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Abstract Circulating insulin-like growth factor-binding proteins (IGFBPs) continue to gain attention as biomarkers of drug activities on insulin like growth factor (IGF)/IGF receptor signaling pathways. A multiplexed LC–MS/MS method was validated for the absolute quantitation of IGFBPs in human serum. The method was used to measure screening concentrations of IGFBPs in spinal and bulbar muscular atrophy (SBMA) patients in a phase 2 clinical trial. Concentrations of IGFBP 1, 2, 3, and 5 were simultaneously determined based on representative signature peptides derived from an optimized trypsin digestion procedure. Signature peptide levels were absolutely quantitated using a sensitive/specific targeted LC–MS/MS method. Corresponding mass-shifted, stable isotope-labeled peptides were employed as internal standards. A true blank matrix for the quantitation of IGFBPs was not available since they are endogenous proteins in human serum. In this method, calibration standards/curves were prepared using authentic synthetic peptides spiked into a surrogate matrix. The surrogate matrix was generated from human serum treated in the same way as the study samples, but using iodoacetic acid instead of iodoacetamide as the alkylation reagent. This surrogate matrix approach allowed for the direct and sensitive/specific quantification of IGFBP 1, 2, 3, and 5 due to the lack of any endogenous background. Equivalent matrix effect and recovery of analytes was achieved for the authentic and surrogate matrices. The fully validated LC–MS/MS assay will allow further evaluation of the utility of IGFBP biomarkers in clinical trials. Graphical abstract Unlabelled Image Highlights • GLP validated multiplex LC–MS/MS assay for efficacy protein biomarker quantitation. • Simultaneous monitoring of four IGFBPs (IGFBP1, 2, 3, and 5) in human serum • Surrogate matrix approach for sensitive/specific measurement of endogenous proteins • Measure concentrations of serum IGFBPs in subjects in a phase 2 clinical trial • Increase quality and throughput of protein biomarker analyses in clinical trials [ABSTRACT FROM AUTHOR]

The Chinese giant salamander ( Andrias davidianus, Blanchard, 1871) is the largest amphibian on earth. While the number of the wild Chinese giant salamanders is declining and becoming a rare endangered species, breeding of giant salamander in China has launched since 1980s. However, scoliosis often occurs in the breeding giant salamander juveniles. To explore the pathomorphological changes and bone mineral density of the morbid breeding giant salamander, molybdenum-rhodium target X-ray photography and conventional histopathological analysis have been adopted to investigate the disease occurred in affected salamander juveniles. Vertebra, spinal core, vertebral foramen, paravertebral skeletal muscle, and other related parts were examined. The results showed that the bone mineral density in the body-curved giant salamander juveniles is significant lower compared to the peer normal controls ( p > 0.05). In addition, spinal cord, spine, and its surrounding muscles were deformed in the diseased salamander. [ABSTRACT FROM AUTHOR]

This brief presents an approach for identifying the parameters of linear time-varying systems that repeat their trajectories. The identification is based on the concept that parameter identification results can be improved by incorporating information learned from previous executions. The learning laws for this iterative learning identification are determined through an optimization framework. The convergence analysis of the algorithm is presented along with the experimental results to demonstrate its effectiveness. The algorithm is demonstrated to be capable of simultaneously estimating rapidly varying parameters and addressing robustness to noise by adopting a time-varying design approach. [ABSTRACT FROM PUBLISHER]

This brief presents an approach for identifying the lateral dynamics of an automated off-highway agricultural vehicle for the purpose of automatic steering controller design. A second-order model is proposed to represent the vehicle lateral dynamics. An iterative learning identification (ILI) method is used to identify the model parameters. Simulation and experimental results under various test conditions show parameter convergence. The ILI results are compared with a gradient-based adaptive parameter estimation approach. The results highlight the practical benefit of the ILI approach for systems with repeated trajectories. [ABSTRACT FROM AUTHOR]

Abstract Drug-induced kidney injury (DIKI) is a major concern in drug risk assessment given its clinical importance and the absence of a sensitive/specific method of diagnosis. Pharmaceutical regulatory agencies have qualified and issued letters of support for new biomarkers to better evaluate DIKI in nonclinical toxicity and clinical studies. Additional efforts have focused on drug-induced phospholipidosis (DIPL) and its potential link with collateral renal damage. The combined use of urinary biomarkers is an efficient way to evaluate renal safety in nonclinical and clinical studies. Eight FDA/EMA/PMDA qualified (or supported) urinary biomarkers, including kidney injury molecule-1 (KIM-1), β2-microglobulin (B2M), clusterin (CLU), cystatin C (CysC), trefoil factor 3 (TFF3), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and alpha-glutathione S-transferase (α-GST), were quantified by multiplex UPLC-MS/MS in a repeat dose study of gentamicin in rats. Rats administered gentamicin at 100 mg/kg/day for 2 weeks developed renal lesions detected by histopathology. Biomarkers of tubular damage (CLU, KIM-1, OPN) increased 9.8, 34.7, and 35.6-fold (relative to concurrent controls), respectively, after 2 weeks of dosing. Biomarkers of glomerular damage and/or impairment of tubular reabsorption (CysC, B2M) increased 11.7 and 22.6-fold. NGAL and α-GST increased <3-fold after 2 weeks of dosing. TFF3 was comparable to concurrent controls. The elevated biomarker concentrations met PSTC threshold criteria and were consistent with mechanisms of gentamicin nephrotoxicity. Increased urinary di-22:6-BMP indicated concomitant DIPL as confirmed by TEM. This work provides evidence supporting the combined use of the DIKI biomarker panel and di-22:6-BMP as a biomarker of DIPL in drug risk assessment. Graphical abstract Unlabelled Image Highlights • Evaluate drug-induced kidney injury and phospholipidosis with safety biomarkers • Assess kidney injury with eight FDA/EMA/PMDA qualified/ supported urine proteins • Monitor drug-induced phospholipidosis with urine di-22:6-BMP • Effectively monitor the locale/sequence of injury with a combined biomarker approach • Evaluate nonclinical and clinical drug candidates with potential safety risks [ABSTRACT FROM AUTHOR]