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Preventive effect of pregabalin on oxaliplatin-related neurotoxicity for patients with advanced/recurrent colorectal cancer: a prospective phase 2 study

ABSTRACT: Interventions: Pregabalin is administered during FOLFOX or XELOX therapy. Initial dose:75mg twice daily(150mg/day),increased to 300 - 600mg/day if there was persistent paresthesia or functional impariment(Grade2 or more). Primary outcome(s): Neurotoxicity frequency of accumulation dose 500mg/m2 of L-OHP (Grade2 or more) Study Design: Single arm Non-randomized

DISEASE(S): Colorectal Cancer

PROVIDER: 2624861 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Preventive effect and safety of pregabalin on FOLFOX-related peripheral neurotoxicity for patients with advanced and recurrent colorectal cancer

Project description:Interventions: In case of FOLFOX related-peripheral neurotoxicity (Grade1), pregabalin is administered. Primary outcome(s): Neurotoxicity frequency of cumulative dose 500mg/m2 of oxaliplatin (Grade2 and more) Study Design: Single arm Non-randomized

| 2628289 | ecrin-mdr-crc

Preventive effect of shakuyaku-kanzo-to on neurotoxicity of FOLFOX plus bevacizumab for patients with metastatic colorectal cancer: a prospective phase II study

Project description:Interventions: Patients receive FOLFOX4 plus bevacizumab or modified FOLFOX6 plus bevacizumab and take shakuyaku-kanzo-to (7.5g/day) orally every day during FOLFOX plus bevacizumab treatment. Primary outcome(s): Neurotoxicity frequency of accumulation dose 500mg/m2 of oxaliplatin Study Design: Single arm Non-randomized

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Human pluripotent stem cell-derived 2D neural tissue samples for predictive neurotoxicity screening

Project description:There is a growing need for fast and accurate methods for testing developmental neurotoxicity across industrial, pharmaceutical, and environmental chemical exposures. Current approaches, such as in vivo animal studies, and assays of animal and human primary cell cultures, suffer from challenges related to time, cost, and applicability to human physiology. Prior research demonstrated success employing machine learning to predict developmental neurotoxicity using gene expression data collected from complex human 3D tissue models exposed to various compounds, but the complexity of 3D tissue models require extensive expertise and effort to employ. While a 3D tissue model is more physiologically accurate, by focusing only on the goal of constructing an assay of developmental neurotoxicity, we propose that a simpler 2D tissue model may prove sufficient. We thus compared the accuracy of predictive models trained on data from a 2D tissue model with those trained on prior dataset from a more complex 3D tissue model, and found the accuracy of the 2D model to be substantially better than the 3D model. Furthermore, we found that the 2D tissue model is more robust and consistent under stringent gene set selection, whereas the 3D tissue model suffers substantial degradation of accuracy. While both approaches have advantages and disadvantages, we propose that our described 2D tissue model has the potential to serve as a valuable tool for decision makers when prioritizing neurotoxicity screening.

2019-05-06 | GSE126786 | GEO

Integrated multi-omics analysis reveals the underlying molecular mechanism for developmental neurotoxicity of perfluorooctanesulfonic acid in zebrafish

Project description:Limited studies on multi-omics have been conducted to comprehensively investigate the molecular mechanism underlying the developmental neurotoxicity of perfluorooctanesulfonic acid (PFOS). In this study, the locomotor behavior of zebrafish larvae was assessed under the exposure to 0.1–20 μM PFOS based on its reported neurobehavioral effect. After the number of zebrafish larvae was optimized for proteomics and metabolomics studies, three kinds of omics (i.e., transcriptomics, proteomics, and metabolomics) were carried out with zebrafish larvae exposed to 0.1, 1, 5, and 10 μM PFOS. More importantly, a data-driven integration of multi-omics was performed to elucidate the toxicity mechanism involved in developmental neurotoxicity. In a concentration-dependent manner, exposure to PFOS provoked hyperactivity and hypoactivity under light and dark conditions, respectively. Individual omics revealed that PFOS exposure caused perturbations in the pathways of neurological function, oxidative stress, and energy metabolism. Integrated omics implied that there were decisive pathways for axonal deformation, neuroinflammatory stimulation, and dysregulation of calcium ion signaling, which are more clearly specified for neurotoxicity. Overall, our findings broaden the molecular understanding of the developmental neurotoxicity of PFOS, for which multi-omics and integrated omics analyses are efficient for discovering the significant molecular pathways related to developmental neurotoxicity in zebrafish.

2023-04-04 | GSE228664 | GEO

Acrylamide acute neurotoxicity in adult zebrafish

Project description:Acute exposure to acrylamide (ACR), a type-2 alkene, may lead to a ataxia, skeletal muscles weakness and numbness of the extremities in exposed human and laboratory animals. Recently, a zebrafish model for ACR neurotoxicity mimicking most of the pathophysiological processes described in mammalian models, was generated in 8 days post-fertilization larvae. In order to better understand the predictive value of the zebrafish larvae model of acute ACR neurotoxicity, in the present manuscript the ACR acute neurotoxicity has been characterized in the brain of adult zebrafish, and the results compared with those obtained with the whole-larvae. Although qualitative and quantitative analysis of the data shows important differences in the ACR effects between the adult brain and the whole-larvae, the overall effects of ACR in adult zebrafish, including a significant decrease in locomotor activity, altered expression of transcriptional markers of proteins involved in synaptic vesicle cycle, presence of ACR-adducts on cysteine residues of some synaptic proteins, and changes in the profile of some neurotransmitter systems, are similar to those described in the larvae. Thus, these results support the suitability of the zebrafish ACR acute neurotoxicity recently developed in larvae for screening of molecules with therapeutic value to treat this toxic neuropathy.

2018-10-19 | PXD008993 | Pride

Chemotherapy neurotoxicity is codependent on cancer

Project description:Chemotherapy neurotoxicity is codependent on cancer

| PRJNA523238 | ENA

Prediction of sensitivity of rectal cancer cells in response to preoperative chemoradiotherapy by DNA microarray analysis of gene expression profiles.

Project description:Samples were prospectively collected during colonoscopic examination from 46 rectal cancer patients before starting preoperative chemoradiotherapy. The expression profiles were determined using Affymetrix Human Genome U133 Plus 2.0 arrays. Comparison between the sample groups allow to identify a set of discriminating genes that can be used for prediction of the response to radiotherapy in rectal cancer. Specimens from 46 rectal cancer patients who approved to receive preoperative chemoradiotherapy were studied. We prospectively collected biopsy specimens during colonoscopic examination from rectal cancer before starting preoperative chemoradiotherapy. Specimens from tumors were snap-frozen in liquid nitrogen and stored at -80 C until use. Paralleled tumor specimens were formalin fixed and paraffin embedded for histologic examination and other specimens were used for RNA extraction. RNA was extracted from tumor tissue using frozen samples. The patients provided written, informed consent to the collection of specimens, and the local Ethics Committee approved the study protocol. All patients received a total dose of 50.4 Gy of radiation, UFT(300-500mg/day) and LV (75mg/day) and underwent standardized curative resection, following an interval of 4 weeks after chemoradiotherapy.

2013-01-29 | E-GEOD-35452 | biostudies-arrayexpress

Gene Expression Analysis of Carbonyl Sulfide Neurotoxicity

Project description:To gain insight into the pathogenesis of carbonyl sulfide induced neurotoxicity, we examined the gene expression profile of exposed rats before the onset of morphological changes (days 1 and 2) using the most consistently affected brain region, the posterior colliculus.

2009-07-07 | GSE12018 | GEO

Defective mitochondrial dynamics underlie manganese-induced neurotoxicity

Project description:Defective mitochondrial dynamics underlie manganese-induced neurotoxicity

| PRJNA641207 | ENA

Modeling acrylamide acute neurotoxicity in zebrafish larvae

Project description:Background: Acrylamide (ACR) is a broadly spread neurotoxic chemical of public health concern, as occupational or environmental exposure of humans to ACR may lead to a synaptopathy characterized by ataxia, skeletal muscles weakness and numbness of the extremities. Currently, only the mildly affected patients undergo complete recovery, and identification of new molecules with therapeutic bioactivity against ACR acute neurotoxicity is urgently needed. Objectives: We aimed to develop a zebrafish model for human ACR neurotoxicity. Methods: Adverse effects have been assessed at different levels, including analysis of the motor function (basal locomotor activity, visual motor response, kinematic of the touch-evoked escape response), histopathological evaluation (toluidine blue and whole-mount immunofluorescence), analysis of neural transcriptional markers (qPCR), proteomic analysis (μLC-MS-MS) and neurotransmitters profile (LC-MS/MS). Results: Our results show that zebrafish mimics most of the pathophysiological processes described in humans and mammalian models. Motor function was altered, including the response to sudden changes in light intensity. Specific effects were found on the presynaptic nerve terminals at the neuromuscular junction level, but not on the axonal tracts or myelin sheath integrity. Transcriptional markers of proteins involved in synaptic vesicle cycle were selectively altered, and the proteomic analysis showed that ACR-adducts were formed on cysteine residues of some synaptic proteins. Finally, analysis of neurotransmitters profile showed a significant effect found on cholinergic and dopaminergic systems. Conclusions: Thus, the zebrafish model for ACR acute neurotoxicity is suitable to be used larvae for in vivo high-throughput screening of small molecule libraries for identifying new drugs against this synaptopathy.

2018-10-24 | PXD007169 | Pride

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