Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

INTRODUCTION: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. METHODS: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15-180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. RESULTS: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). CONCLUSIONS: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Deconstructing taxa x taxa xenvironment interactions in the microbiota: A theoretical examination.

A major objective of microbial ecology is to identify how the composition of microbial taxa shapes host phenotypes. However, most studies focus on pairwise interactions and ignore the potentially significant effects of higher-order microbial interactions.Here, we quantify the effects of higher-order interactions among taxa on host infection risk. We apply our approach to an in silico dataset that is built to resemble a population of insect hosts with gut-associated microbial communities at risk of infection from an intestinal parasite across a breadth of nutrient environmental contexts.We find that the effect of higher-order interactions is considerable and can change appreciably across environmental contexts. Furthermore, we show that higher-order interactions can stabilize community structure thereby reducing host susceptibility to parasite invasion.Our approach illustrates how incorporating the effects of higher-order interactions among gut microbiota across environments can be essential for understanding their effects on host phenotypes.

Resource Competition and Host Feedbacks Underlie Regime Shifts in Gut Microbiota.

AbstractThe spread of an enteric pathogen in the human gut depends on many interacting factors, including pathogen exposure, diet, host gut environment, and host microbiota, but how these factors jointly influence infection outcomes remains poorly characterized. Here we develop a model of host-mediated resource competition between mutualistic and pathogenic taxa in the gut that aims to explain why similar hosts, exposed to the same pathogen, can have such different infection outcomes. Our model successfully reproduces several empirically observed phenomena related to transitions between healthy and infected states, including (1) the nonlinear relationship between pathogen inoculum size and infection persistence, (2) the elevated risk of chronic infection during or after treatment with broad-spectrum antibiotics, (3) the resolution of gut dysbiosis with fecal microbiota transplants, and (4) the potential protection from infection conferred by probiotics. We then use the model to explore how host-mediated interventions-namely, shifts in the supply rates of electron donors (e.g., dietary fiber) and respiratory electron acceptors (e.g., oxygen)-can potentially be used to direct gut community assembly. Our study demonstrates how resource competition and ecological feedbacks between the host and the gut microbiota can be critical determinants of human health outcomes. We identify several testable model predictions ready for experimental validation.

Quantifying the roles of seed dispersal, filtering, and climate on regional patterns of grassland biodiversity.

Seed dispersal and local filtering interactively govern community membership and scale up to shape regional vegetation patterns, but data revealing how and why particular species are excluded from specific communities in nature are scarce. This lack of data is a missing link between our theoretical understanding of how diversity patterns can form and how they actually form in nature, and it hampers our ability to predict community responses to climate change. Here, we compare seed, seedling, and adult plant communities at 12 grassland sites with different climates in southern Norway to examine how community membership is interactively shaped by seed dispersal and local filtering, and how this process varies with climate across sites. To do this, we divide species at each site into two groups: locally transient species, which occur as seeds but are rare or absent as adults (i.e., they arrive but are filtered out), and locally persistent species, which occur consistently as adults in annual vegetation surveys. We then ask how and why locally transient species are disfavored during community assembly. Our results led to four main conclusions: (1) the total numbers of seeds and species that arrived, but failed to establish locally persistent populations, rose with temperature, indicating an increase in the realized effects of local filtering on community assembly, as well as an increase in the number of species poised to rapidly colonize those warmer sites if local conditions change in their favor, (2) locally transient species were selectively filtered out during seedling emergence, but not during seedling establishment, (3) selective filtering was partly driven by species climate preferences, exemplified by the poor performance of seeds dispersing outside of their realized climate niches into colder and drier foreign climates, and (4) locally transient species had traits that likely made them better dispersers (i.e., smaller seeds) but poorer competitors for light (i.e., shorter statures and less persistent clonal connections) than locally persistent species, potentially explaining why these species arrived to new sites but did not establish locally persistent adult populations. Our study is the first to combine seed, seedling, and adult survey data across sites to rigorously characterize how seed dispersal and local filtering govern community membership and shape climate-associated vegetation patterns.

Counting niches: Abundance-by-trait patterns reveal niche partitioning in a Neotropical forest.

Tropical forests challenge us to understand biodiversity, as numerous seemingly similar species persist on only a handful of shared resources. Recent ecological theory posits that biodiversity is sustained by a combination of species differences reducing interspecific competition and species similarities increasing time to competitive exclusion. Together, these mechanisms counterintuitively predict that competing species should cluster by traits, in contrast with traditional expectations of trait overdispersion. Here, we show for the first time that trees in a tropical forest exhibit a clustering pattern. In a 50-ha plot on Barro Colorado Island in Panama, species abundances exhibit clusters in two traits connected to light capture strategy, suggesting that competition for light structures community composition. Notably, we find four clusters by maximum height, quantitatively supporting the classical grouping of Neotropical woody plants into shrubs, understory, midstory, and canopy layers.

Assembly and seasonality of core phyllosphere microbiota on perennial biofuel crops.

Perennial grasses are promising feedstocks for biofuel production, with potential for leveraging their native microbiomes to increase their productivity and resilience to environmental stress. Here, we characterize the 16S rRNA gene diversity and seasonal assembly of bacterial and archaeal microbiomes of two perennial cellulosic feedstocks, switchgrass (Panicum virgatum L.) and miscanthus (Miscanthus x giganteus). We sample leaves and soil every three weeks from pre-emergence through senescence for two consecutive switchgrass growing seasons and one miscanthus season, and identify core leaf taxa based on occupancy. Virtually all leaf taxa are also detected in soil; source-sink modeling shows non-random, ecological filtering by the leaf, suggesting that soil is an important reservoir of phyllosphere diversity. Core leaf taxa include early, mid, and late season groups that were consistent across years and crops. This consistency in leaf microbiome dynamics and core members is promising for microbiome manipulation or management to support crop production.

Trait-based community assembly and succession of the infant gut microbiome.

The human gut microbiome develops over early childhood and aids in food digestion and immunomodulation, but the mechanisms driving its development remain elusive. Here we use data curated from literature and online repositories to examine trait-based patterns of gut microbiome succession in 56 infants over their first three years of life. We also develop a new phylogeny-based approach of inferring trait values that can extend readily to other microbial systems and questions. Trait-based patterns suggest that infant gut succession begins with a functionally variable cohort of taxa, adept at proliferating rapidly within hosts, which gradually matures into a more functionally uniform cohort of taxa adapted to thrive in the anoxic gut and disperse between anoxic patches as oxygen-tolerant spores. Trait-based composition stabilizes after the first year, while taxonomic turnover continues unabated, suggesting functional redundancy in the traits examined. Trait-based approaches powerfully complement taxonomy-based approaches to understanding the mechanisms of microbial community assembly and succession.

Can trait patterns along gradients predict plant community responses to climate change?

Plant functional traits vary consistently along climate gradients and are therefore potential predictors of plant community response to climate change. We test this space-for-time assumption by combining a spatial gradient study with whole-community turf transplantation along temperature and precipitation gradients in a network of 12 grassland sites in Southern Norway. Using data on eight traits for 169 species and annual vegetation censuses of 235 turfs over 5 yr, we quantify trait-based responses to climate change by comparing observed community dynamics in transplanted turfs to field-parameterized null model simulations. Three traits related to species architecture (maximum height, number of dormant meristems, and ramet-ramet connection persistence) varied consistently along spatial temperature gradients and also correlated to changes in species abundances in turfs transplanted to warmer climates. Two traits associated with resource acquisition strategy (SLA, leaf area) increased along spatial temperature gradients but did not correlate to changes in species abundances following warming. No traits correlated consistently with precipitation. Our study supports the hypothesis that spatial associations between plant traits and broad-scale climate variables can be predictive of community response to climate change, but it also suggests that not all traits with clear patterns along climate gradients will necessarily influence community response to an equal degree.

Scarlet Macaw (Ara macao, Psittaciformes: Psittacidae) nest characteristics in the Osa Peninsula Conservation Area (ACOSA), Costa Rica.

The Scarlet Macaw (Ara macao) is an endangered species. In Costa Rica, the Scarlet Macaw population of the Central Pacific Conservation Area (ACOPAC, n =432 individuals) has undergone considdrable study and has been used effectively as a flagship species for regional conservation. Costa Rica's only other viable Scarlet Macaw population, located in the Osa Peninsula Conservation Area (ACOSA, n=800-1200 individuals), remains virtually unstudied. We studied ACOSA Scarlet Macaw nest cavities from February 19th to March 22nd 2006. Through informal interviews with park guards and residents, we found a total of 57 potential nests in 52 trees. Eleven nests were reported as frequently poached. Scarlet Macaws used 14 identified tree species, ten of which are unrecorded in Costa Rica. The most common nesting trees were Caryocar costaricense (n=12, 24%), Schizolobium parahyba (n=9, 18.0%), Ceibapentandra (n=7, 14.0%) and Ficus sp. (n=5, 10.0%). We compare nesting characteristics to those recorded in ACOPAC. A combination of bottom-up and top-down strategies are necessary to ensure the Scarlet Macaw's long-term success, including environmental education in local schools, community stewardship of active nests, and the advertisement of stricter penalties for poaching.

Scarlet Macaw (Ara macao, Psittaciformes: Psittacidae) Nest Characteristics in the Osa Peninsula Conservation Area (ACOSA), Costa Rica

The Scarlet Macaw (Ara macao) is an endangered species. In Costa Rica, the Scarlet Macaw population of the Central Pacific Conservation Area (ACOPAC, n =432 individuals) has undergone considerable study and has been used effectively as a flagship species for regional conservation. Costa Rica’s only other viable Scarlet Macaw population, located in the Osa Peninsula Conservation Area (ACOSA, n=800-1200 individuals), remains virtually unstudied. We studied ACOSA Scarlet Macaw nest cavities from February 19th to March 22nd 2006. Through informal interviews with park guards and residents, we found a total of 57 potential nests in 52 trees. Eleven nests were reported as frequently poached. Scarlet Macaws used 14 identified tree species, ten of which are unrecorded in Costa Rica. The most common nesting trees were Caryocar costaricense (n=12, 24%), Schizolobium parahyba (n=9, 18.0%), Ceiba pentandra (n=7, 14.0%) and Ficus sp. (n=5, 10.0%). We compare nesting characteristics to those recorded in ACOPAC. A combination of bottom-up and top-down strategies are necessary to ensure the Scarlet Macaw’s long-term success, including environmental education in local schools, community stewardship of active nests, and the advertisement of stricter penalties for poaching. Rev. Biol. Trop. 57 (1-2): 387-393. Epub 2009 June 30.