A tumor-homing peptide with a targeting specificity related to lymphatic vessels

Blood vessels of tumors carry specific markers that are usually angiogenesis-related. We previously used phage-displayed peptide libraries in vivo to identify peptides that home to tumors through the circulation and that specifically bind to the endothelia of tumor blood vessels. Here we devised a phage screening procedure that would favor tumor-homing to targets that are accessible to circulating phage, but are not blood vessels. Screening on MDA-MB-435 breast carcinoma xenografts yielded multiple copies of a phage that displays a cyclic 9-amino-acid peptide, LyP-1. Homing and binding to tumor-derived cell suspensions indicated that LyP-1 also recognizes an osteosarcoma xenograft, and spontaneous prostate and breast cancers in transgenic mice, but not two other tumor xenografts. Fluorescein-labeled LyP-1 peptide was detected in tumor structures that were positive for three lymphatic endothelial markers and negative for three blood vessel markers. LyP-1 accumulated in the nuclei of the putative lymphatic cells, and in the nuclei of tumor cells. These results suggest that tumor lymphatics carry specific markers and that it may be possible to specifically target therapies into tumor lymphatics.     

A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors

A delicate balance of signals regulates cell survival. One set of these signals is derived from integrin-mediated cell adhesion to the extracellular matrix (ECM). Loss of cell attachment to the ECM causes apoptosis, a process known as anoikis. In searching for proteins involved in cell adhesion-dependent regulation of anoikis, we identified Bit1, a mitochondrial protein that is released into the cytoplasm during apoptosis. Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein, and induces cell death with characteristics of caspase-independent apoptosis. Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES. Increasing Bit1 expression enhances anoikis, while suppressing the expression reduces it. Thus, we have elucidated an integrin-controlled pathway that is, at least in part, responsible for the cell survival effects of cell-ECM interactions.     

Male-female Parental Roles in Sarotherodon galilaeus (Pisces: Cichlidae)

Sarotherodon galilaeus is a predominantly biparental, sexually monomorphic mouthbrooder. 15 spawnings of pairs in the weight range 150–450 g were observed in aquaria. Only clutches of females larger than 320 g were reared jointly; with those of smaller females, the first fish to pick up eggs brooded alone, while the comparatively few eggs left for the second fish were invariably eaten. The latency after which eggs were picked up increased with the duration of spawning and indirectly with fish size. This increase was larger in males than in females, so large males started to collect eggs later than their mates. In small pairs (female weight < 200 g), by contrast, the male would pick up eggs first and carry them alone. This is the case in a smaller congeneric species, S. melanotheron, indicating that the apportioning of broodcare is based on a unitary, size-dependent mechanism among Sarotherodon. Yet picking-up order was not entirely determined by these equations. Some fish did not show any reaction towards the eggs and occasionally males became care-givers despite expected longer latency, seemingly because of aggressive dominance.     

Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans

A single-nucleotide variant, C/T(-13910), located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T(-13910) variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8-H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T(-13910) H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T(-13910) H98 allele (approximately 5,000-12,000 years old) is relatively older than the other geographically restricted LP alleles (approximately 1,400-3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T(-13910) allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans.     

Lethal interactions among vertebrate top predators: a review of concepts,assumptions and terminology

Lethal interactions among large vertebrate predators have long interested researchers because of ecological and conservation issues. Research focusing on lethal interactions among vertebrate top predators has used several terms with a broad sense, and also introduced new terminology. We analysed the published literature with reference to the main underlying concepts and the use of terminology and its ecological context. The most frequently used terms in the literature were ‘predation’, ‘intraguild predation’, ‘interference competition’, and ‘interspecific killing’. Most studies presented evidence of the killing of the victim (77%), but information regarding its consumption was not given in 48% of cases. More than half of the analysed studies (56%) had no solid information on the degree of competition between interacting species. By reviewing definitions and their underlying assumptions, we demonstrate that lethal interactions among large vertebrate predators could be designated using four terms—‘predation’, ‘intraguild predation’, ‘interspecific competitive killing’, and ‘superpredation’—without the need to employ additional terminology that may increase confusion and misuse. For a correct framework of these lethal interactions it is critical to assess if the kill is consumed, if the victim is indeed a competitor of the killer, and if the prey is a high‐order predator. However, these elements of the framework are simultaneously the most common constraints to studies of lethal interactions, since they often require a great effort to obtain. The proper use of terms and concepts is fundamental to understanding the causes behind lethal interactions and, ultimately, what is actually happening in these complex interactions.     

Predator–vole interactions in northern Europe: the role of small mustelids revised

The cyclic population dynamics of vole and predator communities is a key phenomenon in northern ecosystems, and it appears to be influenced by climate change. Reports of collapsing rodent cycles have attributed the changes to warmer winters, which weaken the interaction between voles and their specialist subnivean predators. Using population data collected throughout Finland during 1986–2011, we analyse the spatio-temporal variation in the interactions between populations of voles and specialist, generalist and avian predators, and investigate by simulations the roles of the different predators in the vole cycle. We test the hypothesis that vole population cyclicity is dependent on predator–prey interactions during winter. Our results support the importance of the small mustelids for the vole cycle. However, weakening specialist predation during winters, or an increase in generalist predation, was not associated with the loss of cyclicity. Strengthening of delayed density dependence coincided with strengthening small mustelid influence on the summer population growth rates of voles. In conclusion, a strong impact of small mustelids during summers appears highly influential to vole population dynamics, and deteriorating winter conditions are not a viable explanation for collapsing small mammal population cycles.     

Varying impacts of cervid, hare and vole browsing on growth and survival of boreal tree seedlings

The negative impacts of mammalian herbivores on plants have been studied quite extensively, but typically with only a single herbivore species at a time. We conducted a novel comparison of the browsing effects of voles, hares and cervids upon the growth and survival of boreal tree seedlings. This was done by excluding varying assemblages of these key mammalian herbivores from silver birch, Scots pine and Norway spruce seedlings for 3 years. We hypothesised that the pooled impacts of the herbivores would be greater than that of any individual group, while the cervids would be the group with the strongest impact. Growth of birch seedlings advanced when cervids were excluded whereas growth of seedlings accessible to cervids was hindered. Survival of all seedlings was lowest when they were accessible to voles and voles plus hares, whereas cervids seemed not to influence seedling survival. Our results show that the impact of herbivores upon woody plants can be potent in the boreal forests, but the mechanism and strength of this link depends on the tree and herbivore species in question. Risk of abated stand regeneration appears highest for the deciduous birch, though there is need for seedling protection also in coniferous stands. The clear cervid-mediated growth limitation of birch also indicates potential for a trophic cascade effect by mammalian top predators, currently returning to boreal ecosystems.     

Novel peptide inhibitors of human kallikrein 2

Human kallikrein 2 (hK2) is a serine protease produced by the secretory epithelial cells in the prostate. Because hK2 activates several factors participating in proteolytic cascades that may mediate metastasis of prostate cancer, modulation of the activity of hK2 is a potential way of preventing tumor growth and metastasis. Furthermore, specific ligands for hK2 are potentially useful for targeting and imaging of prostate cancer and for assay development. We have used enzymatically active recombinant hK2 captured by a monoclonal antibody exposing the active site of the enzyme to screen phage display peptide libraries. Using libraries expressing 10 or 11 amino acids long linear peptides, we identified six different peptides binding to hK2. Three of these were shown to be specific and efficient inhibitors of the enzymatic activity of hK2 toward a peptide substrate. Furthermore, the peptides inhibited the activation of the proform of prostate-specific antigen by hK2. Amino acid substitution analyses revealed that motifs of six amino acids were required for the inhibitory activity. These peptides are potentially useful for treatment and targeting of prostate cancer.