QT-Interval Prolongation, Torsades de Pointes, and Heart Failure With EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: Systematic Review.

A systematic literature review was conducted to determine the incidence and mortality of QT-interval prolongation (QTp), torsades de pointes (TdP), and heart failure (HF) in patients with non-small cell lung cancer (NSCLC) who received epidermal growth factor receptor (EGFR) TKIs. Of 296 identified publications, 95 met eligibility criteria and were abstracted for QTp/TdP and HF outcomes (QTp/TdP: 83 publications, including 5 case study publications; HF: 79 publications, including 6 case study publications [involving 8 patients]). QTp incidence ranged from 0% to 27.8% in observational studies and from 0% to 11% in clinical trials, with no deaths due to QTp. There were no TdP events or deaths due to TdP. The incidence of HF ranged from 0% to 8%, and HF mortality rates ranged from 0% to 4%. Patients receiving treatment with EGFR TKIs should be monitored for signs of QTp, TdP, and HF per prescribing information. Standardized definitions and methods to improve monitoring of QTp, TdP, and HF-related events are needed in patients with NSCLC.

Aqueous two-phase system antibody confinement enables cost-effective analysis of protein analytes by sandwich enzyme-linked immunosorbent assay with minimal optical crosstalk.

An aqueous two-phase system formed from polyethylene glycol and dextran was used to uniformly coat the bottom surfaces of the wells of standard 96-well assay plates with capture and detection antibodies to improve the performance and cost-effectiveness of sandwich enzyme-linked immunosorbent assay (ELISA). Using this approach, limits of detection and linear dynamic range values comparable to those obtained for conventional sandwich ELISA were obtained using considerably lower antibody quantities due to the much lower reagent volumes required when antibodies are applied in a dextran solution beneath a polyethylene glycol overlay. Confinement of the antibody reagents to the bottom surfaces of the wells within the dextran phase also dramatically decreased the optical crosstalk present between neighboring wells when using transparent microplates. Adaptation of the conventional single sandwich ELISA for aqueous two-phase system antibody confinement was demonstrated by analysis of standard curves for C-reactive protein, transforming growth factor beta 1, and the chemokine CXCL10.

Monoclonal Antibodies and Fc-Fusion Proteins for Pediatric Use: Dosing, Immunogenicity, and Modeling and Simulation in Data Submitted to the US Food and Drug Administration.

The experience with the use of monoclonal antibodies and Fc-fusion proteins (mAb/Fc) in the pediatric population is limited. The objective of this study is to review those factors impacting the clinical efficacy and product safety of mAb/Fc products in pediatric patients during drug development. We reviewed the list of biologic products in the US Food and Drug Administration's Purple Book as of March 2018 with a focus on mAb/Fc products that are indicated for use in both adults and pediatric patients. Of 68 mAb/Fc products in the Purple Book (excluding biosimilars), 20 products have approved indications in both adults and children. Thirteen products had concurrent approval for both adult and pediatric populations. The sample size of pediatric studies generally ranged from approximately 2% to 70% of the sample size of adult studies with the same indication. In general, pediatric dosing regimens were found to be more based on body weight and weight tiered than the regimens for adults. Modeling and simulation techniques comprised mainly population pharmacokinetic and pharmacodynamic models. A review of the immunogenicity incidence did not reveal any notable difference in the 5 products having data on both pediatric and adult patients. In conclusion, most of the mAb/Fc products have a different weight-based dosing regimen for pediatric patients versus adults. An understanding of the comparative experience in drug development for mAb/Fc products between adult and pediatric patients coupled with the application of advanced modeling and simulation methods should assist future development of new mAb/Fc products for pediatric patients.

Metabolic Remodeling during Liver Regeneration.

Liver disease is linked to a decreased capacity of hepatocytes to divide. In addition, cellular metabolism is important for tissue homeostasis and regeneration. Since metabolic changes are a hallmark of liver disease, we investigated the connections between metabolism and cell division. We determined global metabolic changes at different stages of liver regeneration using a combination of integrated transcriptomic and metabolomic analyses with advanced functional redox in vivo imaging. Our data indicate that blocking hepatocyte division during regeneration leads to mitochondrial dysfunction and downregulation of oxidative pathways. This resulted in an increased redox ratio and hyperactivity of alanine transaminase allowing the production of alanine and α-ketoglutarate from pyruvate when mitochondrial functions are impaired. Our data suggests that during liver regeneration, cell division leads to hepatic metabolic remodeling. Moreover, we demonstrate that hepatocytes are equipped with a flexible metabolic machinery able to adapt dynamically to changes during tissue regeneration.

Green tea polyphenols extend the lifespan of male drosophila melanogaster while impairing reproductive fitness.

Green tea is a popular beverage believed to have many health benefits, including a reduction in the risks of heart disease and cancer. Rich in polyphenolic compounds known as catechins, green tea and its components have been shown to increase the lifespan of various animal models, including Drosophila melanogaster. Here, we investigated the gender-specific effects of green tea on the lifespan of fruit flies and observed that green tea extended the lifespan of male flies only. This effect was found to be independent of typical aging interventions, such as dietary restriction, modulation of oxidative energy metabolism, and improved tolerance to environmental stresses. The one exception was that green tea did protect male flies against iron toxicity. Since there is an inverse correlation between lifespan and reproduction, the impact of green tea on male reproductive fitness was also investigated. We found that green tea negatively impacted male fertility as shown by a reduced number of offspring produced and increased mating latency. We further identified that the lifespan extension properties of green tea was only observed in the presence of females which alludes to a reproductive (or mating) dependent mechanism. Our findings suggest that green tea extends the lifespan of male flies by inhibiting reproductive potential, possibly by limiting iron uptake. To our knowledge, our study is the first to report the negative impact of green tea on Drosophila male reproduction. Our results also support previous studies that suggest that green tea might have a negative effect on reproductive fitness in humans.