Recent Decisions

Comments on recent decisions by Philip Byrne, Thomas Kavadas, John R. Martzell, George P. McAndrews, Edward J. Fillenwarth, Jr., Dennis R. Powell, Charles Griffin, Thomas R. Joyce, Jr., Patrick Crooks, J. Michael Guenther, Robert G. Berry, and Classen Gramm

Book Reviews

Book reviews by Waldo Beach, James J. Harrington, Rocco L. Puntureri, George P. McAndrews, and William J. Gerardo

Gene Ontology annotations: what they mean and where they come from

To address the challenges of information integration and retrieval, the computational genomics community increasingly has come to rely on the methodology of creating annotations of scientific literature using terms from controlled structured vocabularies such as the Gene Ontology (GO). Here we address the question of what such annotations signify and of how they are created by working biologists. Our goal is to promote a better understanding of how the results of experiments are captured in annotations, in the hope that this will lead both to better representations of biological reality through annotation and ontology development and to more informed use of GO resources by experimental scientists

Investigation of COVID-19 comorbidities reveals genes and pathways coincident with the SARS-CoV-2 viral disease.

The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic initiated intense research into the mechanisms of action for this virus. It was quickly noted that COVID-19 presents more seriously in conjunction with other human disease conditions such as hypertension, diabetes, and lung diseases. We conducted a bioinformatics analysis of COVID-19 comorbidity-associated gene sets, identifying genes and pathways shared among the comorbidities, and evaluated current knowledge about these genes and pathways as related to current information about SARS-CoV-2 infection. We performed our analysis using GeneWeaver (GW), Reactome, and several biomedical ontologies to represent and compare common COVID-19 comorbidities. Phenotypic analysis of shared genes revealed significant enrichment for immune system phenotypes and for cardiovascular-related phenotypes, which might point to alleles and phenotypes in mouse models that could be evaluated for clues to COVID-19 severity. Through pathway analysis, we identified enriched pathways shared by comorbidity datasets and datasets associated with SARS-CoV-2 infection

The impact of induction chemotherapy on the outcome of second-line therapy with pemetrexed or docetaxel in patients with advanced non-small-cell lung cancer

Background: Using data from a large phase III study of previously treated advanced non-small-cell lung cancer (NSCLC) that showed similar efficacy for pemetrexed and docetaxel, this retrospective analysis evaluates the impact of first-line chemotherapy on the outcome of second-line chemotherapy. Patients and methods: In all, 571 patients with advanced NSCLC were randomly assigned to receive pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 on day 1 of a 21-day cycle. Comparisons were made based on type of first-line therapy [gemcitabine + platinum (GP), taxane + platinum (TP), or other therapies (OT)], response to initial therapy, time since initial therapy, and clinical characteristics. The two second-line treatment groups were pooled for this analysis due to similar efficacy and were assumed to have no interaction with the first-line therapies. Results: Baseline characteristics were generally balanced. By multivariate analysis, gender, stage at diagnosis, performance status (PS), and best response to first-line therapy significantly influenced overall survival (OS). Additional factors by univariate analysis, histology, and time elapsed from first- to second-line therapy significantly influenced OS. Conclusions: Future trials in the second-line setting should stratify patients by gender, stage at diagnosis, PS, and best response to first-line therap

Nrf2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age

Accumulation of reactive oxygen species (ROS) is an important pathogenic mechanism underling the loss of bone mass and strength with aging and other conditions leading to osteoporosis. The transcription factor erythroid 2-related factor2 (Nrf2) plays a central role in activating the cellular response to ROS. Here, we examined the endogenous response of bone regulated by Nrf2, and its relationship with bone mass and architecture in the male and female murine skeleton. Young (3 month-old) and old (15 month-old) Nrf2 knockout (KO) mice of either sex exhibited the expected reduction in Nrf2 mRNA expression compared to wild type (WT) littermates. Nrf2 deletion did not lead to compensatory increase in Nrf1 or Nrf3, other members of this transcription factor family; and instead, Nrf1 expression was lower in KO mice. Compared to the respective WT littermate controls, female KO mice, young and old, exhibited lower expression of both detoxifying and antioxidant enzymes; young male KO mice, displayed lower expression of detoxifying enzymes but not antioxidant enzymes; and old male KO mice showed no differences in either detoxifying or antioxidant enzymes. Moreover, old male WT mice exhibited lower Nrf2 levels, and consequently lower expression of both detoxifying and antioxidant enzymes, compared to old female WT mice. These endogenous antioxidant responses lead to delayed rate of bone acquisition in female KO mice and higher bone acquisition in male KO mice as quantified by DXA and μCT, demonstrating that Nrf2 is required for full bone accrual in the female skeleton but unnecessary and even detrimental in the male skeleton. Therefore, Nrf2 regulates the antioxidant endogenous response and bone accrual differently depending on sex and age. These findings suggest that therapeutic interventions that target Nrf2 could be developed to enhance the endogenous antioxidant response in a sex- and age-selective manner

Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance.

BACKGROUND: Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. METHODS: In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. RESULTS: We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. CONCLUSIONS: We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response

Overcoming Barriers to Vaccination By Empowering Citizens to Make Deliberate Choices

Copyright © The authors. Overcoming Barriers to Vaccination By Empowering Citizens to Make Deliberate Choices is one of ten in-depth transatlantic reports published by The British Academy exploring COVID-19 vaccine engagement in the UK and the US. For more details, see: https://www.thebritishacademy.ac.uk/news/the-british-academy-publishes-studies-examining-covid-vaccine-engagement-in-uk-and-usa/.British Academy (COVG7210005); Department for Business, Energy and Industrial Strategy.https://www.thebritishacademy.ac.uk/news/the-british-academy-publishes-studies-examining-covid-vaccine-engagement-in-uk-and-usa