Potential biomarker for immunotherapy-related toxicity
Illustration of T cells attacking a tumor cell. Image courtesy of iStockphoto/royaltystockphoto.
Despite striking therapeutic benefits for some patients, cancer immunotherapy using checkpoint-blocking drugs can cause toxic and potentially fatal side effects, including inflammation of the skin, liver, and gastrointestinal tract. Sumit Subudhi et al. (pp. 11919–11924) attempted to determine whether such side effects stem from drug-induced unchecked T-cell activity against unintended cellular targets in blood. To retrospectively detect signs of T-cell expansion in peripheral blood, the authors sequenced T-cell receptor genes from helper and killer T cells in blood collected from 27 patients treated with the checkpoint blocker ipilimumab and androgen deprivation therapy (ADT) in a phase II trial of metastatic castration-sensitive prostate cancer that was prematurely terminated due to safety concerns. Blood samples collected before the onset of toxic side effects in treated patients revealed a link between grade 2–3 adverse events and the expansion of 55 or more killer T-cell clones in blood, suggesting that such clonal expansion might contribute to checkpoint drug toxicity. Separate analysis of a cohort of nine patients treated with ipilimumab and ADT for localized, castration-resistant prostate cancer confirmed the link. According to the authors, prospective, longitudinal studies of a large cohort of patients could help determine whether T-cell clonal expansion can serve as a clinically useful biomarker to identify patients at risk of developing toxic side effects from checkpoint-blocking cancer immunotherapy drugs. — P.N.
Diversity in human genomes
The 46 chromosomes of a human genome. Image courtesy of National Human Genome Research Institute.
Clinical use of human genome sequencing requires suitable quality standards with respect to coverage and accuracy. To evaluate the quality of current whole genome sequencing methods, Amalio Telenti et al. (pp. 11901–11906) sequenced more than 10,000 human genomes at 30×–40× mean coverage using a state-of-the-art sequencing platform. Based on the reproducibility of a reference genome, the authors determined that 84% of the human genome could be sequenced at high confidence, including more than 90% of exons and more than 95% of known pathogenic variant sites. Sequencing revealed more than 150 million single nucleotide variations, 82 million of which had not been previously reported. Most of these variations occurred with less than 1% frequency. On average, each additional genome sequenced contributed more than 8,500 novel variations. From the distribution of variations, the authors identified certain sites, such as splice sites, which were particularly intolerant of variation. These variation-intolerant sites were associated with high frequencies of known pathogenic variants, suggesting that these sites might be essential for health. According to the authors, the results suggest that current sequencing platforms provide genome coverage sufficient for clinical purposes. — B.D.
Physicians’ political affiliations and patient care
Physicians’ treatment decisions can vary with political party affiliation. Image courtesy of Flickr/DonkeyHotey.
Recent evidence suggests that political beliefs can spill over into nonpolitical domains, such as consumer spending, romantic partner choice, and job hiring. To determine whether political beliefs affect physicians’ treatment decisions, Eitan Hersh and Matthew Goldenberg (pp. 11811–11816) linked records of more than 20,000 primary care physicians in the United States to their political party affiliation and surveyed a sample of more than 200 physicians. Respondents evaluated patients in a series of scenarios, some of which involved politically sensitive health issues—abortion, marijuana use, and firearm possession. Republican and Democratic physicians differed significantly in their perceptions of seriousness and on their choices of treatment for the politically sensitive issues, but not for less politicized issues such as alcohol abuse and depression. Republicans were more likely than Democrats to discuss the health and legal risks of marijuana and to urge patients to cut down on marijuana use. Republicans were also more likely than Democrats to discuss the mental health aspects of abortion and to encourage patients not to have abortions in the future. Democrats were more likely than Republicans to urge patients not to store firearms at home, whereas Republicans were more likely to ask about the safe storage of firearms. The results suggest that physicians’ political views might influence patient care, according to the authors. — B.D.
Reevaluating mass extinctions
The magnitude of a mass extinction has traditionally been calculated as the fraction of genera that went extinct during a particular time period. Steven Stanley (pp. E6325–E6334) reports that for geologic intervals during which no mass extinctions occurred, a significant correlation exists between the length of the interval and the fraction of marine genera that went extinct during the interval, suggesting a significant degree of background extinction between mass extinctions. Therefore, some of the genera that went extinct during mass extinctions would likely have gone extinct due to this background extinction. The author developed a mathematical method for estimating the number of extinctions that can be attributed to background extinction during any given interval. Subtracting this number from the total extinctions during a mass extinction event improves the accuracy of the estimated number of extinctions attributable to the mass extinction. Application of this method to the Late Permian mass extinction yielded a loss of approximately 81% of marine species, significantly less than the oft-cited estimate of 90–96%. According to the author, the findings suggest that marine life did not come close to disappearing during the Late Permian, as previously thought. — B.D.
Childhood adversity and adult cellular aging
The shortening of telomeres, which are protective structures that cap the ends of chromosomes, is thought to be a marker of cellular aging and has been linked with stressful events in childhood and adulthood. However, few studies have explored the relationship between telomere length and the accumulation of stress throughout childhood and adulthood. Eli Puterman et al. (pp. E6335–E6342) compared the salivary gland telomere length of 4,598 people, age 50 or older, from the US Health and Retirement Study with the participants’ self-reported financial, traumatic, and social stresses from childhood and adulthood. The likelihood of a participant displaying short telomeres later in life increased with the cumulative number of lifetime stressors, driven mainly by the amount of childhood adversity. The likelihood of a participant having short telomeres increased by 11% for each additional stressor experienced during childhood. Compared with childhood financial problems, social or traumatic stress during childhood had a greater likelihood of being associated with short telomeres. Individual stressful events did not appear to be related to telomere length. According to the authors, the study bolsters previous findings that childhood adversity may influence cellular aging in adulthood. — L.C.
Erosion in fluid flow over granular beds
Spatial organization of erosion in an experimental river model.
When fluid flows across a granular substrate, shearing forces detach material from the interface and transport it downstream. Although erosion and deposition constitute central geomorphological processes that shape Earth’s landforms, decades of research has failed to yield a complete description of these systems at the microscopic level. Using a flume apparatus to simulate river flow over a gravel bed, Pascale Aussillous et al. (pp. 11788–11793) examined the threshold stress beyond which solid flow spontaneously arises and characterized the spatial organization of the erosion flux. The authors found that the flow of particles is spatially heterogeneous near the origin of erosion, carried by only a few concentrated channels in the bed whose distribution is strongly correlated with the power law along the direction of flow. Furthermore, the authors found that the results support a model in which erosion depends on balanced channelization, which accelerates erosion, and interactions among particles that tend to interfere with channeling. The findings suggest that erosion along a fluid-sheared granular bed effectively represents a dynamic phase transition, consistent with other systems such as type II superconductors, according to the authors. — T.J.