An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride

The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B₁ (AFB₁), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB₁ forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people. All three chemicals produce liver tumors in rats. AFB₁ and VCl also produce liver tumors in humans, but Tam induces human uterine tumors, only. To support a mutagenic MOA, the chemical-induced adducts must be characterized, shown to be pro-mutagenic, be present in the tumor target tissue, and produce mutations of the class found in the tumor. The adducts formed by AFB₁ and VCl support a mutagenic MOA for their carcinogenicity. However, the data available for Tam shows a mutagenic MOA for liver tumors in rats, but its carcinogenicity in humans is most likely via a different MOA.     

SAGES research agenda in gastrointestinal and endoscopic surgery: updated results of a Delphi study

Background

Research in gastrointestinal and endoscopic surgery has witnessed unprecedented growth since the introduction of minimally invasive techniques in surgery. Coordination and focus of research efforts could further advance this rapidly expanding field. The objective of this study was to update the SAGES research agenda for gastrointestinal and endoscopic surgery.

Methods

A modified Delphi methodology was used to create the research agenda. Using an iterative, anonymous web-based survey, the general membership and leadership of SAGES were asked for input over three rounds. Initially submitted research questions were reviewed and consolidated by an expert panel and redistributed to the membership for priority ranking using a 5-point Likert scale of importance. The top 40 research questions of this round were then redistributed to and re-rated by members, and a final ranking was established. Comparisons were made between membership and leadership responses.

Results

283 initially submitted research questions were condensed into 89 distinct questions, which were rated by 388 respondents to determine the top 40 questions. 460 respondents established the final ranking of these 40 most important research questions. Topics represented included training and technique, gastrointestinal, hernia, GERD, bariatric surgery, and endoscopy. The top question was, “How do we best train, assess, and maintain proficiency of surgeons and surgical trainees in flexible endoscopy, laparoscopy, and open surgery?” 28 % of responders were leadership and the rest general members with the majority of ratings (73 %) being similar between the groups. While SAGES leadership rated the majority of questions (89 %) lower, they rated nonclinical questions higher compared with general membership.

Conclusions

An updated research agenda for gastrointestinal and endoscopic surgery was developed using a systematic methodology. This agenda may assist investigators and funding organizations to concentrate their efforts in the highest research priority areas and editors and reviewers in assessing the merit and relevance of scientific work.     

Nerve regeneration and elastin formation within poly(glycerol sebacate)-based synthetic arterial grafts one-year post-implantation in a rat model

The objective of this study was to evaluate the long-term performance of cell-free vascular grafts made from a fast-degrading elastic polymer. We fabricated small arterial grafts from microporous tubes of poly(glycerol sebacate) (PGS) reinforced with polycaprolactone (PCL) nanofibers on the outer surface. Grafts were interpositioned in rat abdominal aortas and characterized at 1 year post-implant. Grafts remodeled into “neoarteries” (regenerated arteries) with similar gross appearance to native rat aortas. Neoarteries mimic arterial tissue architecture with a confluent endothelium and media and adventita-like layers. Patent vessels (80%) showed no significant stenosis, dilation, or calcification. Neoarteries contain nerves and have the same amount of mature elastin as native arteries. Despite some differences in matrix organization, regenerated arteries had similar dynamic mechanical compliance to native arteries in vivo. Neoarteries responded to vasomotor agents, albeit with different magnitude than native aortas. These data suggest that an elastic vascular graft that resorbs quickly has potential to improve the performance of vascular grafts used in small arteries. This design may also promote constructive remodeling in other soft tissues.     

The Indented Paragraph Reading Test in the assessment of left hemi-neglect.

We investigated the validity of the Indented Paragraph Reading Test (IPRT), designed to assess left hemi-neglect (LHN) in reading behavior, with regard to education effects, scoring properties, and sensitivity to recovery of LHN. The IPRT was administered aspart of a larger battery to 50 right-hemisphere stroke patients approximately 1, 2, 3, and 7 months post-stroke if, and only if, the patient demonstrated LHN on the previous test battery. Contrary to expectations, performance on the IPRT was not correlated with education and even patients with minimal formal education were able to complete the test. We demonstrated that the author's suggested scoring criterion was valid and sensitive to the presence of LHN as well as to its recovery over time.     

New perspectives on rural EMT defibrillation

In recent years, several studies have produced contradictory data regarding the impact of emergency medical technicians trained in defibrillation on hospital admission and dismissal survival rates in rural areas. Fourteen communities (service area populations, 4,000 to 36,000) in rural south-eastern Minnesota participated in a two-year crossover study to further define the factors necessary for success. Automatic external defibrillators were used to defibrillate and record patient rhythms in the treatment group and to only record in the control group. Although six of 36 patients (17%) in ventricular fibrillation who experienced a witnessed arrest survived in communities using automatic external defibrillators, compared with one of 27 (4%) in the control group, five of the six survivors were from a single large community with a 911 system, full-time emergency medical technicians, police first-responders, and a well-equipped emergency facility. Our data suggest that certain prerequisites, especially CPR prior to ambulance arrival and collapse to defibrillation times of less than ten minutes, are clearly essential to produce significant benefits from emergency medical technicians trained in defibrillation in rural communities.     

Automated Network Assembly of Mechanistic Literature for Informed Evidence Identification to Support Cancer Risk Assessment

Background: Mechanistic data is increasingly used in hazard identification of chemicals. However, the volume of data is large, challenging the efficient identification and clustering of relevant data.Objectives: We investigated whether evidence identification for hazard assessment can become more efficient and informed through an automated approach that combines machine reading of publications with network visualization tools.Methods: We chose 13 chemicals that were evaluated by the International Agency for Research on Cancer (IARC) Monographs program incorporating the key characteristics of carcinogens (KCCs) approach. Using established literature search terms for KCCs, we retrieved and analyzed literature using Integrated Network and Dynamical Reasoning Assembler (INDRA). INDRA combines large-scale literature processing with pathway databases and extracts relationships between biomolecules, bioprocesses, and chemicals into statements (e.g., “benzene activates DNA damage”). These statements were subsequently assembled into networks and compared with the KCC evaluation by the IARC, to evaluate the informativeness of our approach.Results: We found, in general, larger networks for those chemicals which the IARC has evaluated the evidence to be strong for KCC induction. Larger networks were not directly linked to publication count, given that we retrieved small networks for several chemicals with little support for KCC activation according to the IARC, despite the significant volume of literature for these specific chemicals. In addition, interpreting networks for genotoxicity and DNA repair showed concordance with the IARC KCC evaluation.Discussion: Our method is an automated approach to condense mechanistic literature into searchable and interpretable networks based on an a priori ontology. The approach is no replacement of expert evaluation but, instead, provides an informed structure for experts to quickly identify which statements are made in which papers and how these could connect. We focused on the KCCs because these are supported by well-described search terms. The method needs to be tested in other frameworks as well to demonstrate its generalizability. https://doi.org/10.1289/EHP9112     

Bilateral ophthalmic artery occlusion in a patient with acquired immunodeficiency syndrome and central nervous system lymphoma

PURPOSE: Clinical course and autopsy findings in a patient with human immunodeficiency virus-1 immunodeficiency, central nervous system lymphoma, and bilateral, simultaneous ophthalmic artery occlusions. DESIGN: Observational case report. METHODS: Clinical examination, fundus photography, gross and microscopic pathologic study. RESULTS: Fundus photographs disclosed stasis in retinal arterioles, the absence of a cherry-red spot; internal carotid arteriography disclosed bilateral ophthalmic artery occlusions; postmortem histopathologic examination disclosed bilateral ophthalmic artery atherosclerosis, retinal ischemic necrosis, ischemic optic neuropathy, diffuse large-cell lymphoma of multiple areas of the central nervous system, cytomegalovirus encephalitis, atherosclerosis, and bronchopneumonia. CONCLUSIONS: A 47-year-old male with acquired immunodeficiency syndrome, profound immunodeficiency, systemic hypertension, and central nervous system lymphoma, developed deep vein thrombosis, bilateral ophthalmic artery occlusions, and died of pneumonia 7 weeks after the onset of blindness. Postmortem study revealed bilateral ophthalmic artery hemorrhagic atherosclerosis, ischemic optic neuropathy, ischemic retinal necrosis, diffuse large-cell central nervous system lymphoma, cytomegalovirus encephalitis, pneumonitis, and systemic atherosclerosis.