exist, most of these are the result of post-hoc hypothesis testing, rather than a priori hypothesis creation. Indeed, part of this disconnection between pre-clinical and clinical results has been driven by paradigms used at both the pre-clinical level (measurement of behaviors that might not be relevant to a patient population) and the clinical level (use of test batteries that cannot be modeled in a pre-clinical environment). However, automated cognition batteries that require responses to stimuli displayed upon a video monitor are decreasing the distance between pre-clinical and clinical behavioral studies. In the last 5 years, numerous papers have been published demonstrating that cognitive functions can be measured in a similar manner in the rodent as in a clinical setting via touch-screen-equipped operant boxes. Here, we argue that the touch-screen approach has the potential of being a powerful tool for the translation of pre-clinical hypotheses into positive clinical findings. 相似文献
6.
《Cytotherapy》2021,23(11):974-979
Although biologically appealing, the concept of tissue regeneration underlying first- and second-generation cell therapies has failed to translate into consistent results in clinical trials. Several types of cells from different origins have been tested in pre-clinical models and in patients with acute myocardial infarction (AMI). Mesenchymal stromal cells (MSCs) have gained attention because of their potential for immune modulation and ability to promote endogenous tissue repair, mainly through their secretome. MSCs can be easily obtained from several human tissues, the umbilical cord being the most abundant source, and further expanded in culture, making them attractive as an allogeneic “of-the-shelf” cell product, suitable for the AMI setting. The available evidence concerning umbilical cord-derived MSCs in AMI is reviewed, focusing on large animal pre-clinical studies and early human trials. Molecular and cellular mechanisms as well as current limitations and possible translational solutions are also discussed. 相似文献
7.
Animal models of inflammatory bowel disease (IBD) and colorectal cancer (CRC) have provided significant insight into the cell intrinsic and extrinsic mechanisms that contribute to the onset and progression of intestinal diseases. The identification of new molecules that promote these pathologies has led to a flurry of activity focused on the development of potential new therapies to inhibit their function. As a result, various pre-clinical mouse models with an intact immune system and stromal microenvironment are now heavily used. Here we describe three experimental protocols to test the efficacy of new therapeutics in pre-clinical models of (1) acute mucosal damage, (2) chronic colitis and/or colitis-associated colon cancer, and (3) sporadic colorectal cancer. We also outline procedures for serial endoscopic examination that can be used to document the therapeutic response of an individual tumor and to monitor the health of individual mice. These protocols provide complementary experimental platforms to test the effectiveness of therapeutic compounds shown to be well tolerated by mice. 相似文献
8.
HANNE Salmenkari ANITA LAITINEN RICHARD A. FORSGÅRD MERVI HOLAPPA JERE LINDÉN LAURI PASANEN MATTI KORHONEN RIITTA KORPELA JOHANNA NYSTEDT 《Cytotherapy》2019,21(2):175-188
Background
Mesenchymal stromal cells (MSCs) are a promising candidate for treatment of inflammatory disorders, but their efficacy in human inflammatory bowel diseases (IBDs) has been inconsistent. Comparing the results from various pre-clinical and clinical IBD studies is also challenging due to a large variation in study designs.Methods
In this comparative pre-clinical study, we compared two administration routes and investigated the safety and feasibility of both fresh and cryopreserved platelet-lysate–expanded human bone marrow–derived MSCs without additional licensing in a dextran sodium sulfate (DSS) colitis mouse model both in the acute and regenerative phases of colitis. Body weight, macroscopic score for inflammation and colonic interleukin (IL)-1β and tumor necrosis factor (TNF)α concentrations were determined in both phases of colitis. Additionally, histopathology was assessed and Il-1β and Agtr1a messenger RNA (mRNA) levels and angiotensin-converting enzyme (ACE) protein levels were measured in the colon in the regenerative phase of colitis.Results
Intravenously administered MSCs exhibited modest anti-inflammatory capacity in the acute phase of colitis by reducing IL-1β protein levels in the inflamed colon. There were no clear improvements in mice treated with fresh or cryopreserved unlicensed MSCs according to weight monitoring results, histopathology and macroscopic score results. Pro-inflammatory ACE protein expression and shedding were reduced by cryopreserved MSCs in the colon.Conclusions
In conclusion, we observed a good safety profile for bone marrow–derived platelet lysate–expanded MSCs in a mouse pre-clinical colitis model, but the therapeutic effect of MSCs prepared without additional licensing (i.e. such as MSCs are administered in graft-versus-host disease) was modest in the chosen in vivo model system and limited to biochemical improvements in cytokines without a clear benefit in histopathology or body weight development. 相似文献9.
Peter E. Batchelor Taryn E. Wills Peta Skeers Camila R. Battistuzzo Malcolm R. Macleod David W. Howells Emily S. Sena 《PloS one》2013,8(8)
Background
The use of early decompression in the management of acute spinal cord injury (SCI) remains contentious despite many pre-clinical studies demonstrating benefits and a small number of supportive clinical studies. Although the pre-clinical literature favours the concept of early decompression, translation is hindered by uncertainties regarding overall treatment efficacy and timing of decompression.Methods
We performed meta-analysis to examine the pre-clinical literature on acute decompression of the injured spinal cord. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of (i) the reporting of efficacy of decompression at various time intervals (ii) number of animals and (iii) the mean outcome and variance in each group. Random effects meta-analysis was used and the impact of study design characteristics assessed with meta-regression.Results
Overall, decompression improved behavioural outcome by 35.1% (95%CI 27.4-42.8; I2=94%, p<0.001). Measures to minimise bias were not routinely reported with blinding associated with a smaller but still significant benefit. Publication bias likely also contributed to an overestimation of efficacy. Meta-regression demonstrated a number of factors affecting outcome, notably compressive pressure and duration (adjusted r2=0.204, p<0.002), with increased pressure and longer durations of compression associated with smaller treatment effects. Plotting the compressive pressure against the duration of compression resulting in paraplegia in individual studies revealed a power law relationship; high compressive forces quickly resulted in paraplegia, while low compressive forces accompanying canal narrowing resulted in paresis over many hours.Conclusion
These data suggest early decompression improves neurobehavioural deficits in animal models of SCI. Although much of the literature had limited internal validity, benefit was maintained across high quality studies. The close relationship of compressive pressure to the rate of development of severe neurological injury suggests that pressure local to the site of injury might be a useful parameter determining the urgency of decompression. 相似文献10.
James O’Callaghan Jack Wells Simon Richardson Holly Holmes Yichao Yu Simon Walker-Samuel Bernard Siow Mark F. Lythgoe 《PloS one》2014,9(5)
High-field, pre-clinical MRI systems are widely used to characterise tissue structure and volume in small animals, using high resolution imaging. Both applications rely heavily on the consistent, accurate calibration of imaging gradients, yet such calibrations are typically only performed during maintenance sessions by equipment manufacturers, and potentially with acceptance limits that are inadequate for phenotyping. To overcome this difficulty, we present a protocol for gradient calibration quality assurance testing, based on a 3D-printed, open source, structural phantom that can be customised to the dimensions of individual scanners and RF coils. In trials on a 9.4 T system, the gradient scaling errors were reduced by an order of magnitude, and displacements of greater than 100 µm, caused by gradient non-linearity, were corrected using a post-processing technique. The step-by-step protocol can be integrated into routine pre-clinical MRI quality assurance to measure and correct for these errors. We suggest that this type of quality assurance is essential for robust pre-clinical MRI experiments that rely on accurate imaging gradients, including small animal phenotyping and diffusion MR. 相似文献
11.
12.
Christoph Kleinschnitz Henrike Grund Kirstin Wingler Melanie E. Armitage Emma Jones Manish Mittal David Barit Tobias Schwarz Christian Geis Peter Kraft Konstanze Barthel Michael K. Schuhmann Alexander M. Herrmann Sven G. Meuth Guido Stoll Sabine Meurer Anja Schrewe Lore Becker Valérie Gailus-Durner Helmut Fuchs Thomas Klopstock Martin Hrabé de Angelis Karin Jandeleit-Dahm Ajay M. Shah Norbert Weissmann Harald H. H. W. Schmidt 《PLoS biology》2010,8(9)
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4
−/−) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4
−/− mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. 相似文献
13.
Lucian Beer Michael Mildner Mariann Gyöngyösi Hendrik Jan Ankersmit 《Apoptosis : an international journal on programmed cell death》2016,21(12):1336-1353
For almost two decades, cell-based therapies have been tested in modern regenerative medicine to either replace or regenerate human cells, tissues, or organs and restore normal function. Secreted paracrine factors are increasingly accepted to exert beneficial biological effects that promote tissue regeneration. These factors are called the cell secretome and include a variety of proteins, lipids, microRNAs, and extracellular vesicles, such as exosomes and microparticles. The stem cell secretome has most commonly been investigated in pre-clinical settings. However, a growing body of evidence indicates that other cell types, such as peripheral blood mononuclear cells (PBMCs), are capable of releasing significant amounts of biologically active paracrine factors that exert beneficial regenerative effects. The apoptotic PBMC secretome has been successfully used pre-clinically for the treatment of acute myocardial infarction, chronic heart failure, spinal cord injury, stroke, and wound healing. In this review we describe the benefits of choosing PBMCs instead of stem cells in regenerative medicine and characterize the factors released from apoptotic PBMCs. We also discuss pre-clinical studies with apoptotic cell-based therapies and regulatory issues that have to be considered when conducting clinical trials using cell secretome-based products. This should allow the reader to envision PBMC secretome-based therapies as alternatives to all other forms of cell-based therapies. 相似文献
14.
Rana Baraz Adam Cisterne Philip O. Saunders John Hewson Marilyn Thien Jocelyn Weiss Jordan Basnett Kenneth F. Bradstock Linda J. Bendall 《PloS one》2014,9(7)
Increasingly, anti-cancer medications are being reported to induce cell death mechanisms other than apoptosis. Activating alternate death mechanisms introduces the potential to kill cells that have defects in their apoptotic machinery, as is commonly observed in cancer cells, including in hematological malignancies. We, and others, have previously reported that the mTOR inhibitor everolimus has pre-clinical efficacy and induces caspase-independent cell death in acute lymphoblastic leukemia cells. Furthermore, everolimus is currently in clinical trial for acute lymphoblastic leukemia. Here we characterize the death mechanism activated by everolimus in acute lymphoblastic leukemia cells. We find that cell death is caspase-independent and lacks the morphology associated with apoptosis. Although mitochondrial depolarization is an early event, permeabilization of the outer mitochondrial membrane only occurs after cell death has occurred. While morphological and biochemical evidence shows that autophagy is clearly present it is not responsible for the observed cell death. There are a number of features consistent with paraptosis including morphology, caspase-independence, and the requirement for new protein synthesis. However in contrast to some reports of paraptosis, the activation of JNK signaling was not required for everolimus-induced cell death. Overall in acute lymphoblastic leukemia cells everolimus induces a cell death that resembles paraptosis. 相似文献
15.
Sean V. Murphy Amritha Kidyoor Tanya Reid Anthony Atala Euan M. Wallace Rebecca Lim 《Journal of visualized experiments : JoVE》2014,(94)
Human amnion epithelial cells (hAECs) derived from term or pre-term amnion membranes have
attracted attention from researchers and clinicians as a potential source of cells for
regenerative medicine. The reason for this interest is evidence that these cells have
highly multipotent differentiation ability, low immunogenicity, and anti-inflammatory
functions. These properties have prompted researchers to investigate the potential of
hAECs to be used to treat a variety of diseases and disorders in pre-clinical animal
studies with much success.hAECs have found widespread application for the treatment of a range of diseases and
disorders. Potential clinical applications of hAECs include the treatment of stroke,
multiple sclerosis, liver disease, diabetes and chronic and acute lung diseases.
Progressing from pre-clinical animal studies into clinical trials requires a higher
standard of quality control and safety for cell therapy products. For safety and quality
control considerations, it is preferred that cell isolation protocols use animal
product-free reagents. We have developed protocols to allow researchers to isolate, cryopreserve and culture
hAECs using animal product-free reagents. The advantage of this method is that these cells
can be isolated, characterized, cryopreserved and cultured without the risk of delivering
potentially harmful animal pathogens to humans, while maintaining suitable cell yields,
viabilities and growth potential. For researchers moving from pre-clinical animal studies
to clinical trials, these methodologies will greatly accelerate regulatory approval,
decrease risks and improve the quality of their therapeutic cell population. 相似文献
16.
Ana Maria Blanco Martinez Camila de Oliveira Goulart Bruna dos Santos Ramalho Júlia Teixeira Oliveira Fernanda Martins Almeida 《World journal of stem cells》2014,6(2):179-194
Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury.These effects are believed to be due to their ability to differentiate into other cell lineages,modulate inflammatory and immunomodulatory responses,reduce cell apoptosis,secrete several neurotrophic factors and respond to tissue injury,among others.There are many pre-clinical studies on MSC treatment for spinal cord injury(SCI)and peripheral nerve injuries.However,the same is not true for clinical trials,particularly those concerned with nerve trauma,indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions.As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies.For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes.This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now.At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves,respectively. 相似文献
17.
MicroRNAs are 19-24 nucleotides noncoding RNAs which silence modulate the expression of target genes by binding to the messenger RNAs. Myeloid malignancies include a broad spectrum of acute and chronic disorders originating from from the clonal transformation of a hematopoietic stem cell. Specific genetic abnormalities may define myeloid malignancies, such as translocation t(9;22) that represent the hallmark of chronic myeloid leukemia. Although next-generation sequencing pro-vided new insights in the genetic characterization and pathogenesis of myeloid neoplasms, the molecular mechanisms underlying myeloid neoplasms are lacking in most cases. Recently, several studies have demonstrated that the expression levels of specific miRNAs may vary among patients with myeloid malignancies compared with healthy individuals and partially unveiled how miRNAs participate in the leukemic transformation process. Finally, in vitro experiments and pre-clinical model provided preliminary data of the safety and efficacy of miRNA inhibitory molecules, opening new avenue in the treatment of myeloid hematological malignancies. 相似文献
18.
Adipose tissue is an abundant, accessible, and replenishable source of adult stem cells that can be isolated from liposuction waste tissue by collagenase digestion and differential centrifugation. These adipose-derived adult stem (ADAS) cells are multipotent, differentiating along the adipocyte, chondrocyte, myocyte, neuronal, and osteoblast lineages, and can serve in other capacities, such as providing hematopoietic support and gene transfer. ADAS cells have potential applications for the repair and regeneration of acute and chronically damaged tissues. Additional pre-clinical safety and efficacy studies will be needed before the promise of these cells can be fully realized. 相似文献
19.
20.
Bueno JM Manzano P García MC Chicharro J Puente M Lorenzo M García A Ferrer S Gómez RM Fraile MT Lavandera JL Fiandor JM Vidal J Herreros E Gargallo-Viola D 《Bioorganic & medicinal chemistry letters》2011,21(18):5214-5218
Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species. 相似文献