Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Angiolymphoid hyperplasia with eosinophilia of the orbit associated with obstructive airway disease

Two patients with angiolymphoid hyperplasia with eosinophilia isolated to the orbit had eyelid swelling, a superior orbital mass, and histories of intermittent obstructive airway disease. One patient later developed a transient peripheral blood eosinophilia as high as 36%. One lesion recurred 38 months postoperatively and responded to systemic corticosteroid therapy.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Extracorporeal membrane oxygenation for pediatric cardiopulmonary failure

Extracorporeal membrane oxygenation is now standard treatment of severe respiratory failure in newborn infants in our center (200 cases) and worldwide (over 2500 cases), but there are few reports of such trials in older children. We reviewed our experience with extracorporeal membrane oxygenation in 33 children aged 1 week to 18 years between 1971 and 1989. The modality was used when all other treatment failed. Extracorporeal membrane oxygenation provided excellent cardiopulmonary support for 1 to 25 days (average 7 1/2 days). The survival rate was 25% for cardiac support patients and 47% for respiratory failure patients (36% overall survival). Mechanical complications included membrane lung failure, tubing rupture, and pump failure, all managed without mortality. Physiologic complications included bleeding, pneumothorax, cardiac arrest, renal failure, hepatic failure, and brain injury. The major cause of death was irreversible injury to lung, heart, or brain. Extracorporeal life support is a reasonable approach for children with serious but reversible cardiopulmonary failure.     

Endoscopic laser ablation of obstructing congenital duodenal webs in the newborn: a case report of limited success with criteria for patient selection.

Standard approaches to intrinsic obstructing duodenal lesions in the newborn include laparotomy with enteroenterostomy, bypassing the obstruction, or duoduodenotomy with excision. The advent of improved pediatric flexible fiberoptic endoscopes and fiberoptic laser technology makes endoscopic ablation of duodenal webs and windsocks in the newborn possible.     

Depressed pathological gamblers

Depressed gamblers (n = 14) were compared with normal controls (n = 41) for antecedent life events. The depressed gamblers had experienced significantly more life events, and undesirable or exit life events, during the 6 months before the onset of depression.