[Evolution of cancer resistance in the animal kingdom]. / Évolution de la résistance au cancer dans le monde animal.

Cancer is an inevitable collateral problem inherent in the evolution of multicellular organisms, which appeared at the end of the Precambrian. Faced to this constraint, a range of diverse anticancer defenses has evolved across the animal kingdom. Today, investigating how animal organisms, especially those of large size and long lifespan, manage cancer-related issues has both fundamental and applied outcomes, as it could inspire strategies for preventing or treating human cancers. In this article, we begin by presenting the conceptual framework for understanding evolutionary theories regarding the development of anti-cancer defenses. We then present a number of examples that have been extensively studied in recent years, including naked mole rats, elephants, whales, placozoa, xenarthras (such as sloths, armadillos and anteaters) and bats. The contributions of comparative genomics to understanding evolutionary convergences are also discussed. Finally, we emphasize that natural selection has also favored anti-cancer adaptations aimed at avoiding mutagenic environments, for example by maximizing immediate reproductive efforts in the event of cancer. Exploring these adaptive solutions holds promise for identifying novel approaches to improve human health.

Title: Évolution de la résistance au cancer dans le monde animal. Abstract: Le cancer est un dommage collatéral inévitable inhérent à l'évolution des organismes multicellulaires, apparus à la fin du Précambrien. L'exploration de la manière dont les animaux, en particulier ceux de grande taille et de longue durée de vie, font face au cancer, comporte des enjeux à la fois fondamentaux et appliqués. Dans cet article, nous commençons par présenter le cadre conceptuel nécessaire pour comprendre les théories qui traitent de l'évolution des défenses anti-cancéreuses. Nous présentons ensuite un certain nombre d'exemples, notamment les rats-taupes nus, les éléphants, les baleines, les xénarthres (paresseux, tatous et fourmiliers), les chauves-souris et les placozoaires1. Les contributions de la génomique comparative à la compréhension des convergences évolutives sont également abordées. Enfin, nous indiquons que la sélection naturelle a également favorisé des adaptations visant à éviter les zones mutagènes, par exemple, ou à maximiser l'effort de reproduction immédiat en cas de cancer. L'exploration de ces solutions, intéressante conceptuellement, pourrait aussi permettre d'envisager de nouvelles approches thérapeutiques pour la santé humaine.

Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer.

The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.

Long-term, non-invasive FTIR detection of low-dose ionizing radiation exposure.

Non-invasive methods of detecting radiation exposure show promise to improve upon current approaches to biological dosimetry in ease, speed, and accuracy. Here we developed a pipeline that employs Fourier transform infrared (FTIR) spectroscopy in the mid-infrared spectrum to identify a signature of low dose ionizing radiation exposure in mouse ear pinnae over time. Mice exposed to 0.1 to 2 Gy total body irradiation were repeatedly measured by FTIR at the stratum corneum of the ear pinnae. We found significant discriminative power for all doses and time-points out to 90 days after exposure. Classification accuracy was maximized when testing 14 days after exposure (specificity > 0.9 with a sensitivity threshold of 0.9) and dropped by roughly 30% sensitivity at 90 days. Infrared frequencies point towards biological changes in DNA conformation, lipid oxidation and accumulation and shifts in protein secondary structure. Since only hundreds of samples were used to learn the highly discriminative signature, developing human-relevant diagnostic capabilities is likely feasible and this non-invasive procedure points toward rapid, non-invasive, and reagent-free biodosimetry applications at population scales.

In vitro competition between two transmissible cancers and potential implications for their host, the Tasmanian devil.

Since the emergence of a transmissible cancer, devil facial tumour disease (DFT1), in the 1980s, wild Tasmanian devil populations have been in decline. In 2016, a second, independently evolved transmissible cancer (DFT2) was discovered raising concerns for survival of the host species. Here, we applied experimental and modelling frameworks to examine competition dynamics between the two transmissible cancers in vitro. Using representative cell lines for DFT1 and DFT2, we have found that in monoculture, DFT2 grows twice as fast as DFT1 but reaches lower maximum cell densities. Using co-cultures, we demonstrate that DFT2 outcompetes DFT1: the number of DFT1 cells decreasing over time, never reaching exponential growth. This phenomenon could not be replicated when cells were grown separated by a semi-permeable membrane, consistent with exertion of mechanical stress on DFT1 cells by DFT2. A logistic model and a Lotka-Volterra competition model were used to interrogate monoculture and co-culture growth curves, respectively, suggesting DFT2 is a better competitor than DFT1, but also showing that competition outcomes might depend on the initial number of cells, at least in the laboratory. We provide theories how the in vitro results could be translated to observations in the wild and propose that these results may indicate that although DFT2 is currently in a smaller geographic area than DFT1, it could have the potential to outcompete DFT1. Furthermore, we provide a framework for improving the parameterization of epidemiological models applied to these cancer lineages, which will inform future disease management.

Toxoplasma gondii infection in people with schizophrenia is related to higher hair glucocorticoid levels.

Introduction: Toxoplasma gondii (TG) is a common protozoan parasite infecting approximately one third of the human population. Animal studies have shown that this parasite can manipulate its host behavior. Based on this, human studies have assessed if TG can be involved in mental health disorders associated with important behavioral modifications such as schizophrenia. However, results have been discrepant. Given that TG has a strong impact on fear and risk-taking processes in animal studies and that fear and risk-taking behaviors are associated with the human stress response, we tested whether glucocorticoid biomarkers (salivary and hair) differ in people with schizophrenia and controls as a function of TG status. Methods: We measured TG antibodies in blood samples, as well as salivary and hair glucocorticoid levels in 226 people with schizophrenia (19.9% women, mean age = 39 years old) and 129 healthy individuals (controls) (45.7% women, mean age = 41 years old). Results: The results showed that people with schizophrenia infected with TG presented significantly higher hair glucocorticoid concentrations than non-infected people with schizophrenia. This effect was not found in control participants. No effect was observed for salivary glucocorticoid levels. Additionally, there were no associations between TG infection and positive psychotic symptoms nor impulsivity. Discussion: These results show that people with schizophrenia present high levels of hair glucocorticoid levels only when they are infected with TG. Further studies performed in populations suffering from other mental health disorders are needed to determine if this effect is specific to schizophrenia, or whether it is generalized across mental health disorders.

Residential energy transition and chronic respiratory diseases.

Obtaining clean energy is of prime importance for planetary health and sustainable development. We aimed to assess the association between residential energy transition and the risk of chronic respiratory diseases. Using data from the Global Health Observatory and Global Burden of Diseases, Injuries, and Risk Factors Study, we delineated the spatial distribution and temporal trends of the population using clean fuels for cooking at a global scale. In the China Health and Retirement Longitudinal Study, we performed rigorous and well-structured multistage analyses incorporating both cross-sectional and prospective data analyses to examine the associations between solid fuel use, residential energy transition, duration of solid fuel use, and the risk of chronic respiratory diseases. Despite great progress, huge disparities in access to clean energy persist globally. Residential energy transition was associated with a lower risk of chronic respiratory diseases. In the period of 2011-2013, compared with persistent solid fuel users, both participants who switched from solid to clean fuels (adjusted risk ratio [RR] 0.78, 95% confidence interval [CI] 0.62-0.98) and persistent clean fuel users (adjusted RR 0.71, 95% CI 0.57-0.89) had significantly lower risk of chronic respiratory diseases (p < 0.001 for trend). Consistent associations were observed in the period of 2011-2015 and 2011-2018. Household energy transition from solid to clean fuels could reduce the risk of chronic respiratory diseases. This is a valuable lesson for policy-makers and the general public to accelerate energy switching to alleviate the burden of chronic respiratory diseases and achieve health benefits, particularly in low- and middle-income countries.

Home enteral nutrition does not decrease oral feeding in children during the first year of nutritional support.

BACKGROUND: Enteral nutrition is necessary when nutritional status is poor and oral intake is insufficient or impossible. Although it has been suspected to reduce spontaneous oral feeding, no study has formally assessed the influence of enteral nutrition on pediatric oral intake. The present study aimed to evaluate variation in oral feeding intake after enteral nutrition initiation, and to identify factors influencing oral feeding. METHODS: This retrospective cohort study included 149 pediatric patients from two French tertiary care hospitals, who received home enteral nutrition from 2009 to 2022. The patients were aged 2 months to 17 years (median age 3 years, interquartile range 1.3-9.2). Oral and enteral intakes were assessed when enteral nutrition was initiated (M0), and again at M3 (n = 123), M6 (n = 129), and M12 (n = 134) follow-ups, based on dieticians' and home services' reports. Oral feeding and body mass index z score variations during follow-ups were evaluated using a linear mixed regression model, including "time" as a fixed effect and "patient" as a random effect. Factors associated with oral feeding changes were assessed using a model interaction term. RESULTS: Oral intake did not vary significantly (P = 0.99) over time and accounted for 47.4% ± 27.4%, 46.9% ± 27.4%, 48.4% ± 28.2%, and 46.6% ± 26.9% of the ideal recommended daily allowance (calculated for the ideal weight for height) at M0, M3, M6, and M12, respectively. Delivery method (nasogastric tube versus gastrostomy), prematurity, underlying disease, history of intrauterine growth retardation, and speech therapy intervention did not influence oral intake. Administration (i.e., exclusively continuous nocturnal infusion versus daytime bolus) led to different oral intake development, although oral intake also differed at M0. CONCLUSIONS: Enteral nutrition, although increasing total energy intake, does not alter oral feeding during the first year of administration. Only the mode of administration might influence oral intake.

Behavioural ecology meets oncology: quantifying the recovery of animal behaviour to a transient exposure to a cancer risk factor.

Wildlife is increasingly exposed to sublethal transient cancer risk factors, including mutagenic substances, which activates their anti-cancer defences, promotes tumourigenesis, and may negatively impact populations. Little is known about how exposure to cancer risk factors impacts the behaviour of wildlife. Here, we investigated the effects of a sublethal, short-term exposure to a carcinogen at environmentally relevant concentrations on the activity patterns of wild Girardia tigrina planaria during a two-phase experiment, consisting of a 7-day exposure to cadmium period followed by a 7-day recovery period. To comprehensively explore the effects of the exposure on activity patterns, we employed the double hierarchical generalized linear model framework which explicitly models residual intraindividual variability in addition to the mean and variance of the population. We found that exposed planaria were less active compared to unexposed individuals and were able to recover to pre-exposure activity levels albeit with a reduced variance in activity at the start of the recovery phase. Planaria showing high activity levels were less predictable with larger daily activity variations and higher residual variance. Thus, the shift in behavioural variability induced by an exposure to a cancer risk factor can be quantified using advanced tools from the field of behavioural ecology. This is required to understand how tumourous processes affect the ecology of species.

Maternally derived avian corticosterone affects offspring genome-wide DNA methylation in a passerine species.

Avian embryos develop in an egg composition which reflects both maternal condition and the recent environment of their mother. In birds, yolk corticosterone (CORT) influences development by impacting pre- and postnatal growth, as well as nestling stress responses and development. One possible mechanism through which maternal CORT may affect offspring development is via changes to offspring DNA methylation. We sought to investigate this, for the first time in birds, by quantifying the impact of manipulations to maternal CORT on offspring DNA methylation. We non-invasively manipulated plasma CORT concentrations of egg-laying female zebra finches (Taeniopygia castanotis) with an acute dose of CORT administered around the time of ovulation and collected their eggs. We then assessed DNA methylation in the resulting embryonic tissue and in their associated vitelline membrane blood vessels, during early development (5 days after lay), using two established methods - liquid chromatography-mass spectrometry (LC-MS) and methylation-sensitive amplification fragment length polymorphism (MS-AFLP). LC-MS analysis showed that global DNA methylation was lower in embryos from CORT-treated mothers, compared to control embryos. In contrast, blood vessel DNA from eggs from CORT-treated mothers showed global methylation increases, compared to control samples. There was a higher proportion of global DNA methylation in the embryonic DNA of second clutches, compared to first clutches. Locus-specific analyses using MS-AFLP did not reveal a treatment effect. Our results indicate that an acute elevation of maternal CORT around ovulation impacts DNA methylation patterns in their offspring. This could provide a mechanistic understanding of how a mother's experience can affect her offspring's phenotype.

Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Based Clinical Target Volume Delineation Guideline for Postprostatectomy Salvage Radiation Therapy: The PERYTON Guideline.

PURPOSE: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) scan is the standard imaging procedure for biochemical recurrent prostate cancer postprostatectomy because of its high detection rate at low serum prostate-specific antigen levels. However, existing guidelines for clinical target volume (CTV) in prostate bed salvage external beam radiation therapy (sEBRT) are primarily based on experience-based clinical consensus and have been validated using conventional imaging modalities. Therefore, this study aimed to optimize CTV definition in sEBRT by using PSMA PET/CT-detected local recurrences (LRs). METHODS AND MATERIALS: Patients with suspected LR on PSMA PET/CT postprostatectomy were retrospectively enrolled in 9 Dutch centers. Anonymized scans were centrally reviewed by an expert nuclear medicine physician. Each boundary of the CTV guideline from the Groupe Francophone de Radiothérapie en Urologie (GFRU) was evaluated and adapted to improve the accuracy and coverage of the area at risk of LR (CTV) on PSMA PET/CT. The proposed CTV adaptation was discussed with the radiation oncologists of the participating centers, and final consensus was reached. To assess reproducibility, the participating centers were asked to delineate 3 new cases according to the new PERYTON-CTV, and the submitted contours were evaluated using the Dice similarity coefficient (DSC). RESULTS: After central review, 93 LRs were identified on 83 PSMA PET/CTs. The proposed CTV definition improved the coverage of PSMA PET/CT-detected LRs from 67% to 96% compared with the GFRU-CTV, while reducing the GFRU-CTV by 25%. The new CTV was highly reproducible, with a mean DSC of 0.82 (range, 0.81-0.83). CONCLUSIONS: This study contributes to the optimization of CTV definition in postprostatectomy sEBRT by using the pattern of LR detected on PSMA PET/CT. The PERYTON-CTV is highly reproducible across the participating centers and ensures coverage of 96% LRs while reducing the GFRU-CTV by 25%.

The effect of mitochondrial recombination on fertilization success in blue mussels.

The presence of doubly uniparental inheritance (DUI) in bivalves represents a unique mode of mitochondrial transmission, whereby paternal (male-transmitted M-type) and maternal (female-transmitted F-type) haplotypes are transmitted to offspring separately. Male embryos retain both haplotypes, but the M-type is selectively removed from females. Due to the presence of heteroplasmy in males, mtDNA can recombine resulting in a 'masculinized' haplotype referred to as Mf-type. While mtDNA recombination is usually rare, it has been recorded in multiple mussel species across the Northern Hemisphere. Given that mitochondria are the powerhouse of the cell, different mtDNA haplotypes may have different selective advantages under diverse environmental conditions. This may be particularly important for sperm fitness and fertilization success. In this study we aimed to i) determine the presence, prevalence of the Mf-type in Australian blue mussels (Mytilus sp.) and ii) investigate the effect of Mf-mtDNA on sperm performance (a fitness correlate). We found a high prevalence of recombined mtDNA (≈35 %) located within the control region of the mitochondrial genome, which occurred only in specimens that contained Southern Hemisphere mtDNA. The presence of two female mitotypes were identified in the studied mussels, one likely originating from the Northern Hemisphere, and the other either representing the endemic M. planulatus species or introduced genotypes from the Southern Hemisphere. Despite having recombination events present in a third of the studied population, analysis of sperm performance indicated no difference in fertilization success related to mitotype.

One Health Determinants of Escherichia coli Antimicrobial Resistance in Humans in the Community: An Umbrella Review.

To date, the scientific literature on health variables for Escherichia coli antimicrobial resistance (AMR) has been investigated throughout several systematic reviews, often with a focus on only one aspect of the One Health variables: human, animal, or environment. The aim of this umbrella review is to conduct a systematic synthesis of existing evidence on Escherichia coli AMR in humans in the community from a One Health perspective. PubMed, EMBASE, and CINAHL were searched on "antibiotic resistance" and "systematic review" from inception until 25 March 2022 (PROSPERO: CRD42022316431). The methodological quality was assessed, and the importance of identified variables was tabulated across all included reviews. Twenty-three reviews were included in this study, covering 860 primary studies. All reviews were of (critically) low quality. Most reviews focused on humans (20), 3 on animals, and 1 on both human and environmental variables. Antibiotic use, urinary tract infections, diabetes, and international travel were identified as the most important human variables. Poultry farms and swimming in freshwater were identified as potential sources for AMR transmission from the animal and environmental perspectives. This umbrella review highlights a gap in high-quality literature investigating the time between variable exposure, AMR testing, and animal and environmental AMR variables.

The impact of food availability on tumorigenesis is evolutionarily conserved.

The inability to control cell proliferation results in the formation of tumors in many multicellular lineages. Nonetheless, little is known about the extent of conservation of the biological traits and ecological factors that promote or inhibit tumorigenesis across the metazoan tree. Particularly, changes in food availability have been linked to increased cancer incidence in humans, as an outcome of evolutionary mismatch. Here, we apply evolutionary oncology principles to test whether food availability, regardless of the multicellular lineage considered, has an impact on tumorigenesis. We used two phylogenetically unrelated model systems, the cnidarian Hydra oligactis and the fish Danio rerio, to investigate the impact of resource availability on tumor occurrence and progression. Individuals from healthy and tumor-prone lines were placed on four diets that differed in feeding frequency and quantity. For both models, frequent overfeeding favored tumor emergence, while lean diets appeared more protective. In terms of tumor progression, high food availability promoted it, whereas low resources controlled it, but without having a curative effect. We discuss our results in light of current ideas about the possible conservation of basic processes governing cancer in metazoans (including ancestral life history trade-offs at the cell level) and in the framework of evolutionary medicine.

Genetic architecture of the acute and persistent immune cell response after radiation exposure.

Hematologic toxicity is a common side effect of multimodal cancer therapy. Nearly all animal studies investigating the causes of radiotherapy-induced hematologic toxicity use inbred strains with limited genetic diversity and do not reflect the diverse responses observed in humans. We used the population-based Collaborative Cross (CC) mouse resource to investigate the genetic architecture of the acute and persistent immune response after radiation exposure by measuring 22 immune parameters in 1,720 CC mice representing 35 strains. We determined relative acute and persistent radiation resistance scores at the individual strain level considering contributions from all immune parameters. Genome-wide association analysis identified quantitative trait loci associated with baseline and radiation responses. A cross-species radiation resistance score predicted recurrence-free survival in medulloblastoma patients. We present a community resource of immune parameters and genome-wide association analyses before and after radiation exposure for future investigations of the contributions of host genetics on radiosensitivity.

A Novel Platform for Evaluating Dose Rate Effects on Oxidative Damage to Peptides: Toward a High-Throughput Method to Characterize the Mechanisms Underlying the FLASH Effect.

High dose rate radiation has gained considerable interest recently as a possible avenue for increasing the therapeutic window in cancer radiation treatment. The sparing of healthy tissue at high dose rates relative to conventional dose rates, while maintaining tumor control, has been termed the FLASH effect. Although the effect has been validated in animal models using multiple radiation sources, it is not yet well understood. Here, we demonstrate a new experimental platform for quantifying oxidative damage to protein sidechains in solution as a function of radiation dose rate and oxygen availability using liquid chromatography mass spectrometry. Using this reductionist approach, we show that for both X-ray and electron sources, isolated peptides in solution are oxidatively modified to different extents as a function of both dose rate and oxygen availability. Our method provides an experimental platform for exploring the parameter space of the dose rate effect on oxidative changes to proteins in solution.

A theoretical model for host-controlled regulation of symbiont density.

There is growing empirical evidence that animal hosts actively control the density of their mutualistic symbionts according to their requirements. Such active regulation can be facilitated by compartmentalization of symbionts within host tissues, which confers a high degree of control of the symbiosis to the host. Here, we build a general theoretical framework to predict the underlying ecological drivers and evolutionary consequences of host-controlled endosymbiont density regulation for a mutually obligate association between a host and a compartmentalized, vertically transmitted symbiont. Building on the assumption that the costs and benefits of hosting a symbiont population increase with symbiont density, we use state-dependent dynamic programming to determine an optimal strategy for the host, i.e., that which maximizes host fitness, when regulating the density of symbionts. Simulations of active host-controlled regulation governed by the optimal strategy predict that the density of the symbiont should converge to a constant level during host development, and following perturbation. However, a similar trend also emerges from alternative strategies of symbiont regulation. The strategy which maximizes host fitness also promotes symbiont fitness compared to alternative strategies, suggesting that active host-controlled regulation of symbiont density could be adaptive for the symbiont as well as the host. Adaptation of the framework allowed the dynamics of symbiont density to be predicted for other host-symbiont ecologies, such as for non-essential symbionts, demonstrating the versatility of this modelling approach.

Larval diet and temperature alter mosquito immunity and development: using body size and developmental traits to track carry-over effects on longevity.

BACKGROUND: Estimating arbovirus transmission potential requires a mechanistic understanding of how environmental factors influence the expression of adult mosquito traits. While preimaginal exposure to environmental factors can have profound effects on adult traits, tracking and predicting these effects remains challenging. METHODS: Using Aedes albopictus and a structural equation modeling approach, we explored how larval nutrition and temperature jointly affect development rate and success, female body size, and whether these metrics capture carry-over effects on adult female longevity. Additionally, we investigated how larval diet and temperature affect the baseline expression of 10 immune genes. RESULTS: We found that larval development success was primarily determined by diet, while temperature and diet both affected development rate and female body size. Under a low larval diet, pupal wet weight and wing length both declined with increasing temperature. In contrast, responses of the two morphometric measures to rearing temperature diverged when females were provided higher larval nutrition, with pupal wet weight increasing and wing length decreasing at higher temperatures. Our analyses also revealed opposing relationships between adult female lifespan and the two morphometric measures, with wing length having a positive association with longevity and pupal weight a negative association. Larval diet indirectly affected adult longevity, and the time to pupation was negatively correlated with longevity. The expression of eight immune genes from the toll, JAK-STAT and Imd pathways was enhanced in mosquitoes with higher nutrition. CONCLUSIONS: Our results highlight deficiencies from using a single body size measure to capture carry-over effects on adult traits. Further studies of larval development rate under varying environmental conditions and its potential for tracking carry-over effects on vectorial capacity are warranted.

Embracing Heterogeneity: Challenging the Paradigm of Replisomes as Deterministic Machines.

The paradigm of cellular systems as deterministic machines has long guided our understanding of biology. Advancements in technology and methodology, however, have revealed a world of stochasticity, challenging the notion of determinism. Here, we explore the stochastic behavior of multi-protein complexes, using the DNA replication system (replisome) as a prime example. The faithful and timely copying of DNA depends on the simultaneous action of a large set of enzymes and scaffolding factors. This fundamental cellular process is underpinned by dynamic protein-nucleic acid assemblies that must transition between distinct conformations and compositional states. Traditionally viewed as a well-orchestrated molecular machine, recent experimental evidence has unveiled significant variability and heterogeneity in the replication process. In this review, we discuss recent advances in single-molecule approaches and single-particle cryo-EM, which have provided insights into the dynamic processes of DNA replication. We comment on the new challenges faced by structural biologists and biophysicists as they attempt to describe the dynamic cascade of events leading to replisome assembly, activation, and progression. The fundamental principles uncovered and yet to be discovered through the study of DNA replication will inform on similar operating principles for other multi-protein complexes.