The current status of biomarkers for predicting toxicity

Campion, Sarah N.; Aubrecht, Jiri; Boekelheide, Kim; Brewster, David; Vaidya, Vishal S.; Anderson, Linda M.; Burt, Deborah A.; Dere, Edward; Hwang, Kathleen; Pacheco, Sara; Saikumar, Janani; Schomaker, Shelli; Sigman, Mark; Goodsaid, Federico

doi:10.1517/17425255.2013.827170

Cited by 84 publications

(52 citation statements)

References 111 publications

(90 reference statements)

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“…Although a powerful tool for both diagnosing and understanding neurological disease, an ideal diagnostic biomarker must fulfill 3 key criteria. 19,32,39,57,118 First, it must be accessible; for a biomarker to be a viable diagnostic option, it must be easily obtained with minimal risk or discomfort to the patient. Following mTBI, CSF may contain elevated proteins from damaged neurons and neuroglia.…”

Section: Diagnostic Biomarkers Key Considerationsmentioning

confidence: 99%

Sports-related brain injuries: connecting pathology to diagnosis

Pan¹,

Connolly²,

Dangelmajer³

et al. 2016

FOC

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Neurosurg Focus 40 (4):E14, 2016M any sports-related brain injuries involve mild traumatic brain injuries (mTBIs), which result from physical blows to the head sustained over a period of time. Sports associated with an increased risk of head injury include American football, ice hockey, soccer, rugby, the martial arts, boxing, and bicycling. 21,90 These injuries are often unrecognized, undiagnosed, or underreported, which reflects the fact that this is a growing medical concern, often labeled a "silent epidemic." 8,66 Chronic exposure to mild brain injuries can result in long-term neurological consequences and represents a spectrum of disorders. The most remarkable outcome of mTBI is termed chronic traumatic encephalopathy (CTE), a clinical syndrome that is associated with neurodegeneration and behavioral, cognitive, and/or motor deficits. Although this disease has distinct pathological features, CTE is considered a diagnosis of exclusion because only postmortem biopsies can confirm the diagnosis. Therefore, new diagnostic methods need to be developed to: 1) inform patients of a definitive diagnosis, 2) better understand the epidemiology and risk factors of the disease, and 3) implement intervention programs to prevent any potential long-term complications. This review examines how understanding the pathology and molecular changes associated with repeated head trauma can lead to the discovery of novel imaging techniques and biomarkers. Mild Traumatic Brain Injury and CTEChronic traumatic encephalopathy has evolved from the so-called punch-drunk syndrome, which was used to describe a distinct neuropsychiatric condition that seemed to affect boxers, eventually becoming known as dementia pugilistica during the 1920s and 1930s. Symptoms such ABBrEvIATIoNs AD = Alzheimer's disease; APOE = apolipoprotein E; ASL = arterial spin labeling; BBB = blood-brain barrier; BOLD = blood oxygen level-dependent; CA = cornu ammonis; CTE = chronic traumatic encephalopathy; DTI = diffusion tensor imaging; FA = fractional anisotropy; fMRI = functional MRI; GFAP = glial fibrillary acidic protein; GRE = gradient recall echo; miRNA = microRNA; MRS = MR spectroscopy; mTBI = mild traumatic brain injury; NFL = National Football League; NFT = neurofibrillary tangle; NINDS = National Institute of Neurological Disorders and Stroke; NSE = neuron-specific enolase; p-tau = phosphorylated tau; SWI = susceptibility-weighted imaging; TDP-43 = TAR DNA-binding protein 43;18 F-FDDNP = 2-(1-{6- [(2-[fluorine-18] Brain injuries are becoming increasingly common in athletes and represent an important diagnostic challenge. Early detection and management of brain injuries in sports are of utmost importance in preventing chronic neurological and psychiatric decline. These types of injuries incurred during sports are referred to as mild traumatic brain injuries, which represent a heterogeneous spectrum of disease. The most dramatic manifestation of chronic mild traumatic brain injuries is termed chronic traumatic encephalopathy, which is associated with profo...

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Section: Diagnostic Biomarkers Key Considerationsmentioning

confidence: 99%

Sports-related brain injuries: connecting pathology to diagnosis

Pan¹,

Connolly²,

Dangelmajer³

et al. 2016

FOC

View full text Add to dashboard Cite

show abstract

“…Medicines may cause endocrinological evident body changes, libido loss, anejaculation, oligozoospermia and azoospermia, which pose a problem during pharmaceutical drug development [31]. The majority of testicular toxicants show an early cell-specific and spermatogenesis stage-specific pattern of damage, and both morphological and molecular evaluations of the testis, epididymis and sperm may give important information [38].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding hormones, follicle stimulating hormone, luteinizing hormone, estradiol, progesterone, prolactin, testosterone, inhibin B (Sertoli cell product), anti-Mullerian hormone (Sertoli cell product) and insulinlike peptide 3 (Leydig cell product) can be easily performed [40,41]. However, changes may be undetectable in cases of mild testicular injury [31].…”

Section: Discussionmentioning

confidence: 99%

“…Histopathology studies can only be used in experimental animals [31]. Of the sperm biomarkers, the human sperm membrane protein SP22 was shown to decline after exposure to both epidydimal and testicular toxicants in rat and ram models, changes in human sperm gene expression or mRNA transcript content [24,[42][43][44].…”

Section: Discussionmentioning

confidence: 99%

“…During the same period genotoxicity is also investigated [9,28]. As a substantial number of compounds do not surpass the preclinical investigation stage due to the lack of evaluation tools that can accurately monitor toxicity, efforts have been made to improve the newly available organ-specific toxicity detection tools through the identification and characterization of toxicity biomarkers [28][29][30][31].…”

Section: Methodsmentioning

confidence: 99%

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Assessing Male Reproductive Toxicity during Drug Development

Sousa¹,

Ferreira²,

Rabaça³

et al. 2017

Andrology

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Medical drug development is a crucial research field that attends to population healthcare needs, comprising several preclinical and clinical steps before the approval of a new compound. One major cause of pharmaceutical drug development failure is toxicity, especially in respect to kidney and liver. Nonetheless, the male reproductive system may also be a target for drug toxicity. Although the reproductive health is an important component of the person life, reproductive toxicology testing is rarely performed, both in pre-clinical and clinical trial phases. As reproductive and testicular toxicity is found at a low incidence during the early stages of drug development, companies devote the majority of research investments to more frequent areas of toxic occurrence. It is here suggested the inclusion of comprehensive studies and more precise methods to uncover the toxic reproductive effects and causes when developing new pharmacological drugs.

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Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development

Reynolds

Abernathy

Baracani

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Nonclinical safety assessment is an essential component of drug discovery and development. Early in the drug discovery/development continuum, there are no regulatory guidelines and sponsors typically harness a range of in silico , in vitro , and short‐term in vivo toxicology screens and pilot studies to develop comparative toxicity profiles for compounds under consideration. Results from these early evaluations can be used to terminate the development of compounds with undesirable toxicity liabilities as well as to prioritize other compounds for further evaluation. As drug candidate molecules approach entry into clinical trials, regulatory expectations regarding nonclinical safety assessment become more explicit. Scientists in the pharmaceutical industry have worked with their regulatory counterparts to establish an organizational structure – the International Conference on Harmonisation (ICH) – to develop internationally accepted guidelines that specify requirements for nonclinical safety assessment activities in a phase‐specific manner. The ICH guidelines cover the need for repeat‐dose toxicology studies of increasing duration in rodents and nonrodents, safety pharmacology studies, genetic toxicity tests, immunotoxicity and immunogenicity evaluations, phototoxicity assessments, developmental and reproductive toxicity studies, and carcinogenicity assessments. In planning, conducting, and reporting these studies, the toxicologist must ensure that a fully integrated assessment of potential safety liabilities associated with the test drug is communicated to the development team so that potential safety concerns can be properly addressed.

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The current status of biomarkers for predicting toxicity

Cited by 84 publications

References 111 publications

Sports-related brain injuries: connecting pathology to diagnosis

Sports-related brain injuries: connecting pathology to diagnosis

Assessing Male Reproductive Toxicity during Drug Development

Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development

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