AACT Career Development Workshop
Date: Tuesday, March 17
Time: 12:15 PM–2:00 PM
Location: Anaheim Marriott, Orange County Ballroom 3-4
AACT Distinguished Chinese Toxicologist Lecture, Business Meeting and Reception
Date: Monday, March 16
Time: 5:00 PM–9:00 PM
Location: Anaheim Marriott, Marquis Ballroom South
Title: Immunotoxicology: History and Current Advances
Date and Time: February 25, 2020
Presenter: Kenneth L. Hastings, DrPH, DABT, ATS Hastings Toxicology Consulting LLC
Description: Immunotoxicology research and testing have evolved from early studies of anaphylaxis to the robust and diverse field of immunotoxicology as we know it today. Early studies connecting immune dysfunction with exposure to exogenous agents focused on adverse reactions to vaccines, industrial chemicals, and ionizing radiation. Over time, immunologists described the fundamental mechanisms of immunogenic agents as well as understanding the concept of immunosuppression. These myriad achievements greatly improved public health and led to the development of immunotoxicology methods to determine all types of adverse immunological responses to designed agents such as drugs and biologics.
Title: PM2.5-Induced Imbalance of Intracellular Reactive Oxygen Species Cause Vascular Dysfunction & Development
Date and Time: November 26, 2018
Presenter: Ming-Wei Chao, PhD, DABT
Description: Epidemiological studies suggest that an increase of PM2.5 particles in ambient air corresponds to an increase in hospital-recorded myocardial infarctions within 48 h after exposure. The mechanisms for such PM2.5-induced vascular permeability remain unknown. One of the major mechanisms underlying the effects of PM2.5 is suggested to be oxidative stress. Experiments have shown that PM2.5 induces the generation of ROS and pro-inflammatory TNF-α and IL-6 in endothelia. Transcription factor Nrf2 is translocated to the cell nucleus, activated transcription of the antioxidative enzyme HO-1, and the downstream VEGFA release. These results demonstrated that the adherens junctional VE-cadherin becomes redistributed from the membrane at cell-cell borders to the cytoplasm in response to PM2.5, disrupting cell-cell junction integrity. In addition, PM2.5-induced ROS plays also a central role in the initiation of both autophagy and apoptosis. Acute exposure to low dose of PM2.5, the levels of ATG12-ATG5-p62-LC3 increase, followed by sequentially colocalized with LAMP-2. When cells lacked the ability for autophagy, PM2.5 cannot induce cell senescence and most of the cells survived. Nevertheless, high dose PM2.5 exposure stimulates ATP depletion, followed by depolarization of their actin cytoskeleton, which sequentially inhibits PI3K/Akt activity and augments endothelial apoptosis but disrupts the p53 negative regulator, Mdm2. Furthermore, exposed prenatal rats to long-term PM2.5 might cause dose-dependently decrease both of pregnancy rate and birth rate, and induce cytokines and free radicals release in the amniotic fluid. Microarray data indicated that PM2.5 increased expression levels of various cortical miRNAs, which are positively correlated to the genes Pkn2 (astrocyte migration), Gorab (neuritogenesis), and Mobp (induces experimental allergic encephalomyelitis). In contrast, PM2.5 decreased expression of miR-338-5p and let-7e-5p, both related to mental development. In hippocampus, miR-99b-5p, miR-92b-5p and miR-99a-5p were decreased as well, leading to reduced expression of Kbtbd8 and Adam11 which demonstrated reduced cell mitosis, migration, and differentiation, and hampered learning abilities and motor coordination of the fetus. On the other hand, the fetal cerebral cortex on E18 were collected, and we found that laminar positioning of early born cortical cells expressing Tbr1 and Ctip2 were disturbed, with a scattering distribution. The effect was similar, but minor, in later born Satb2 expressed cortical cells. The neurological behaviors of the six weeks old fetal rats were examined with using Morris water maze and suggested that PM2.5 might integrate into pre-existing neuronal circuits and contribute to learning and memory loss.
Keywords: PM2.5, reactive oxygen species, endothelia, pro-inflammation, permeability, apoptosis, fetus, brain development, neuron, learning and memory
Title: Preclinical Considerations for Gene Therapy Products: An FDA Perspective
Date and Time: November 14, 2017
Presenter: Ying Huang, Ph.D.
Description: FDA/CBER has a long history of regulating gene therapy (GT) products. The regulatory approach for assessing the safety and effectiveness of individual GT products can vary based on the biological properties of each respective product. There is no standard set of preclinical studies and testing parameters that are uniformly applicable to all GT products. The regulatory review of GT products employs a science-based approach that considers the benefits and risks of each investigational product in the framework of the respective clinical trial. The introduction of gene editing (GE) technologies in the generation of GT products raises unique concerns regarding how the GE process may impact the product safety profile. This presentation will include an overview of CBER preclinical considerations for GT products, with a focus on specific safety concerns for GT products that incorporate GE technologies and the types of preclinical evaluations conducted for these products to support administration in human clinical trials.
Speaker Biography: Dr. Huang is a Pharm/Tox master reviewer at FDA/CBER/OTAT/DCEPT since 2004. She is responsible for the review of the preclinical evalu ations for proof-of-concept and safety related to cell and gene therapies, and gene editing derived gene therapy products on oncology and non-oncology disea ses. Her review activities have been involved in submissions of Investigational New Drug (IND) including pre-preIND and pre-IND, and Biologics License Applic ation (BLA). In addition to her review work, she is one of the representatives for the US FDA in the International Pharmaceutical Regulators Forum (IPRF) / Ge ne Therapy Working Group (GTWG). She was the co-representative for FDA/CBER in the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) during 2006–April 2017. Prior to the FDA, Dr. Huang received her Ph.D. degree in Pharmacology and Toxicology at the University of Toronto , Canada, and subsequently an NIH IRTA fellowship at NIH/NIDDK before became a senior scientist at former Genetic Therapy Inc., a Novartis Company.
International collaborations are increasingly vital in science. In an effort to build bridges to other toxicological organizations and enhance the visibility of AACT among other scientific groups, AACT board is organizing a delegation of AACT members to attend the 8th Chinese SOT conference on October 15–18 in Jinan, Shandong. Several travel awards are provided from AACT. A total of ten AACT members will give talks on this conference. Among them, Drs. Alex Xu (Session Chair), Yi Jin, Matt Liu, Ting Su, Qihong Huang, and Robert Li (Session Chair) will deliver their talks at AACT session; Drs. Zhibin Wang, Sherwin Yan, Zemin Wang, and Pan Chen will present their research at other sessions.