1,781 research outputs found
Recommended from our members
Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field
Human Pluripotent Stem Cells and Drug Discovery: A New Beginning
Human pluripotent stem cells (hPSCs) offer unique opportunities to discover and develop a new generation of drugs. Their ability to differentiate into virtually any cell type renders them a cost-effective, renewable source of tissue-specific cell types capable of predicting human responses towards novel chemical entities. Using these improved in vitro models based on physiologically relevant human cell types could result in identifying highly precise and safe compounds, thereby reducing drug attrition rates. Moreover, ability to develop humanised disease models for patient-stratified drug screening makes hPSCs an impeccable tool in translational medicine. In this mini-review we focus on the positives and negatives of utilising hPSC-derived cell types as drug discovery platforms with special emphasis on cardio-, hepato- and embryotoxicity
The sixth international RASopathies symposium: Precision medicine—From promise to practice
The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS‐mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life‐limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion
A deep learning algorithm to translate and classify cardiac electrophysiology
The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology, and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability, and immature phenotype of the iPSC-CM platform. The rationale for combining translation and classification tasks is because the most likely application of the deep learning technology we describe here is to translate iPSC-CMs following application of a perturbation. The deep learning network was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter
Towards Early Prediction of Human iPSC Reprogramming Success
This paper presents advancements in automated early-stage prediction of the
success of reprogramming human induced pluripotent stem cells (iPSCs) as a
potential source for regenerative cell therapies.The minuscule success rate of
iPSC-reprogramming of around to makes it labor-intensive,
time-consuming, and exorbitantly expensive to generate a stable iPSC line.
Since that requires culturing of millions of cells and intense biological
scrutiny of multiple clones to identify a single optimal clone. The ability to
reliably predict which cells are likely to establish as an optimal iPSC line at
an early stage of pluripotency would therefore be ground-breaking in rendering
this a practical and cost-effective approach to personalized medicine. Temporal
information about changes in cellular appearance over time is crucial for
predicting its future growth outcomes. In order to generate this data, we first
performed continuous time-lapse imaging of iPSCs in culture using an ultra-high
resolution microscope. We then annotated the locations and identities of cells
in late-stage images where reliable manual identification is possible. Next, we
propagated these labels backwards in time using a semi-automated tracking
system to obtain labels for early stages of growth. Finally, we used this data
to train deep neural networks to perform automatic cell segmentation and
classification. Our code and data are available at
https://github.com/abhineet123/ipsc_prediction.Comment: Accepted for publication at the Journal of Machine Learning for
Biomedical Imaging (MELBA) https://melba-journal.org/2023:01
Dynamic full-field optical coherence tomography: 3D live-imaging of retinal organoids
Optical coherence tomography offers astounding opportunities to image the
complex structure of living tissue, but lacks functional information. We
present dynamic full-field optical coherence tomography to image living human
induced pluripotent stem cell-derived retinal organoids non-invasively. Colored
images with an endogenous contrast linked to organelle motility are generated,
with sub-micrometer spatial resolution and millisecond temporal resolution,
opening an avenue to identify specific cell types in living tissue via their
function.Comment: 14 pages, 5 figures, 1 table, 6 video
Gene and Cell Therapy for AIPL1-Associated Leber Congenital Amaurosis: Challenges and Prospects
Leber congenital amaurosis (LCA) caused by AIPL1 mutations is one of the most severe forms of inherited retinal degeneration (IRD). The rapid and extensive photoreceptor degeneration challenges the development of potential treatments. Nevertheless, preclinical studies show that both gene augmentation and photoreceptor transplantation can regenerate and restore retinal function in animal models of AIPL1-associated LCA. However, questions regarding long-term benefit and safety still remain as these therapies advance towards clinical application. Ground-breaking advances in stem cell technology and genome editing are examples of alternative therapeutic approaches and address some of the limitations associated with previous methods. The continuous development of these cutting-edge biotechnologies paves the way towards a bright future not only for AIPL1-associated LCA patients but also other forms of IRD
Genetics meets Pathology - an increasingly important relationship.
The analytical power of modern methods for DNA analysis has outstripped our capability to interpret and understand the data generated. To make good use of this genomic data in a biomedical setting (whether for research or diagnosis), it is vital that we understand the mechanisms through which mutations affect biochemical pathways and physiological systems. This lies at the centre of what genetics is all about, and it is the reason why genetics and genomics should go hand in hand whenever possible. In this Annual Review Issue of the Journal of Pathology, we have assembled a collection of 16 expert reviews covering a wide range of topics. Through these, we illustrate the power of genetic analysis to improve our understanding of normal physiology and disease pathology, and thereby to think in rational ways about clinical management
Culturing Adult Stem Cells for Cell-Based Therapeutics: Neuroimmune Applications
Pluripotent stem cells can be successfully isolated from a variety of tissues from adult organisms. This fact opens the exciting possibility of cell-based therapies for a large number of clinical treatments. However, the development of optimized protocols to obtain, grow, and cryopreserve cells, as well as that of effective clinical treatment procedures, is no easy task. The therapeutic potential of cells expanded in vitro depends on a multitude of factors including isolation procedures, donor and tissue types, expansion and preservation methods, etc. Researchers are investing great efforts to determine which of these many variables significantly impact downstream performance of in vitro expanded stem cells by studying associated changes in molecular profiles and their effect on the host immune system. This chapter reviews the current status of stem cell production and its derivatives, which are paving the way to different treatments in the clinic. Due to the research interests of our labs, particular emphasis is placed on the potential benefits of stem cell-based therapeutics for the treatment of spinal cord injuries and the neuroimmune disease myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) not only derived from differentiation and cell engraftment mechanisms but also due to the anti-inflammatory and immunoregulatory capacities of these cells
- …