Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives.

When eradication is impossible, cancer treatment aims to delay the emergence of resistance while minimizing cancer burden and treatment. Adaptive therapies may achieve these aims, with success based on three assumptions: resistance is costly, sensitive cells compete with resistant cells, and therapy reduces the population of sensitive cells. We use a range of mathematical models and treatment strategies to investigate the tradeoff between controlling cell populations and delaying the emergence of resistance. These models extend game theoretic and competition models with four additional components: 1) an Allee effect where cell populations grow more slowly at low population sizes, 2) healthy cells that compete with cancer cells, 3) immune cells that suppress cancer cells, and 4) resource competition for a growth factor like androgen. In comparing maximum tolerable dose, intermittent treatment, and adaptive therapy strategies, no therapeutic choice robustly breaks the three-way tradeoff among the three therapeutic aims. Almost all models show a tight tradeoff between time to emergence of resistant cells and cancer cell burden, with intermittent and adaptive therapies following identical curves. For most models, some adaptive therapies delay overall tumor growth more than intermittent therapies, but at the cost of higher cell populations. The Allee effect breaks these relationships, with some adaptive therapies performing poorly due to their failure to treat sufficiently to drive populations below the threshold. When eradication is impossible, no treatment can simultaneously delay emergence of resistance, limit total cancer cell numbers, and minimize treatment. Simple mathematical models can play a role in designing the next generation of therapies that balance these competing objectives.

Molecular data suggest that microsporidian parasites in freshwater snails are diverse.

Microsporidian parasites infect almost all invertebrate and vertebrate hosts and have significant effects on individual and population fitness. Phylogenetic analysis demonstrates that the phylum is highly divergent and that some lineages show strong associations with host taxa. We here examine the diversity and distribution of parasites in gastropod molluscs to test for host-parasite co-association. 16 populations representing 10 species of freshwater snails were screened using microsporidian specific small subunit rDNA primers. Four novel microsporidian parasite sequences were detected within populations of three host species from the genera Bulinus, Biomphalaria and Planorbis. Prevalence ranged from 5 to 84%. Phylogenetic analysis of these novel sequences reveals that they group together as a paraphyletic assemblage in the microsporidian tree basal to the two lineages containing the genera Encephalitozoon and Nosema. Preliminary observation of one microsporidian infection, show parasites distributed in all tissue systems of Bulinus globosus. However, infection is most prevalent in the digestive gland while also in the egg sacs, suggesting that the microsporidium is using a mixed strategy of horizontal and vertical transmission in this population.

Development and molecular characterisation of the microsporidian Schroedera airthreyi n. sp. in a freshwater bryozoan Plumatella sp. (Bryozoa: Phylactolaemata).

The development of a new species of microsporidian, infecting a freshwater Plumatellid bryozoan, is described. The small-subunit rDNA, internal transcribed spacer region (ITS), and partial large-subunit rDNA genes were sequenced. Phylogenetic analysis demonstrated that the parasite clustered with Schroedera plumatellae. However, while there were morphological affinities with this species, significant differences were also observed. The infection initially appeared as a roughening of the peritoneum lining the metacoelom of the bryozoan. This roughening resolved into meront-infected syncytia, composed of interconnected cells of the body wall that detached to float in the coleomic cavity. Spores were observed to develop within these syncytia. All stages of development were diplokaryotic in contrast to S. plumatellae, which has a distinct monokaryotic merogony preceding sporogony. The infection was pathogenic to the host. Direct bryozoan-bryozoan transmission was not observed. We propose to name the microsporidian Schroedera aithreyi n. sp.

Widespread vertical transmission and associated host sex-ratio distortion within the eukaryotic phylum Microspora.

Vertical transmission (VT) and associated manipulation of host reproduction are widely reported among prokaryotic endosymbionts. Here, we present evidence for widespread use of VT and associated sex-ratio distortion in a eukaryotic phylum. The Microspora are an unusual and diverse group of eukaryotic parasites that infect all animal phyla. Following our initial description of a microsporidian that feminizes its crustacean host, we survey the diversity and distribution of VT within the Microspora. We find that vertically transmitted microsporidia are ubiquitous in the amphipod hosts sampled and that they are also diverse, with 11 species of microsporidia detected within 16 host species. We found that infections were more common in females than males, suggesting that host sex-ratio distortion occurs in five out of eight parasite species tested. Phylogenetic reconstruction demonstrates that VT occurs in all major lineages of the phylum Microspora and that sex-ratio distorters are found on multiple branches of the phylogenetic tree. We propose that VT is either an ancestral trait or evolves with peculiar frequency in this phylum. If the association observed here between VT and host sex-ratio distortion holds true across other host taxa, these eukaryotic parasites may join the bacterial endosymbionts in their importance as sex-ratio distorters.

Invasion success of Fibrillanosema crangonycis, n.sp., n.g.: a novel vertically transmitted microsporidian parasite from the invasive amphipod host Crangonyx pseudogracilis.

Parasitism is known to be an important factor in determining the success of biological invasions. Here we examine Crangonyx pseudogracilis, a North American amphipod invasive in the United Kingdom and describe a novel microsporidium, Fibrillanosema crangonycis n.sp., n.g. The primary site of infection is the female gonad and the parasite is transovarially transmitted to the eggs. PCR screening reveals a female bias in the distribution of parasites (96.6% of females, N=29; 22.2% of males, N=27), which is indicative of host sex ratio distortion. The morphological and molecular characterisations of this new microsporidium place it outside all currently established genera. On the basis of these differences, we erect the new genus Fibrillanosema n.g. While F. crangonycis is morphologically identical to uncharacterised microsporidia from populations of North American amphipods, it is distinct from microsporidia found in European populations of amphipods. These data support the hypothesis that vertically transmitted parasites may be selectively retained during invasion events. Furthermore where vertical transmission is combined with host sex ratio distortion these parasites may directly enhance host invasion success through increased rates of population growth.

Parasite-mediated predation between native and invasive amphipods.

Parasites can structure biological communities directly through population regulation and indirectly by processes such as apparent competition. However, the role of parasites in the process of biological invasion is less well understood and mechanisms of parasite mediation of predation among hosts are unclear. Mutual predation between native and invading species is an important factor in determining the outcome of invasions in freshwater amphipod communities. Here, we show that parasites mediate mutual intraguild predation among native and invading species and may thereby facilitate the invasion process. We find that the native amphipod Gammarus duebeni celticus is host to a microsporidian parasite, Pleistophora sp. (new species), with a frequency of infection of 0-90%. However, the parasite does not infect three invading species, G. tigrinus, G. pulex and Crangonyx pseudogracilis. In field and laboratory manipulations, we show that the parasite exhibits cryptic virulence: the parasite does not affect host fitness in single-species populations, but virulence becomes apparent when the native and invading species interact. That is, infection has no direct effect on G. d. celticus survivorship, size or fecundity; however, in mixed-species experiments, parasitized natives show a reduced capacity to prey on the smaller invading species and are more likely to be preyed upon by the largest invading species. Thus, by altering dominance relationships and hierarchies of mutual predation, parasitism strongly influences, and has the potential to change, the outcome of biological invasions.

Resolution of a taxonomic conundrum: an ultrastructural and molecular description of the life cycle of Pleistophora mulleri (Pfeiffer 1895; Georgevitch 1929).

The classification of a microsporidian parasite observed in the abdominal muscles of amphipod hosts has been repeatedly revised but still remains inconclusive. This parasite has variable spore numbers within a sporophorous vesicle and has been assigned to the genera Glugea, Pleistophora, Stempellia, and Thelohania. We used electron microscopy and molecular evidence to resolve the previous taxonomic confusion and confirm its identification as Pleistophora mulleri. The life cycle of P. mulleri is described from the freshwater amphipod host Gammarus duebeni celticus. Infection appeared as white tubular masses within the abdominal muscle of the host. Light and transmission electron microscope examination revealed the presence of an active microsporidian infection that was diffuse within the muscle block with no evidence of xenoma formation. Paucinucleate merogonial plasmodia were surrounded by an amorphous coat immediately external to the plasmalemma. The amorphous coat developed into a merontogenetic sporophorous vesicle that was present throughout sporulation. Sporogony was polysporous resulting in uninucleate spores, with a bipartite polaroplast, an anisofilar polar filament and a large posterior vacuole. SSU rDNA analysis supported the ultrastructural evidence clearly placing this parasite within the genus Pleistophora. This paper indicates that Pleistophora species are not restricted to vertebrate hosts.