PDGFRα monoclonal antibody: Assessment of toxicity in juvenile mice administered a murine surrogate antibody of olaratumab.

Background: Olaratumab (Lartruvo™) is a recombinant human IgG1 monoclonal antibody that specifically binds PDGFRα. In order to support use of Lartruvo in pediatric patients, a definitive juvenile animal study in neonatal mice was conducted with a human anti-mouse PDGFRα antibody analog of olaratumab (LSN3338786).

Methods: A pilot study was used to set doses for the definitive juvenile mouse study.

Juvenile Bone Toxicity: Study Considerations, Regulations, and Techniques for Assessment.

Recommendations on study designs that adequately evaluate the in-life effects leading to juvenile bone toxicity, the various imaging modalities that can aid interpretation of the bone effects, biomarkers that may be useful, and regulatory issues were presented in this 2020 ACT symposium. The pathologies encountered in past studies were briefly mentioned. The first speaker covered study design and the numbers of juveniles that may be necessary to power the evaluation.

Pattern of grade C molar-incisor pattern periodontitis in families.

Background: The aim of this study was to determine the clinical and inflammatory response patterns for individual siblings diagnosed with grade C molar-incisor pattern periodontitis (C-MIP) and between the related siblings within families.

Methods: Sixty-nine siblings within 28 families with moderate-to-severe C-MIP were included. Clinical parameters were evaluated for symmetry regarding the affected type of teeth, side and/or arch, and bone loss pattern.

LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept.

With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R).

The benefits, limitations and opportunities of preclinical models for neonatal drug development.

Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases - bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic-ischemic encephalopathy and neonatal sepsis - and the available in vivo, in vitro and in silico preclinical models for studying these diseases. Better understanding of the strengths and weaknesses of specialized neonatal disease models will help to improve their utility, may add to the understanding of the mode of action and efficacy of a therapeutic, and/or may improve the understanding of the disease pathology to aid in identification of new therapeutic targets.

Science-Based Approach to Harmonize Contraception Recommendations in Clinical Trials and Pharmaceutical Labels.

This review presents a European Federation of Pharmaceutical Industries and Association/PreClinical Development Expert Group (EFPIA-PDEG) topic group consensus on a data-driven approach to harmonized contraception recommendations for clinical trial protocols and product labeling. There is no international agreement in pharmaceutical clinical trial protocols or product labeling on when/if female and/or male contraception is warranted and for how long after the last dose. This absence of consensus has resulted in different recommendations among regions.

Periodontal health and disease: The contribution of genetics.

Periodontitis is an infectious, inflammatory disease that is associated with a complex interplay between specific bacteria, host response, and environmental factors. Because of its high degree of familial aggregation, specifically for the more aggressive forms of the disease, genetics factors have been implicated in disease pathogenesis for several decades. This review provides an overview of what we currently know regarding the genetic and epigenetic contributions to periodontal disease and discusses future opportunities in the field.

Dysregulation of genes and microRNAs in localized aggressive periodontitis.

Aim: Previous data from our laboratory have demonstrated that localized aggressive periodontitis (LAP) patients produce elevated levels of pro-inflammatory cytokines in response to TLR4 and TLR2 ligation compared to unrelated and periodontally healthy controls (HC). The aim of the present work is to evaluate the contribution of TLR-related gene expression and miRNA regulation in LAP disease.

Material And Methods: Peripheral blood mononuclear cells (PBMCs) from LAP and health control (HC) patients were isolated.

Inflammatory Genotype Moderates the Association Between Anxiety and Systemic Inflammation in Adults at Risk for Cardiovascular Disease.

Background: Cardiovascular disease is a significant health problem in the United States, attributed to more than 30% of all deaths annually. Anxiety has been associated with cardiovascular disease risk and is thought to be associated with cardiovascular disease risk through inflammatory pathways.

Objective: The purposes of this study were to examine the relationship between anxiety and systemic inflammation in individuals at risk for cardiovascular disease and to determine if single-nucleotide polymorphisms (SNPs) associated with inflammation moderate this relationship.

Applying a weight of evidence approach to the evaluation of developmental toxicity of biopharmaceuticals.

Toxicity studies in pregnant animals are not always necessary for assessing the human risk of developmental toxicity of biopharmaceuticals. The growing experience and information on target biology and molecule-specific pharmacokinetics present a powerful approach to accurately anticipate effects of target engagement by biopharmaceuticals using a weight of evidence approach. The weight of evidence assessment should include all available data including target biology, pharmacokinetics, class effects, genetically modified animals, human mutations, and a thorough literature review.

Rethinking developmental toxicity testing: Evolution or revolution?

Background: Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing?

Methods: A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution).

Heredity, Genetics and Orthodontics - How Much Has This Research Really Helped?

Uncovering the genetic factors that correlate with a clinical deviation of previously unknown etiology helps to diminish the unknown variation influencing the phenotype. Clinical studies, particularly those that consider the effects of an appliance or treatment regimen on growth, need to be a part of these types of genetic investigations in the future. While the day-to-day utilization of "testing" for genetic factors is not ready for practice yet, genetic testing for monogenic traits such as Primary Failure of Eruption (PFE) and Class III malocclusion is showing more promise as knowledge and technology advances.

Bone Density and Dental External Apical Root Resorption.

When orthodontic patients desire shorter treatment times with aesthetic results and long-term stability, it is important for the orthodontist to understand the potential limitations and problems that may arise during standard and/or technology-assisted accelerated treatment. Bone density plays an important role in facilitating orthodontic tooth movement (OTM), such that reductions in bone density can significantly increase movement velocity. Lifestyle, genetic background, environmental factors, and disease status all can influence a patients' overall health and bone density.

Aging, inflammation, immunity and periodontal disease.

The increased prevalence and severity of periodontal disease have long been associated with aging, such that this oral condition affects the majority of the adult population over 50 years of age. Although the immune system is a critical component for maintaining health, aging can be characterized by quantitative and qualitative modifications of the immune system. This process, termed 'immunosenescence', is a progressive modification of the immune system that leads to greater susceptibility to infections, neoplasia and autoimmunity, presumably reflecting the prolonged antigenic stimulation and/or stress responses that occur across the lifespan.

Current Topics in Postnatal Behavioral Testing.

The study of developmental neurotoxicity (DNT) continues to be an important component of safety evaluation of candidate therapeutic agents and of industrial and environmental chemicals. Developmental neurotoxicity is considered to be an adverse change in the central and/or peripheral nervous system during development of an organism and has been primarily evaluated by studying functional outcomes, such as changes in behavior, neuropathology, neurochemistry, and/or neurophysiology. Neurobehavioral evaluations are a component of a wide range of toxicology studies in laboratory animal models, whereas neurochemistry and neurophysiology are less commonly employed.

Genetic and treatment-related risk factors associated with external apical root resorption (EARR) concurrent with orthodontia.

Objective: As genetic variation accounts for two-thirds of the variation in external apical root resorption (EARR) concurrent with orthodontic treatment, we analyzed the association of selected genetic and treatment-related factors with EARR concurrent with orthodontic treatment.

Setting And Sample Population: This case-control study of 134 unrelated, orthodontically treated Caucasian individuals was conducted in part at an Indiana Private Practice, Indiana University and the University of Kentucky.

Methods: Utilizing a research data bank containing information from ~1450 orthodontically treated patients, pre- and post-treatment radiographs from 460 individuals were evaluated for EARR of the four permanent maxillary incisors.

Comparison of BMI, AHI, and apolipoprotein E ε4 (APOE-ε4) alleles among sleep apnea patients with different skeletal classifications.

Study Objectives: This case-control study investigated whether variations within the APOE-ε gene were associated with having a convex facial profile (skeletal Class II) compared to exhibiting a straight or concave facial profile (Class I or Class III) among patients with obstructive sleep apnea (OSA). Associations between the apnea-hypopnea index (AHI) and body mass index (BMI) scores for these OSA patients were also examined in the context of facial profile.

Method: OSA patients with an AHI ≥ 15 were recruited from a sleep clinic and classified by facial and dental occlusal relationships based on a profile facial analysis, lateral photographs, and dental examination.

Total IgA and IgA reactivity to antigen I/II epitopes in HLA-DRB1*04 positive subjects.

Bacterial adherence to the acquired dental pellicle, important in dental caries (caries), is mediated by receptor-adhesins such as salivary agglutinin binding to antigen I/II (I/II). Ten selected I/II epitopes were chosen to determine their reactivity to human salivary IgA. Previous studies suggested that a specific HLA biomarker group (HLA-DRB1*04) may have differential influence of immune responses to I/II.

Periodontal disease immunology: 'double indemnity' in protecting the host.

During the last two to three decades our understanding of the immunobiology of periodontal disease has increased exponentially, both with respect to the microbial agents triggering the disease process and the molecular mechanisms of the host engagement maintaining homeostasis or leading to collateral tissue damage. These foundational scientific findings have laid the groundwork for translating cell phenotype, receptor engagement, intracellular signaling pathways and effector functions into a 'picture' of the periodontium as the host responds to the 'danger signals' of the microbial ecology to maintain homeostasis or succumb to a disease process. These findings implicate the chronicity of the local response in attempting to manage the microbial challenge, creating a 'Double Indemnity' in some patients that does not 'insure' health for the periodontium.

Genetics and non-syndromic facial growth.

Just as pediatricians and endocrinologists are interested in understanding statural growth patterns and the prediction of adult height, pediatric dentists, orthodontists, and oral/maxillofacial surgeons need to be knowledgeable about a patient's facial growth patterns to effectively treat them. Some variations in facial growth have been clinically associated with a poor esthetic self-image, malocclusion formation and the development of physical and/or functional deformity. To understand how different genetic factors influence growth and development patterns, scientists and clinicians study developmental sequences, malformations and syndromes.

Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug.

Rationale: Whether selective serotonin reuptake inhibitors (SSRIs) exposure during adolescent brain development causes lasting effects remains unresolved.

Objective: Assess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug.

Methods: Male Sprague-Dawley littermates (41 litters) were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day), paroxetine (3, 10 or, 17 mg/kg/day), or water; half were tested while on-drug (21 litters) and half after 60 days off-drug (20 litters).

Preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals: strategy, challenges, current practices.

Evaluation of pharmaceutical agents in children is now conducted earlier in the drug development process. An important consideration for this pediatric use is how to assess and support its safety. This article is a collaborative effort of industry toxicologists to review strategies, challenges, and current practice regarding preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals.

A theoretical application of selectable markers in bacterial episomes for a DNA cryptosystem.

A theoretical model utilizing the principle of selection for the purposes of DNA cryptography is proposed. A method to enhance the security of DNA cryptosystems that utilize polymerase chain reaction primer keys is presented. Double-encryption systems--encryption systems that have two keys--like the cryptosystem advanced in this paper, are generally more secure than systems that have one key.

The oncofetal gene glypican 3 is regulated in the postnatal liver by zinc fingers and homeoboxes 2 and in the regenerating liver by alpha-fetoprotein regulator 2.

Unlabelled: The Glypican 3 (Gpc3) gene is expressed abundantly in the fetal liver, is inactive in the normal adult liver, and is frequently reactivated in hepatocellular carcinoma (HCC). This reactivation in HCC has led to considerable interest in Gpc3 as a diagnostic tumor marker and its possible role in tumorigenesis. Despite this interest, the basis for Gpc3 regulation is poorly understood.

Interactions of dopamine D1 and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions.

The effects of the dopamine D1 receptor antagonist R(+)-SCH-23390 and D2 receptor antagonist S(-)-eticlopride on d-methamphetamine-induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10-mg/kg doses of d-methamphetamine or saline with a 2-h interval between treatments; 0.5 mg/kg eticlopride or SCH-23390 was administered 15 min before each methamphetamine or saline injection.