Xenopatients 2.0: Reprogramming the epigenetic landscapes of patient-derived cancer genomes

In the science-fiction thriller film Minority Report, a specialized police department called “PreCrime” apprehends criminals identified in advance based on foreknowledge provided by 3 genetically altered humans called “PreCogs”. We propose that Yamanaka stem cell technology can be similarly used to (epi)genetically reprogram tumor cells obtained directly from cancer patients and create self-evolving personalized translational platforms to foresee the evolutionary trajectory of individual tumors. This strategy yields a large stem cell population and captures the cancer genome of an affected individual, i.e., the PreCog-induced pluripotent stem (iPS) cancer cells, which are immediately available for experimental manipulation, including pharmacological screening for personalized “stemotoxic” cancer drugs. The PreCog-iPS cancer cells will re-differentiate upon orthotopic injection into the corresponding target tissues of immunodeficient mice (i.e., the PreCrime-iPS mouse avatars), and this in vivo model will run through specific cancer stages to directly explore their biological properties for drug screening, diagnosis, and personalized treatment in individual patients. The PreCog/PreCrime-iPS approach can perform sets of comparisons to directly observe changes in the cancer-iPS cell line vs. a normal iPS cell line derived from the same human genetic background. Genome editing of PreCog-iPS cells could create translational platforms to directly investigate the link between genomic expression changes and cellular malignization that is largely free from genetic and epigenetic noise and provide proof-of-principle evidence for cutting-edge “chromosome therapies” aimed against cancer aneuploidy. We might infer the epigenetic marks that correct the tumorigenic nature of the reprogrammed cancer cell population and normalize the malignant phenotype in vivo. Genetically engineered models of conditionally reprogrammable mice to transiently express the Yamanaka stemness factors following the activation of phenotypic copies of specific cancer diseases might crucially evaluate a “reprogramming cure” for cancer. A new era of xenopatients 2.0 generated via nuclear reprogramming of the epigenetic landscapes of patient-derived cancer genomes might revolutionize the current personalized translational platforms in cancer research.     

Speciation in Pararge (Satyrinae: Nymphalidae) butterflies – North Africa is the source of ancestral populations of all Pararge species

Abstract.  The genus Pararge comprises three species: P. aegeria , distributed in Europe and North Africa; P. xiphia , endemic to Madeira; and P. xiphioides , endemic to the Canary Islands. Two subspecies are recognized in P. aegeria , P. a. tircis and P. a. aegeria , distributed in northern and southern Europe, respectively. In the 1970s, P. aegeria appeared on Madeira. However, despite the status of P. aegeria as a model species in ecological studies, the evolutionary history of Pararge remains unknown. We studied the phylogenetic relationships of the three Pararge species, using the mitochondrial gene cytochrome oxidase subunit I and the nuclear gene wingless to infer modes and times of speciation. On the basis of our analyses, Pararge forms a strongly supported monophyletic group, with the DNA haplotypes of the three species also forming well-supported monophyletic groups. We found that P. xiphia diverged first from the common ancestor a maximum of five million years ago, with P. xiphioides and P. aegeria being sister species that diverged a maximum of three million years ago. The two subspecies, P. a. tircis and P. a. aegeria , were not distinguishable on the basis of DNA haplotypes; instead, our data clearly distinguished between European specimens and those from North Africa. Madeiran P. aegeria has North African haplotypes and thus originated from there rather than from Europe. We hypothesize that the Mediterranean Sea forms a strong barrier to dispersal for Pararge butterflies, and has done so for approximately the past one million years.     

AUTOTOMY IN ARIONID AND LIMACID SLUGS

The occurrence of autotomy was investigated in five terrestrialslug species. Half of the Dcroceras reticulatum and 80 per centof the Limax tenellus slugs which were stimulated mechanicallyin the tail, autotomized the tail. Anon fasciatus, Anon subfuscusand Limax cinereoniger did not show any signs of being ableto autotomize. The autotomized tail of D. rcticulatum and L.tenellus was small compared to the total body weight and alsoto the weight of many predaceous beetles. D. reticulatum andL. tenellus escaped in a few seconds after the beginning ofmechanical stimulation; the reaction time was significantlyshorter than that used by species which did not autotomize theirtail. Comparison between A. fasciatus and D. reticulatum alsoshowed that D. reticulatum sought for refuges significantlymore effectively than A. fasciatus. The exposure of D. reticulatumto the beetle Ptero-stichus mger indicated that autotomy canstop a beetle long enough to let the slug escape. It seems thatautotomy has evolved more frequently in those species whichrely to a great extent on escaping and hiding when defendingthemselves, than in species whose physiology and/or environmentdo not enable them to hide quickly after an attack. (Received 18 February 1993; accepted 19 March 1993)     

THE IMPORTANCE OF MUCUS AS A DEFENCE AGAINST CARABID BEETLES BY THE SLUGS ARION FASCIATUS AND DEROCERAS RETICULATUM

The effect of mucus exudation on the survival of Arion fasciatusand Deroceras reticulatum was studied by exposing mechanicallystimulated and control slugs to Carabidae beetles for 24 hours.A light stimulation, lasting three minutes, exhausted the copiousflow of mucus for one day. A generalist, Pterostichus niger,significantly preferred stressed D. reticulatum over controlones. Similarly, P. niger exclusively ate stressed individualsof A. fasciatus. Two beetles which specialize in gastropods,Cychrus caraboides and Carabus violaceus, consumed an equalnumber of stressed and control D. reticulatum and A. fasciatus.The susceptibility of the slug species to predation was different:for each beetle species, the proportion of available D. reticulatumpreyed upon was significantly higher than that of A. fasciatus.The differences in the behaviour of A. fasciatus and D. reticulatumin defending themselves against attacks is described. The mainreason why specialist beetles are able to hunt slugs successfullyis their ability to prevent the slugs from exuding large amountsof mucus. This may succeed by different means: C. violaceustargeted their killing strokes against the posterior part ofthe mantle while C. caraboides hit the head of the slug. Inboth case the strokes seemed to paralyze the slugs. (Received 31 March 1993; accepted 1 October 1993)     

FEEDING A VOIDANCE OF TERRESTRIAL GASTROPODS TO CONSPECIFIC AND NONSPECIFIC MATERIAL

In laboratory tests the terrestrial gastropods Arion fasciatus,Deroceras reticulatum, Arianta arbustorum and Bradybaena fruticumpreferred control leaf discs over discs treated with an aqueoussuspension of crushed conspecifics. The response to suspensionsof different species was weaker. The strength of the responseincreased with the concentration of the suspension. The suspension'seffect in deterring feeding was inactivated within 18 to 32hours. Hunger reduced normal responsiveness to conspecific fluids;the quality of the control food also affected the response.The results also imply that ranking among individuals is labile.Spraying lettucc with the suspension affected the dispersalof the animals only in early summer. The article discusses thebiological significance of the response and the use of substancesobtained from slugs and snails in the control of pest gastropods. (Received 21 March 1991; accepted 5 September 1991)