A5081482660- Chronic Kidney Disease and Diabetes
- Acute Kidney Injury Research
- DNA Repair Mechanisms
- Drug Transport and Resistance Mechanisms
- Clusterin in disease pathology
- Trauma, Hemostasis, Coagulopathy, Resuscitation
- Cancer Treatment and Pharmacology
- Coleoptera: Cerambycidae studies
- Metabolism and Genetic Disorders
- Antibiotic Resistance in Bacteria
- Forest Insect Ecology and Management
- Heavy Metal Exposure and Toxicity
- MicroRNA in disease regulation
- CRISPR and Genetic Engineering
- BRCA gene mutations in cancer
- Carcinogens and Genotoxicity Assessment
- Circular RNAs in diseases
- Cardiovascular Effects of Exercise
- Glioma Diagnosis and Treatment
- Liver physiology and pathology
- Escherichia coli research studies
- Asthma and respiratory diseases
- Pediatric health and respiratory diseases
- European Politics and Security
- Biological Control of Invasive Species
Merck & Co., Inc., Rahway, NJ, USA (United States)
2024
United States Military Academy
2010-2023
Charles University
2018
General University Hospital in Prague
2018
Harvard University
1999-2002
Dana-Farber Cancer Institute
1999-2002
Beth Israel Deaconess Medical Center
2002
Howard Hughes Medical Institute
2002
MicroRNAs (miRNAs) are endogenous, small noncoding RNAs. Because of their size, abundance, tissue specificity, and relative stability in plasma, miRNAs hold promise as unique accessible biomarkers to monitor injury.We investigated the use liver-, muscle- brain-specific circulating injury. We used a highly sensitive quantitative PCR assay measure specific (miR-122, miR-133a, miR-124) plasma samples from rats treated with liver or muscle toxicants rat surgical model stroke.We observed...
In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form γ-H2AX) in megabase chromatin domains flanking sites damage. To investigate role we generated H2AX-deficient (H2AX Δ / ) mouse embryonic stem (ES) cells. ES cells are viable. However, they highly sensitive to ionizing radiation (IR) and exhibit elevated levels spontaneous IR-induced genomic instability. Notably, is not required for NHEJ per se because support normal...
Target organ toxicity is often a reason for attritions in nonclinical and clinical drug development. Leveraging emerging safety biomarkers studies provides an opportunity to monitor such toxicities early efficiently, potentially translating trials. As part of the European Union's Innovative Medicines Initiative (IMI), two projects have focused on evaluating nervous system (NS) toxicity: Translational Safety Biomarker Pipeline (TransBioLine) Neurotoxicity De-Risking Preclinical Drug Discovery...
Novel urinary kidney safety biomarkers have been identified recently that may outperform or add value to the conventional renal function biomarkers, blood urea nitrogen (BUN) and serum creatinine (SCr). To assess relative performance of growing list novel a comprehensive evaluation was conducted for 12 in 22 rat studies including toxicants 10 compounds with toxicities observed organs other than kidney. The toxicity included tubular glomerular toxicants. evaluated Kim-1, clusterin,...
Novel skeletal muscle (SKM) injury biomarkers that have recently been identified may outperform or add value to the conventional SKM aspartate transaminase (AST) and creatine kinase (CK). The relative performance of these novel including troponin I (sTnI), myosin light chain 3 (Myl3), CK M Isoform (Ckm), fatty acid binding protein (Fabp3) was assessed in 34 rat studies both toxicants compounds with toxicities tissues other than SKM. sTnI, Myl3, Ckm, Fabp3 all outperformed AST and/or added...
Liver and skeletal muscle-specific microRNAs (miRNAs) are currently being evaluated as novel plasma biomarkers that may out-perform or add value to the conventional liver injury alanine aminotransferase (ALT) aspartate (AST), muscle AST creatine kinase (CK). A comprehensive evaluation was conducted assess relative performance of these miRNAs detect distinguish from tissue injury. The miR-122 miR-192 for miR-1, miR-133a, miR-133b, miR-206 compared with 10 enzymatic protein across 27 compounds...
Newer urinary protein kidney safety biomarkers can outperform the conventional functional blood urea nitrogen (BUN) and serum creatinine (SCr) in rats. However, there is far less experience with relative performance of these dogs nonhuman primates. Here, we report urine biomarker tenofovir-treated cynomolgus monkeys beagle dogs. Tenofovir intravenous daily dosing for 2 or 4 weeks at 30 mg/kg/day resulted minimal to moderate tubular degeneration regeneration, tenofovir disoproxil fumarate...
The skeletal muscle (SKM) injury biomarkers, troponin I (sTnI), myosin light chain 3 (Myl3), and creatine kinase isoform (Ckm) have been shown recently to be more sensitive specific for monitoring drug-induced SKM than the conventional aspartate transaminase (AST) (CK) enzymatic assays in rat toxicology studies. To evaluate utility of these biomarkers across species, they were assessed 2 dog models: a study Beagle dogs 160 km endurance exercise run completed by Alaskan sled dogs. In model,...
Emerging urinary kidney safety biomarkers have been evaluated in recent years and shown to be superior the serum parameters blood urea nitrogen (BUN) creatinine (sCr) for monitoring injury proximal tubule. However, their potential application differentiating location of initial (eg, glomerulus vs tubule) has not fully explored. Here, we assessed performance two algorithms that were constructed using either an empirical or a mathematical model predict site data set consisting 22 rat toxicity...
A summary of Massachusetts's records Cerambycidae reported in the literature is presented, including our own 132 species from years 1999 to 2001. Altogether it represents a total 198 species, which 27 collected during study are noted Massachusetts for first time. Host plants 106 60 new host plant records. and biology Hesperophanes pubescens (Haldeman) discussed
Abstract The growing knowledge of the key role microbiota in maturation neonatal immune system suggests that manipulation could be exploited hampering allergy development. In this study, Escherichia coli O83:K24:H31 (EcO83) was administered to newborns were followed prospectively. Several immunological characteristics (cytokines, specific IgE, total T regulatory cells (Treg) and subpopulation natural Treg (nTreg) induced (iTreg)) tested peripheral blood 8‐year‐old children. Incidence...
To date, there has been very little published data evaluating the performance of novel urinary kidney biomarkers in nonhuman primates (NHPs). assess biomarker and characterize corresponding histomorphologic patterns tubular renal injury NHP, several studies were conducted using mechanistically diverse nephrotoxicants including cefpirome, cisplatin, naproxen, cyclosporine, a combination gentamicin with everninomicin. An evaluation 10 (albumin, clusterin, cystatin C, molecule-1, neutrophil...
Activating mutations of the leucine-rich repeat kinase 2 ( LRRK2) gene are associated with Parkinson disease (PD), prompting development LRRK2 inhibitors as potential treatment for PD. However, kidney safety concerns have surfaced from knockout (KO) mice and rats repeat-dose studies in rodents administered inhibitors. To support drug this therapeutic target, we conducted a study 26 weeks’ duration 2-month-old wild-type KO Long-Evans Hooded to systematically examine performance urinary...
The ability to monitor for general drug-induced tissue injury (DITI) or systemic inflammation in any using blood-based accessible biomarkers would provide a valuable tool early exploratory animal studies understand potential drug liabilities. Here we describe the evaluation of 4 remodeling and (α2-macroglobulin [A2M], α1-acid glycoprotein [AGP], neutrophil gelatinase-associated lipocalin [NGAL], inhibitor metalloproteinases [TIMP-1]) as well traditional serum parameter albumin DITI...
Conjugation with polyethylene glycol (PEG) is a strategy for improving the pharmaceutical properties of therapeutic proteins. In nonclinical studies PEGylated compounds, microscopic tissue vacuolation often observed, characterized ultrastructurally in this report by lysosomal distension. Although PEGylation-associated appears to be limited toxicologic concern when alternative therapies are limited, risk-benefit considerations may impacted uncertainty about reversibility, lack methods...
Abstract Proteins involved in lipid homeostasis are often regulated through the nuclear peroxisome proliferator‐activated receptors (PPAR). PPARα is target for fibrate‐class of drugs. Fenofibrate has been approved its lipid‐lowering effects patients with hypercholesterolemia and hypertriglyceridemia. We were interested understanding expression energy transporters energy‐utilizing tissues like liver, heart, muscle, adipose rat hypothesis that change transporter would align known agonists...
Drug-induced pancreatic injury (DIPI) is an issue seen in drug development both nonclinical and clinical contexts. DIPI typically monitored by measurement of lipase and/or amylase, however, enzymes lack sensitivity specificity. Although candidate protein biomarkers specific to pancreas exist, antibody-based assay difficult due their small size or the rapid cleavage proteolytic released during injury. Here we report a novel multiplexed immunoaffinity-based liquid chromatography mass...