Evaluation of the Relative Performance of Pancreas-Specific MicroRNAs in Rat Plasma as Biomarkers of Pancreas Injury

2019 ◽  
Vol 173 (1) ◽  
pp. 5-18 ◽  
Author(s):  
Zoltan Erdos ◽  
John E Barnum ◽  
Erjia Wang ◽  
Christopher DeMaula ◽  
Paritosh Markus Dey ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Comprehensive Evaluation ◽  
Pancreatic Injury ◽  
Rat Plasma ◽  
Relative Performance ◽  
Cell Degeneration ◽  
Drug Induced ◽  
Drug Candidates ◽  
Increased Sensitivity ◽  
Noninvasive Biomarkers

Abstract Drug-induced pancreatic injury (DIPI) has become linked in recent years to many commonly prescribed medications from several pharmacological classes. Diagnosis is currently most often focused on identification of acute pancreatitis and generally based on subjective clinical assessment and serum amylase and lipase enzymatic activity, which have been criticized as being insufficiently sensitive and specific. The lack of novel noninvasive biomarkers of DIPI can impede the advancement of drug candidates through nonclinical development and translation into clinical settings. Pancreas-specific microRNAs (miRNAs) are currently being evaluated as biomarkers of DIPI that may outperform and/or add value to the interpretation of amylase and lipase. To assess the relative performance of these novel miRNAs, a comprehensive evaluation was conducted to determine the sensitivity and specificity of detecting DIPI in rats. Four miRNAs were evaluated (miR-216a-5p, miR-216b-5p, miR-217-5p, and miR-375-3p) in plasma from 10 studies in which rats were treated with known pancreatic toxicants to assess sensitivity, and from 10 different studies in which toxicity was evident in tissues other than pancreas to assess specificity. The candidate miRNA biomarker performance was compared with amylase and lipase, and receiver operator characteristics (ROC) were determined. Analysis of ROCs demonstrated that all four miRNAs outperformed amylase and lipase in monitoring acute pancreatic injury defined as acinar cell degeneration/necrosis. Specifically, miR-217-5p had the highest performance among all biomarkers assessed. The increased sensitivity and specificity of these miRNAs support their use as biomarkers of DIPI, thereby adding value to the interpretation of amylase and lipase measurements in nonclinical studies. The potential for miRNAs to serve as translational biomarkers in the clinic for the monitoring of DIPI is also supported by this investigation.

scholarly journals Machine Learning for Predicting Risk of Drug-Induced Autoimmune Diseases by Structural Alerts and Daily Dose

2021 ◽  
Vol 18 (13) ◽  
pp. 7139
Author(s):  
Yue Wu ◽  
Jieqiang Zhu ◽  
Peter Fu ◽  
Weida Tong ◽  
Huixiao Hong ◽  
...  
Keyword(s):  
Machine Learning ◽  
Autoimmune Diseases ◽  
Odds Ratio ◽  
Area Under Curve ◽  
Predictive Performance ◽  
Drug Induced ◽  
Drug Candidates ◽  
Daily Dose ◽  
Structural Alerts ◽  
Underlying Mechanisms

An effective approach for assessing a drug’s potential to induce autoimmune diseases (ADs) is needed in drug development. Here, we aim to develop a workflow to examine the association between structural alerts and drugs-induced ADs to improve toxicological prescreening tools. Considering reactive metabolite (RM) formation as a well-documented mechanism for drug-induced ADs, we investigated whether the presence of certain RM-related structural alerts was predictive for the risk of drug-induced AD. We constructed a database containing 171 RM-related structural alerts, generated a dataset of 407 AD- and non-AD-associated drugs, and performed statistical analysis. The nitrogen-containing benzene substituent alerts were found to be significantly associated with the risk of drug-induced ADs (odds ratio = 2.95, p = 0.0036). Furthermore, we developed a machine-learning-based predictive model by using daily dose and nitrogen-containing benzene substituent alerts as the top inputs and achieved the predictive performance of area under curve (AUC) of 70%. Additionally, we confirmed the reactivity of the nitrogen-containing benzene substituent aniline and related metabolites using quantum chemistry analysis and explored the underlying mechanisms. These identified structural alerts could be helpful in identifying drug candidates that carry a potential risk of drug-induced ADs to improve their safety profiles.

scholarly journals An In Silico Model for Predicting Drug-Induced Hepatotoxicity

2019 ◽  
Vol 20 (8) ◽  
pp. 1897 ◽  
Author(s):  
Shuaibing He ◽  
Tianyuan Ye ◽  
Ruiying Wang ◽  
Chenyang Zhang ◽  
Xuelian Zhang ◽  
...  
Keyword(s):  
Large Scale ◽  
Characteristic Curve ◽  
External Validation ◽  
Model Development ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
New Drugs ◽  
Drug Induced ◽  
Drug Candidates ◽  
External Test

As one of the leading causes of drug failure in clinical trials, drug-induced liver injury (DILI) seriously impeded the development of new drugs. Assessing the DILI risk of drug candidates in advance has been considered as an effective strategy to decrease the rate of attrition in drug discovery. Recently, there have been continuous attempts in the prediction of DILI. However, it indeed remains a huge challenge to predict DILI successfully. There is an urgent need to develop a quantitative structure–activity relationship (QSAR) model for predicting DILI with satisfactory performance. In this work, we reported a high-quality QSAR model for predicting the DILI risk of xenobiotics by incorporating the use of eight effective classifiers and molecular descriptors provided by Marvin. In model development, a large-scale and diverse dataset consisting of 1254 compounds for DILI was built through a comprehensive literature retrieval. The optimal model was attained by an ensemble method, averaging the probabilities from eight classifiers, with accuracy (ACC) of 0.783, sensitivity (SE) of 0.818, specificity (SP) of 0.748, and area under the receiver operating characteristic curve (AUC) of 0.859. For further validation, three external test sets and a large negative dataset were utilized. Consequently, both the internal and external validation indicated that our model outperformed prior studies significantly. Data provided by the current study will also be a valuable source for modeling/data mining in the future.

Development and Application of a Transcriptomic Signature of Bioactivation in an Advanced In Vitro Liver Model to Reduce Drug-induced Liver Injury Risk Early in the Pharmaceutical Pipeline

2020 ◽  
Vol 177 (1) ◽  
pp. 121-139 ◽  
Author(s):  
Wen Kang ◽  
Alexei A Podtelezhnikov ◽  
Keith Q Tanis ◽  
Stephen Pacchione ◽  
Ming Su ◽  
...  
Keyword(s):  
Liver Injury ◽  
Human Model ◽  
Reactive Metabolites ◽  
In Vitro Test ◽  
Drug Induced ◽  
Vitro Assay ◽  
Drug Induced Liver Injury ◽  
Drug Candidates ◽  
Transcriptomic Signature

Abstract Early risk assessment of drug-induced liver injury (DILI) potential for drug candidates remains a major challenge for pharmaceutical development. We have previously developed a set of rat liver transcriptional biomarkers in short-term toxicity studies to inform the potential of drug candidates to generate a high burden of chemically reactive metabolites that presents higher risk for human DILI. Here, we describe translation of those NRF1-/NRF2-mediated liver tissue biomarkers to an in vitro assay using an advanced micropatterned coculture system (HEPATOPAC) with primary hepatocytes from male Wistar Han rats. A 9-day, resource-sparing and higher throughput approach designed to identify new chemical entities with lower reactive metabolite-forming potential was qualified for internal decision making using 93 DILI-positive and -negative drugs. This assay provides 81% sensitivity and 90% specificity in detecting hepatotoxicants when a positive test outcome is defined as the bioactivation signature score of a test drug exceeding the threshold value at an in vitro test concentration that falls within 3-fold of the estimated maximum drug concentration at the human liver inlet following highest recommended clinical dose administrations. Using paired examples of compounds from distinct chemical series and close structural analogs, we demonstrate that this assay can differentiate drugs with lower DILI risk. The utility of this in vitro transcriptomic approach was also examined using human HEPATOPAC from a single donor, yielding 68% sensitivity and 86% specificity when the aforementioned criteria are applied to the same 93-drug test set. Routine use of the rat model has been adopted with deployment of the human model as warranted on a case-by-case basis. This in vitro transcriptomic signature-based strategy can be used early in drug discovery to derisk DILI potential from chemically reactive metabolites by guiding structure-activity relationship hypotheses and candidate selection.

The symptoms asymmetry of drug-induced parkinsonism is not related to nigrostriatal cell degeneration: a SPECT-DaTSCAN study

2019 ◽  
Vol 53 (4) ◽  
pp. 311-314
Author(s):  
Agata Gajos ◽  
Janusz Dąbrowski ◽  
Małgorzata Bieńkiewicz ◽  
Anna Płachcińska ◽  
Jacek Kuśmierek ◽  
...  
Keyword(s):  
Cell Degeneration ◽  
Drug Induced

Ultra-sensitive detection of biomarkers and applications in pharmaceutical discovery and development. Example application to rat cardiac troponin I assay via nanoparticle probes

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14594-e14594
Author(s):  
P. Bao ◽  
T. Lubben ◽  
T. Holzman
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Dynamic Range ◽  
High Sensitivity ◽  
Cardiac Troponin I ◽  
Drug Induced ◽  
Drug Candidates ◽  
Broad Dynamic Range ◽  
Probe Test ◽  
Detection Of Biomarkers

e14594 Although specific to heart, rat cardiac troponin I (cTnI) is an example of an important biomarker for assessing drug-induced cardiotoxicity in animal models used in various phases of drug discovery and development. Current commercially available assays can only detect 10 ∼ 100 pg/mL in serum at the lowest limits. To improve the sensitivity of rat cTnI assay, we have developed a generically applicable, microarray based nano-probe test. Our rat cTnI assay algorithm uses a multi-step robotic process, which relies on non- isotropically oriented antibodies on functionalized glass as multiplexed microarrays to capture cTnI from serum. Functionalized, 130 angstrom diameter gold nano-probes (measured by static light scattering, 5 nm S.D.) also bind to the troponin through a molecular-scale complex containing antibodies. The troponin-bound molecular complex is then quantified through silver enhancement of the functionalized gold. Assays in this format can be rapidly configured and implemented for a wide array of potential biomarkers. For cTnI we have demonstrated a robust and ultra-sensitive assay with an LOD of less than 500 femtograms of rat cTnI per mL serum, and an overall CV of less than 20%. The assay also shows very low background, a broad dynamic range and over 3 logs of linear dose response. As an example of the potential of high sensitivity, the nanoparticle-based rat cTnI assay could significantly increase the effectiveness of measuring drug-induced heart damage at very low drug dosages and early times. Such sensitive and early measurements can improve examination of the safety of drug candidates while correspondingly reducing drug development time and cost. [Table: see text]

The role of PET-CT in the follow-up of patients with urothelial cancer diagnosis.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 291-291 ◽  
Author(s):  
G. Jankilevich ◽  
F. Ogresta ◽  
L. Gennari ◽  
A. Ominetti ◽  
M. Bermudez ◽  
...  
Keyword(s):  
Ct Scan ◽  
Sensitivity And Specificity ◽  
Cancer Diagnosis ◽  
Urothelial Cancer ◽  
Great Benefit ◽  
Pet Ct ◽  
Urothelial Tumors ◽  
Increased Sensitivity ◽  
Suspected Recurrence

291 Background: Positron emission tomography (PET) is an imaging technique whose principle is the detection of metabolic activity of tumor cells but in urology its use had been restricted due to urinary excretion of the radiotracer and overlap with urological structures, the use of hybrid PET (PET-CT) would allow its use for monitoring patients with urothelial tumors. Methods: Between 2007 and 2010 we performed PET-TC images in consecutive patients with suspected recurrences in CT scan or MRI. All patients had renal, bladder and uretral cancer and were treated with urothelial cancer diagnosis. We evaluate the usefulness of FDG PET-CT and its impact on behavior therapy in suspected recurrence in patients with urothelial carcinoma, compared with conventional studies. Results: 17 patients were studied for suspected recurrence. All patients had positive images previously on CT scan and MRI; positive PET-TC was observed in 14 and 3 studies were negative. The positive PET-CT showed more number of lesions and change the medical and surgical strategy. Of the three studies negative on PET- CT none had recurrence and remain disease free. PET/CT is in a great benefit to the detection recurrence in the follow up of patients with urothelial cancer diagnosis. These results showed an increased sensitivity and specificity over previous work with conventional PET technology. In the series studied, the implementation of PET-CT (FDG) in the follow up of patients with urothelial tumors were an useful tool. Conclusions: PET/CT is in a great benefit to the detection recurrence in the follow up of patients with urothelial cancer diagnosis. These results showed an increased sensitivity and specificity over previous work with conventional PET technology. In the series studied, the implementation of PET-CT (FDG) in the follow up of patients with urothelial tumors were an useful tool. However, multicenter studies and more patients are required to define its role. No significant financial relationships to disclose.

scholarly journals The Acute Extracellular Flux (XF) Assay to Assess Compound Effects on Mitochondrial Function

2014 ◽  
Vol 20 (3) ◽  
pp. 422-429 ◽  
Author(s):  
Ruolan Wang ◽  
Steven J. Novick ◽  
James B. Mangum ◽  
Kennedy Queen ◽  
David A. Ferrick ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Activity ◽  
Screening Methods ◽  
Drug Induced ◽  
Whole Cells ◽  
Drug Candidates ◽  
Adverse Health Outcomes ◽  
Extracellular Flux ◽  
Screening Platform ◽  
The Impact

Numerous investigations have linked mitochondrial dysfunction to adverse health outcomes and drug-induced toxicity. The pharmaceutical industry is challenged with identifying mitochondrial liabilities earlier in drug development and thereby reducing late-stage attrition. Consequently, there is a demand for reliable, higher-throughput screening methods for assessing the impact of drug candidates on mitochondrial function. The extracellular flux (XF) assay described here is a plate-based method in which galactose-conditioned HepG2 cells were acutely exposed to test compounds, then real-time changes in the oxygen consumption rate and extracellular acidification rate were simultaneously measured using a Seahorse Bioscience XF-96 analyzer. The acute XF assay was validated using marketed drugs known to modulate mitochondrial function, and data analysis was automated using a spline curve fitting model developed at GlaxoSmithKline. We demonstrate that the acute XF assay is a robust, sensitive screening platform for evaluating drug-induced effects on mitochondrial activity in whole cells.

scholarly journals Noninvasive urinary protein signatures associated with colorectal cancer diagnosis and metastasis

2020 ◽  
Author(s):  
Yulin Sun ◽  
Zhengguang Guo ◽  
Zongpan Jing ◽  
Jun Li ◽  
Lijun Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Urinary Protein ◽  
Functional Study ◽  
Protein Biomarkers ◽  
Tissue Samples ◽  
Serum Carcinoembryonic Antigen ◽  
Diagnostic Signature ◽  
Increased Sensitivity ◽  
Noninvasive Biomarkers ◽  
Metastatic Risk

Abstract Currently, imaging and serum carcinoembryonic antigen (CEA) tests are not sufficient for early detection and evaluation of metastasis and recurrence in colorectal cancer (CRC). To comprehensively discover and validate more accurate noninvasive biomarkers in urine, we adopted a staged discovery-verification-validation pipeline in 657 urine and 665 tissue samples from healthy controls and CRC patients with a distinct metastatic risk. The diagnostic signature generated combined with serum CEA levels revealed a significantly increased sensitivity (+34.8%) compared to CEA alone. Moreover, over 50% of CEA-negative metastatic patients were correctly predicted by the metastatic signature generated for metastatic risk. The tissue validation and functional study showed that CORO1C was associated with distant metastasis and enhanced the invasion and metastasis of CRC cells via a novel integrin/FAK/SRC and relevant pathways. Our findings provide novel urinary protein biomarkers and potential interventional targets to reliably detect CRC, especially in patients with metastatic CRC.

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