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Acclimation and evolutionary adaptation can produce phenotypic changes that allow organisms to cope with challenges. Determining the relative contributions and the underlying mechanisms driving phenotypic shifts from acclimation and adaptation is of central importance to understanding animal responses to change. Rates of evolution have traditionally been considered slow relative to ecological processes that shape biodiversity. Many organisms nonetheless show patterns of genetic variation that suggest that adaptation may act sufficiently fast to allow continuous change in phenotypes in response to environmental change (called 'adaptive tracking'). In Drosophila, both plastic and evolved differences in chill tolerance are associated with ionoregulation. Here, we combine an acclimation experiment, field collections along a well-characterized latitudinal cline, and a replicated field experiment to assess the concordance in the direction, magnitude, and potential mechanisms of acclimation and adaptation on chill coma recovery and elemental (Na and K) stoichiometry in both sexes of Drosophila melanogaster. Acclimation strongly shaped chill coma recovery, spatial adaptation produced comparatively modest effects, and temporal adaptation had no significant effect. Leveraging knowledge on the mechanisms underlying variation in chill tolerance traits, we find that relationships between elemental stoichiometry and chill coma recovery in the context of acclimation may differ from those that are associated with spatial adaptive change., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Environmental risk assessment (ERA) is critical for protecting life by predicting population responses to contaminants. However, routine toxicity testing often examines only one genotype from surrogate species, potentially leading to inaccurate risk assessments, as natural populations typically consist of genetically diverse individuals. To evaluate the importance of intraspecific variation in translating toxicity testing to natural populations, we quantified the magnitude of phenotypic variation between 20 Daphnia magna clones exposed to two levels of microcystins, a cosmopolitan cyanobacterial toxin. We observed significant genetic variation in survival, growth, and reproduction, which increased under microcystins exposure. Simulations of survival showed that using a single genotype for toxicity tolerance estimates on average failed to produce accurate predictions within the 95% confidence interval over half of the time. Whole genome sequencing of the 20 clones tested for correlations between toxicological responses and genomic divergence, including candidate loci from prior gene expression studies. We found no overall correlations, indicating that clonal variation, rather than variation at candidate genes, predicts population-level responses to toxins. These results highlight the importance of incorporating broad intraspecific genetic variation, without focusing specifically on variation in candidate genes, into ERAs to more reliably predict how local populations will respond to contaminants., (© 2024. The Author(s).)

Phenotypic plasticity is a primary mechanism by which organismal phenotypes shift in response to the environment. Host-associated microbiomes often exhibit considerable shifts in response to environmental variation and these shifts could facilitate host phenotypic plasticity, adaptation, or rescue populations from extinction. However, it is unclear how much shifts in microbiome composition contribute to host phenotypic plasticity, limiting our knowledge of the underlying mechanisms of plasticity and, ultimately, the fate of populations inhabiting changing environments. In this study, we examined phenotypic responses and microbiome composition in 20 genetically distinct Daphnia magna clones exposed to non-toxic and toxic diets containing Microcystis , a cosmopolitan cyanobacteria and common stressor for Daphnia . Daphnia exhibited significant plasticity in survival, reproduction, and population growth rates in response to Microcystis exposure. However, the effects of Microcystis exposure on the Daphnia microbiome were limited, with the primary effect being differences in abundance observed across five bacterial families. Moreover, there was no significant correlation between the magnitude of microbiome shifts and host phenotypic plasticity. Our results suggest that microbiome composition played a negligible role in driving host phenotypic plasticity or microbiome-mediated rescue., Competing Interests: Competing interest statement: The authors declare no competing interests.

Eco-evolutionary dynamics will play a critical role in determining species' fates as climatic conditions change. Unfortunately, we have little understanding of how rapid evolutionary responses to climate play out when species are embedded in the competitive communities that they inhabit in nature. We tested the effects of rapid evolution in response to interspecific competition on subsequent ecological and evolutionary trajectories in a seasonally changing climate using a field-based evolution experiment with Drosophila melanogaster Populations of D. melanogaster were either exposed, or not exposed, to interspecific competition with an invasive competitor, Zaprionus indianus , over the summer. We then quantified these populations' ecological trajectories (abundances) and evolutionary trajectories (heritable phenotypic change) when exposed to a cooling fall climate. We found that competition with Z. indianus in the summer affected the subsequent evolutionary trajectory of D. melanogaster populations in the fall, after all interspecific competition had ceased. Specifically, flies with a history of interspecific competition evolved under fall conditions to be larger and have lower cold fecundity and faster development than flies without a history of interspecific competition. Surprisingly, this divergent fall evolutionary trajectory occurred in the absence of any detectible effect of the summer competitive environment on phenotypic evolution over the summer or population dynamics in the fall. This study demonstrates that competitive interactions can leave a legacy that shapes evolutionary responses to climate even after competition has ceased, and more broadly, that evolution in response to one selective pressure can fundamentally alter evolution in response to subsequent agents of selection., Competing Interests: The authors declare no competing interest.

The processes of local adaptation and ecological speciation are often strongly shaped by biotic interactions such as competition and predation. One of the strongest lines of evidence that biotic interactions drive evolution comes from the repeated divergence of lineages in association with repeated changes in the community of interacting species. Yet relatively little is known about the repeatability of changes in gut microbial communities and their role in adaptation and divergence of host populations in nature. Here we use three cases of rapid, parallel adaptation and speciation in freshwater threespine stickleback to test for parallel changes in associated gut microbiomes. We find that features of the gut microbial communities have shifted repeatedly in the same direction in association with parallel divergence and speciation of stickleback hosts. These results suggest that changes to gut microbiomes can occur rapidly and predictably in conjunction with host evolution, and that host-microbe interactions might play an important role in host adaptation and diversification.

Population genomic data has revealed patterns of genetic variation associated with adaptation in many taxa. Yet understanding the adaptive process that drives such patterns is challenging; it requires disentangling the ecological agents of selection, determining the relevant timescales over which evolution occurs, and elucidating the genetic architecture of adaptation. Doing so for the adaptation of hosts to their microbiome is of particular interest with growing recognition of the importance and complexity of host-microbe interactions. Here, we track the pace and genomic architecture of adaptation to an experimental microbiome manipulation in replicate populations of Drosophila melanogaster in field mesocosms. Shifts in microbiome composition altered population dynamics and led to divergence between treatments in allele frequencies, with regions showing strong divergence found on all chromosomes. Moreover, at divergent loci previously associated with adaptation across natural populations, we found that the more common allele in fly populations experimentally enriched for a certain microbial group was also more common in natural populations with high relative abundance of that microbial group. These results suggest that microbiomes may be an agent of selection that shapes the pattern and process of adaptation and, more broadly, that variation in a single ecological factor within a complex environment can drive rapid, polygenic adaptation over short timescales., Competing Interests: The authors declare no conflict of interest.

The genes underlying adaptations are becoming known, yet the causes of selection on genes-a key step in the study of the genetics of adaptation-remains uncertain. We address this issue experimentally in a threespine stickleback species pair showing exaggerated divergence in bony defensive armor in association with competition-driven character displacement. We used semi-natural ponds to test the role of a native predator in causing divergent evolution of armor and two known underlying genes. Predator presence/absence altered selection on dorsal spines and allele frequencies at the Msx2a gene across a generation. Evolutionary trajectories of alleles at a second gene, Pitx1 , and the pelvic spine trait it controls, were more variable. Our experiment demonstrates how manipulation of putative selective agents helps to identify causes of evolutionary divergence at key genes, rule out phenotypic plasticity as a sole determinant of phenotypic differences, and eliminate reliance on fitness surrogates. Divergence of predation regimes in sympatric stickleback is associated with coevolution in response to resource competition, implying a cascade of biotic interactions driving species divergence. We suggest that as divergence proceeds, an increasing number of biotic interactions generate divergent selection, causing more evolution in turn. In this way, biotic adaptation perpetuates species divergence through time during adaptive radiation in an expanding number of traits and genes., (© 2019 The Author(s). Evolution Letters published by Wiley Periodicals, Inc. on behalf of Society for the Study of Evolution (SSE) and European Society for Evolutionary Biology (ESEB).)

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP., Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP., Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm., Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs., Trial Registration: Clinicaltrials.gov: NCT00268476.

Colonisation can expose organisms to novel combinations of abiotic and biotic factors and drive adaptive divergence. Yet, studies investigating the interactive effects of multiple abiotic factors on the evolution of physiological traits remain rare. Here we examine the effects of low salinity, low temperature, and their interaction on the growth of three North American populations of threespine stickleback (Gasterosteus aculeatus). In north-temperate freshwater habitats, stickleback populations experience a combination of low salinity and low winter temperatures that are not experienced by the ancestral marine and anadromous populations. Here we show that both salinity and temperature, and their interaction, have stronger negative effects on marine and anadromous populations than a freshwater population. Freshwater stickleback showed only a ~20% reduction in specific growth rate when exposed to 4 °C, while marine and anadromous stickleback showed sharp declines (82% and 74% respectively) under these conditions. The modest decreases in growth in freshwater stickleback in fresh water in the cold strongly suggest that this population has the capacity for physiological compensation to offset the negative thermodynamic effects of low temperature on growth. These results are suggestive of adaptive evolution in response to the interactive effects of low salinity and low temperature during freshwater colonisation.

Young species are highly prone to extinction via increased gene flow after human-caused environmental changes. This mechanism of biodiversity loss, often termed reverse speciation or introgressive extinction, is of exceptional interest because the parent species are typically highly differentiated ecologically. Reverse speciation events are potentially powerful case studies for the role of evolution in driving ecological changes, as the phenotypic shifts associated with introgressive extinction can be large and they occur over particularly short timescales. Furthermore, reverse speciation can lead to novel phenotypes, which may in turn produce novel ecological effects. Here we investigate the ecological shift associated with reverse speciation in threespine stickleback fish using a field study and a replicated experiment. We find that an instance of introgressive extinction had cascading ecological consequences that altered the abundance of both aquatic prey and the pupating aquatic insects that emerged into the terrestrial ecosystem. The community and ecosystem impacts of reverse speciation were novel, and yet they were also predictable based on ecological and morphological considerations. The study suggests that knowledge about the community ecology and changes in functional morphology of a dominant species may lead to some predictive power for the ecological effects of evolutionary change. Moreover, the rapid nature and resultant ecological impacts associated with reverse speciation demonstrates the interplay between biodiversity, evolutionary change, and ecosystem function., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Research in eco-evolutionary dynamics and community genetics has demonstrated that variation within a species can have strong impacts on associated communities and ecosystem processes. Yet, these studies have centred around individual focal species and at single trophic levels, ignoring the role of phenotypic variation in multiple taxa within an ecosystem. Given the ubiquitous nature of local adaptation, and thus intraspecific variation, we sought to understand how combinations of intraspecific variation in multiple species within an ecosystem impacts its ecology. Using two species that co-occur and demonstrate adaptation to their natal environments, black cottonwood (Populus trichocarpa) and three-spined stickleback (Gasterosteus aculeatus), we investigated the effects of intraspecific phenotypic variation on both top-down and bottom-up forces using a large-scale aquatic mesocosm experiment. Black cottonwood genotypes exhibit genetic variation in their productivity and consequently their leaf litter subsidies to the aquatic system, which mediates the strength of top-down effects from stickleback on prey abundances. Abundances of four common invertebrate prey species and available phosphorous, the most critically limiting nutrient in freshwater systems, are dictated by the interaction between genetic variation in cottonwood productivity and stickleback morphology. These interactive effects fit with ecological theory on the relationship between productivity and top-down control and are comparable in strength to the effects of predator addition. Our results illustrate that intraspecific variation, which can evolve rapidly, is an under-appreciated driver of community structure and ecosystem function, demonstrating that a multi-trophic perspective is essential to understanding the role of evolution in structuring ecological patterns., (© 2015 The Author(s).)

Background: Raised serum glucose has been linked to increased risk of many solid cancers. We performed a meta-analysis to quantify and summarise the evidence for this link., Methods: Pubmed and Embase were reviewed, using search terms representing serum glucose and cancer. Inclusion and exclusion criteria focused on epidemiological studies with clear definitions of serum glucose levels, cancer type, as well as well-described statistical methods with sufficient data available. We used 6.1 mmol/L as the cut-off for high glucose, consistent with the WHO definition of metabolic syndrome. Random effects analyses were performed to estimate the pooled relative risk (RR)., Results: Nineteen studies were included in the primary analysis, which showed a pooled RR of 1.32 (95% CI: 1.20 - 1.45). Including only those individuals with fasting glucose measurements did not have a large effect on the pooled RR (1.32 (95% CI: 1.11-1.57). A stratified analysis showed a pooled RR of 1.34 (95% CI: 1.02-1.77) for hormonally driven cancer and 1.21 (95% CI: 1.09-1.36) for cancers thought to be driven by Insulin Growth Factor-1., Conclusion: A positive association between serum glucose and risk of cancer was found. The underlying biological mechanisms remain to be elucidated but our subgroup analyses suggest that the insulin- IGF-1 axis does not fully explain the association. These findings are of public health importance as measures to reduce serum glucose via lifestyle and dietary changes could be implemented in the context of cancer mortality.

Therapeutic antibodies have revolutionised treatment of some cancers and improved prognosis for many patients. Over half of those available are approved for haematological malignancies, but efficacious antibodies for solid tumours are still urgently needed. Clinically available antibodies belong to the IgG class, the most prevalent antibody class in human blood, while other classes have not been extensively considered. We hypothesised that the unique properties of IgE, a class of tissue-resident antibodies commonly associated with allergies, which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumours such as ovarian and breast carcinomas. Our laboratory has examined this concept by evaluating two chimaeric antibodies of the same specificity (MOv18) but different isotype, an IgG1 and an IgE against the tumour antigen folate receptor α (FRα). The latter demonstrates the potency of IgE to mount superior immune responses against tumours in disease-relevant models. We identified Fcε receptor-expressing cells, monocytes/macrophages and eosinophils, activated by MOv18 IgE to kill tumour cells by mechanisms such as ADCC and ADCP. We also applied this notion to a marketed therapeutic, the humanised IgG1 antibody trastuzumab and engineered an IgE counterpart, which retained the functions of trastuzumab in restricting proliferation of HER2/neu-expressing tumour cells but also activated effector cells to kill tumour cells by different mechanisms. On-going efficacy, safety evaluations and future first-in-man clinical studies of IgE therapeutics constitute key metrics for this concept, providing new scope for antibody immunotherapies for solid tumours.

Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

Purpose: AS1409 is a fusion protein comprising a humanized antibody BC1 linked to interleukin-12 (IL-12). It is designed to deliver IL-12 to tumor-associated vasculature using an antibody targeting the ED-B variant of fibronectin., Experimental Design: We conducted a phase 1 trial of weekly infusional AS1409 in renal carcinoma and malignant melanoma patients. Safety, efficacy, markers of IL-12-mediated immune response, and pharmacokinetics were evaluated., Results: A total of 11 melanoma and 2 renal cell carcinoma patients were treated. Doses of 15 and 25 μg/kg were studied. Most drug-related adverse events were grade 2 or less, and included pyrexia, fatigue, chills, headache, vomiting, and transient liver function abnormalities. Three dose limiting toxicities of grade 3 fatigue and transaminase elevation were seen at 25 μg/kg. IFN-γ and interferon-inducible protein-10 (IP-10) were elevated in all patients, indicating activation of cell-mediated immune response; this was attenuated at subsequent cycles. Antidrug antibody responses were seen in all patients, although bioassays indicate these do not neutralize AS1409 activity. Plasma half-life was 22 hours and not dose-dependent. Five patients received 6 cycles or more and a best response of at least stable disease was seen in 6 (46%) patients. Partial response was seen in a melanoma patient, and disease shrinkage associated with metabolic response was maintained beyond 12 months in another melanoma patient despite previous rapid progression., Conclusions: The maximum tolerated dose was established at 15 μg/kg weekly. AS1409 is well tolerated at this dose. Evidence of efficacy assessed by RECIST, functional imaging, and biomarker response warrants the planned further investigation using this dose and schedule in malignant melanoma.

Trastuzumab (Herceptin), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab.

Previous studies have investigated the expression of insulin-like growth factor-I (IGF-I) and its receptor in cultured skin cells or in whole skin. In order to fully understand the role of IGF-I in the skin and its appendages, however, a comprehensive study that details the expression of IGF-I and the IGF-I receptor in sections of human skin is needed. Therefore, we now report an immunocytochemical and in situ hybridization localization study of the cell types expressing IGF-I and its receptor in human adult skin and its appendages. We have observed that (i) dermal fibroblasts produce IGF-I, (ii) the epidermal basal keratinocytes are IGF-I negative but IGF-I receptor positive, and (iii) the keratinocytes of the stratum granulosum produce IGF-I. These observations indicate either that the mitogenesis of the basal keratinocytes is regulated by IGF-I expressed both in the dermis and in the stratum granulosum, or that dermal fibroblasts are responsible for sequestering IGF-I to the basal keratinocytes and that the stratum granulosum-derived IGF-I may be an autocrine regulator of epidermal differentiation. The distribution of IGF-I and its receptor in the hair follicle indicates that IGF-I may be a morphogen, not a mitogen, at those sites, because their proliferating cells, but not their differentiating cells, are IGF-I receptor negative. Further, IGF-I receptor expression by the dermal papilla appears to be switched off during the transition from anagen to catagen, which implies a regulatory role for IGF-I during the hair growth cycle.