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Article: Performance of biomarkers NF-L, NSE, Tau and GFAP in blood and cerebrospinal fluid in rat for the detection of nervous system injury.

Vlasakova, Katerina / Tsuchiya, Takayuki / Garfinkel, Ivy N / Ruth, Michael P / Tyszkiewicz, Cheryl / Detwiler, Theodore J / Somps, Christopher J / Di Cesare Mannelli, Lorenzo / Glaab, Warren E

Frontiers in neuroscience

2024 Volume 17, Page(s) 1285359

Abstract: Background: Target organ toxicity is often a reason for attritions in nonclinical and clinical drug development. Leveraging emerging safety biomarkers in nonclinical studies provides an opportunity to monitor such toxicities early and efficiently, ... ...

Abstract	Background: Target organ toxicity is often a reason for attritions in nonclinical and clinical drug development. Leveraging emerging safety biomarkers in nonclinical studies provides an opportunity to monitor such toxicities early and efficiently, potentially translating to early clinical trials. As a part of the European Union's Innovative Medicines Initiative (IMI), two projects have focused on evaluating safety biomarkers of nervous system (NS) toxicity: Translational Safety Biomarker Pipeline (TransBioLine) and Neurotoxicity De-Risking in Preclinical Drug Discovery (NeuroDeRisk). Methods: Performance of fluid-based NS injury biomarker candidates neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE) and total Tau in plasma and cerebrospinal fluid (CSF) was evaluated in 15 rat Results: NF-L was the best performer in detecting both peripheral nervous system (PNS) and CNS injury in plasma, (AUC of 0.97-0.99; respectively). In CSF, Tau correlated the best with CNS (AUC 0.97), but not PNS injury. NSE and GFAP were suitable for monitoring CNS injury, but with lesser sensitivity. In summary, NF-L is a sensitive and specific biomarker in rats for detecting compound-induced central and peripheral NS injuries. While NF-L measurement alone cannot inform the site of the injury, addition of biomarkers like Tau and NSE and analysis in both blood and CSF can provide additional information about the origin of the NS injury. Conclusion: These results demonstrate the utility of emerging safety biomarkers of drug-induced NS injury in rats and provide additional supporting evidence for biomarker translation across species and potential use in clinical settings to monitor drug-induced NS injury in patients.
Language	English
Publishing date	2024-01-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1285359
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Article: Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species.

Fader, Kelly A / Pardo, Ingrid D / Kovi, Ramesh C / Somps, Christopher J / Wang, Helen Hong / Vaidya, Vishal S / Ramaiah, Shashi K / Sirivelu, Madhu P

Molecular therapy. Methods & clinical development

2022 Volume 25, Page(s) 264–277

Abstract: Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As ... ...

Abstract	Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as day 8 in rats (≥5 × 10
Language	English
Publishing date	2022-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2022.03.017
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Zs.A 7107: Show issues

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Article ; Online: Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy.

Huehnchen, Petra / Schinke, Christian / Bangemann, Nikola / Dordevic, Adam D / Kern, Johannes / Maierhof, Smilla K / Hew, Lois / Nolte, Luca / Körtvelyessy, Peter / Göpfert, Jens C / Ruprecht, Klemens / Somps, Christopher J / Blohmer, Jens-Uwe / Sehouli, Jalid / Endres, Matthias / Boehmerle, Wolfgang

JCI insight

2022 Volume 7, Issue 6

Abstract: BACKGROUNDPaclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. Given that sensory symptoms are challenging to assess objectively in clinical practice, an easily accessible biomarker for chemotherapy-induced ... ...

Abstract	BACKGROUNDPaclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. Given that sensory symptoms are challenging to assess objectively in clinical practice, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as a translational surrogate marker for CIPN.METHODSNFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSNs) to paclitaxel. Patients with breast or ovarian cancer undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy, and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced (TNSr), which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single-molecule array technology.RESULTSNFL was released from iPSC-DSNs upon paclitaxel incubation in a dose- and time-dependent manner and was inversely correlated with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in patients receiving chemotherapy without CIPN or controls, resulting in an 86% sensitivity and 87% specificity. An NFLs increase of +36 pg/mL from baseline was associated with a predicted CIPN probability of more than 0.5.CONCLUSIONNFLs was correlated with CIPN development and severity, which may guide neurotoxic chemotherapy in the future.TRIAL REGISTRATIONClinicalTrials.gov NCT02753036.FUNDINGDeutsche Forschungsgemeinschaft (EXC 257 NeuroCure), BMBF (Center for Stroke Research Berlin, 01 EO 0801), Animalfree Research, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283), Charité 3R - Replace - Reduce - Refine.
MeSH term(s)	Antineoplastic Agents/adverse effects ; Biomarkers ; Cohort Studies ; Humans ; Neurofilament Proteins ; Paclitaxel/adverse effects ; Peripheral Nervous System Diseases/chemically induced ; Peripheral Nervous System Diseases/diagnosis ; Polyneuropathies/chemically induced ; Polyneuropathies/diagnosis
Chemical Substances	Antineoplastic Agents ; Biomarkers ; Neurofilament Proteins ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2022-03-22
Publishing country	United States
Document type	Clinical Study ; Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.154395
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Article ; Online: An in vitro alveolar epithelial cell model recapitulates LRRK2 inhibitor-induced increases in lamellar body size observed in preclinical models.

Harney, Julie / Bajaj, Piyush / Finley, James E / Kopec, Anna K / Koza-Taylor, Petra H / Boucher, Germaine G / Lanz, Thomas A / Doshna, Colleen M / Somps, Christopher J / Adkins, Karissa / Houle, Christopher

Toxicology in vitro : an international journal published in association with BIBRA

2020 Volume 70, Page(s) 105012

Abstract: Alveolar type II (ATII) epithelial cells contain lamellar bodies (LBs) which synthesize and store lung surfactants. In animals, the inhibition or knockout of leucine-rich repeat kinase 2 (LRRK2) causes abnormal enlargement of LBs in ATII cells. This ... ...

Abstract	Alveolar type II (ATII) epithelial cells contain lamellar bodies (LBs) which synthesize and store lung surfactants. In animals, the inhibition or knockout of leucine-rich repeat kinase 2 (LRRK2) causes abnormal enlargement of LBs in ATII cells. This effect of LRRK2 inhibition in lung is largely accepted as being mediated directly through blocking of the kinase function; however, downstream consequences in the lung remain unknown. In this work we established an in vitro alveolar epithelial cell (AEC) model that recapitulates the in vivo phenotype of ATII cells and developed an assay to quantify changes in LB size in response to LRRK2 inhibitors. Culture of primary human AECs at the air-liquid interface on matrigel and collagen-coated transwell inserts in the presence of growth factors promoted the LB formation and apical microvilli and induced expression of LRRK2 and ATII cell markers. Treatment with a selective LRRK2 inhibitor resulted in pharmacological reduction of phospho-LRRK2 and a significant increase in LB size; effects previously reported in lungs of non-human primates treated with LRRK2 inhibitor. In summary, our human in vitro AEC model recapitulates the abnormal lung findings observed in LRRK2-perturbed animals and holds the potential for expanding current understanding of LRRK2 function in the lung.
MeSH term(s)	ATP-Binding Cassette Transporters/metabolism ; Adenocarcinoma of Lung/metabolism ; Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/pathology ; Alveolar Epithelial Cells/ultrastructure ; Cells, Cultured ; Drug Evaluation, Preclinical ; Gene Expression ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Lung Neoplasms/metabolism ; Models, Biological ; Pulmonary Surfactant-Associated Protein C/metabolism
Chemical Substances	ABCA3 protein, human ; ATP-Binding Cassette Transporters ; Pulmonary Surfactant-Associated Protein C ; SFTPC protein, human ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
Language	English
Publishing date	2020-10-10
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/j.tiv.2020.105012
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Zs.A 2223: Show issues

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Article ; Online: No Evidence of Neurogenesis in Adult Rat Sympathetic Ganglia Following Guanethidine-Induced Neuronal Loss.

Walters, Karen M / Boucher, Magalie / Boucher, Germaine G / Opsahl, Alan C / Mouton, Peter R / Liu, Chang-Ning / Ritenour, Casey R / Kawabe, Thomas T / Pryski, Hayley N / Somps, Christopher J

Toxicologic pathology

2019 Volume 48, Issue 1, Page(s) 228–237

Abstract: The potential for neurogenesis in the cranial (superior) cervical ganglia (SCG) of the sympathetic nervous system was evaluated. Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered intraperitoneally to rats in order to destroy ... ...

Abstract	The potential for neurogenesis in the cranial (superior) cervical ganglia (SCG) of the sympathetic nervous system was evaluated. Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered intraperitoneally to rats in order to destroy postganglionic sympathetic neurons in SCG. Following the last dose, animals were allowed to recover 1, 3, or 6 months. Right and left SCG from guanethidine-treated and age-matched, vehicle-treated control rats were harvested for histopathologic, morphometric, and stereologic evaluations. Both morphometric and stereologic evaluations confirmed neuron loss following guanethidine treatment. Morphometric analysis revealed a 50% to 60% lower number of tyrosine hydroxylase (TH)-positive neurons per unit area of SCG at both 3 and 6 months of recovery, compared to ganglia of age-matched controls, with no evidence of restoration of neuron density between 3 and 6 months. Reductions in TH-positive neurons following guanethidine treatment were corroborated by unbiased stereology of total hematoxylin and eosin-stained neuron numbers in SCG. Stereologic analyses revealed that total neuron counts were lower by 37% at 3 months of recovery when compared to age-matched vehicle controls, again with no obvious restoration between 3 and 6 months. Thus, no evidence was found that postganglionic neurons of the sympathetic nervous system in the adult rat have a neurogenic capacity.
MeSH term(s)	Animals ; Ganglia, Sympathetic/physiology ; Guanethidine/toxicity ; Nerve Degeneration ; Neurogenesis ; Neurons ; Rats ; Sympathetic Nervous System ; Sympatholytics/toxicity ; Tyrosine 3-Monooxygenase
Chemical Substances	Sympatholytics ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; Guanethidine (ZTI6C33Q2Q)
Language	English
Publishing date	2019-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	841009-4
ISSN	1533-1601 ; 0192-6233
ISSN (online)	1533-1601
ISSN	0192-6233
DOI	10.1177/0192623319843052
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Zs.A 1975: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 473: Show issues

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Article ; Online: Ocular toxicity assessment from systemically administered xenobiotics: considerations in drug development.

Brock, William J / Somps, Christopher J / Torti, Vince / Render, James A / Jamison, Jeffrey / Rivera, Maria I

International journal of toxicology

2013 Volume 32, Issue 3, Page(s) 171–188

Abstract: The eye is a unique sensory structure, which must be evaluated for toxicity to determine the safety of drugs, industrial chemicals, and consumer products. Changes in the structure and/or function of ocular tissues following systemic administration of a ... ...

Abstract	The eye is a unique sensory structure, which must be evaluated for toxicity to determine the safety of drugs, industrial chemicals, and consumer products. Changes in the structure and/or function of ocular tissues following systemic administration of a potential new drug in preclinical animal models can result in significant delays in the development of a new therapeutic and in some cases lead to termination of the development. The ability to detect and characterize ocular toxicity in preclinical models and to predict risk in patients is critically dependent on the preclinical testing strategy, the availability and use of state-of-the-art ocular safety assessment tools, and the knowledge of drug mechanism of action and the current regulatory environment. This review describes the design and execution of toxicity studies with the incorporation of current methods for in vivo assessment of ocular toxicity, including methods for detecting early changes in the eye. In addition, anatomical differences among laboratory animals, preparation of globes for examination, and iatrogenic and spontaneous ocular findings are described that can affect interpretation of toxicological findings. Finally, the correlation between nonclinical outcomes and clinical evaluations is discussed in terms of expected therapeutic uses, indications, and regulatory consequences of ocular effects.
MeSH term(s)	Animals ; Drug Evaluation, Preclinical/methods ; Eye/drug effects ; Vision, Ocular/drug effects ; Xenobiotics/administration & dosage ; Xenobiotics/toxicity
Chemical Substances	Xenobiotics
Language	English
Publishing date	2013-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1379845-5
ISSN	1092-874X ; 1091-5818
ISSN (online)	1092-874X
ISSN	1091-5818
DOI	10.1177/1091581813484500
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Zs.A 1870: Show issues

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Article ; Online: The role of hypoxia in 2-butoxyethanol-induced hemangiosarcoma.

Laifenfeld, Daphna / Gilchrist, Annalyn / Drubin, David / Jorge, Milena / Eddy, Sean F / Frushour, Brian P / Ladd, Bill / Obert, Leslie A / Gosink, Mark M / Cook, Jon C / Criswell, Kay / Somps, Christopher J / Koza-Taylor, Petra / Elliston, Keith O / Lawton, Michael P

Toxicological sciences : an official journal of the Society of Toxicology

2009 Volume 113, Issue 1, Page(s) 254–266

Abstract: To understand the molecular mechanisms underlying compound-induced hemangiosarcomas in mice, and therefore, their human relevance, a systems biology approach was undertaken using transcriptomics and Causal Network Modeling from mice treated with 2- ... ...

Abstract	To understand the molecular mechanisms underlying compound-induced hemangiosarcomas in mice, and therefore, their human relevance, a systems biology approach was undertaken using transcriptomics and Causal Network Modeling from mice treated with 2-butoxyethanol (2-BE). 2-BE is a hemolytic agent that induces hemangiosarcomas in mice. We hypothesized that the hemolysis induced by 2-BE would result in local tissue hypoxia, a well-documented trigger for endothelial cell proliferation leading to hemangiosarcoma. Gene expression data from bone marrow (BM), liver, and spleen of mice exposed to a single dose (4 h) or seven daily doses of 2-BE were used to develop a mechanistic model of hemangiosarcoma. The resulting mechanistic model confirms previous work proposing that 2-BE induces macrophage activation and inflammation in the liver. In addition, the model supports local tissue hypoxia in the liver and spleen, coupled with increased erythropoeitin signaling and erythropoiesis in the spleen and BM, and suppression of mechanisms that contribute to genomic stability, events that could be contributing factors to hemangiosarcoma formation. Finally, an immunohistochemistry method (Hypoxyprobe) demonstrated that tissue hypoxia was present in the spleen and BM. Together, the results of this study identify molecular mechanisms that initiate hemangiosarcoma, a key step in understanding safety concerns that can impact drug decision processes, and identified hypoxia as a possible contributing factor for 2-BE-induced hemangiosarcoma in mice.
MeSH term(s)	Animals ; Bone Marrow/metabolism ; Bone Marrow/pathology ; Cell Cycle ; Cell Differentiation ; Cell Hypoxia ; Cell Proliferation ; Cell Transformation, Neoplastic/chemically induced ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Disease Models, Animal ; Endothelial Cells/metabolism ; Erythropoiesis ; Erythropoietin/metabolism ; Ethylene Glycols ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic ; Genomic Instability ; Hemangiosarcoma/chemically induced ; Hemangiosarcoma/genetics ; Hemangiosarcoma/metabolism ; Hemangiosarcoma/pathology ; Hematopoietic Stem Cells/metabolism ; Hemolysis ; Hepatitis/metabolism ; Hepatitis/pathology ; Immunohistochemistry ; Liver/metabolism ; Liver/pathology ; Macrophage Activation ; Male ; Mice ; Models, Biological ; Signal Transduction ; Spleen/metabolism ; Spleen/pathology ; Systems Biology ; Time Factors
Chemical Substances	Ethylene Glycols ; Erythropoietin (11096-26-7) ; n-butoxyethanol (I0P9XEZ9WV)
Language	English
Publishing date	2009-10-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfp213
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Article: Performance of biomarkers NF-L, NSE, Tau and GFAP in blood and cerebrospinal fluid in rat for the detection of nervous system injury.

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Article: Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species.

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Article ; Online: Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy.

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Article ; Online: An in vitro alveolar epithelial cell model recapitulates LRRK2 inhibitor-induced increases in lamellar body size observed in preclinical models.

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Article ; Online: No Evidence of Neurogenesis in Adult Rat Sympathetic Ganglia Following Guanethidine-Induced Neuronal Loss.

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Article ; Online: Ocular toxicity assessment from systemically administered xenobiotics: considerations in drug development.

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Article ; Online: The role of hypoxia in 2-butoxyethanol-induced hemangiosarcoma.

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