| 1. |
- Godoy, Patricio, et al.
(författare)
-
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
-
Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
-
Forskningsöversikt (refereegranskat)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
|
|
| 2. |
- Hall, Benjamin, et al.
(författare)
-
In vivo tau PET imaging in dementia : Pathophysiology, radiotracer quantification, and a systematic review of clinical findings
- 2017
-
Ingår i: Ageing Research Reviews. - : ELSEVIER IRELAND LTD. - 1568-1637 .- 1872-9649. ; 36, s. 50-63
-
Forskningsöversikt (refereegranskat)abstract
- In addition to the deposition of beta-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimer's disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging. In this article, we provide a comprehensive discussion of tau pathophysiology, its quantification with novel PET radiotracers, as well as a systematic review of tau PET imaging in normal aging and various dementia conditions: mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and Lewy body dementia. We discuss the main findings in relation to group differences, clinical-cognitive correlations of tau PET, and multi-modal relationships among tau PET and other pathological markers. Collectively, the small but growing literature of tau PET has yielded consistent anatomical patterns of tau accumulation that recapitulate post-mortem distribution of neurofibrillary tangles which correlate with cognitive functions and other markers of pathology. In general, AD is characterised by increased tracer retention in the inferior temporal lobe, extending into the frontal and parietal regions in more severe cases. It is also noted that the spatial topography of tau accumulation is markedly distinct to that of amyloid burden in aging and AD. Tau PET imaging has also revealed characteristic spatial patterns among various non-AD tauopathies, supporting its potential role for differential diagnosis. Finally, we propose novel directions for future tau research, including (a) longitudinal imaging in preclinical dementia, (b) multi-modal mapping of tau pathology onto other pathological processes such as neuroinflammation, and (c) the need for more validation studies against post-mortem samples of the same subjects. (C) 2017 Elsevier B.V. All rights reserved.
|
|
| 3. |
- Heslop, James A., et al.
(författare)
-
Concise Review : Workshop Review: Understanding and Assessing the Risks of Stem Cell-Based Therapies
- 2015
-
Ingår i: Stem Cells Translational Medicine. - : Oxford University Press (OUP). - 2157-6564 .- 2157-6580. ; 4:4, s. 389-400
-
Forskningsöversikt (refereegranskat)abstract
- The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting-edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new products.
|
|
| 4. |
- Respondek, Gesine, et al.
(författare)
-
Which ante mortem clinical features predict progressive supranuclear palsy pathology?
- 2017
-
Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 32:7, s. 995-1005
-
Forskningsöversikt (refereegranskat)abstract
- Background: Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. Objective: To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. Methods: We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Results: Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Conclusions: Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP.
|
|
