Recombination in the Evolution of Enterovirus C Species Sub-Group that Contains Types CVA-21, CVA-24, EV-C95, EV-C96 and EV-C99

Genetic recombination is considered to be a very frequent phenomenon among enteroviruses (Family Picornaviridae, Genus Enterovirus). However, the recombination patterns may differ between enterovirus species and between types within species. Enterovirus C (EV-C) species contains 21 types. In the capsid coding P1 region, the types of EV-C species cluster further into three sub-groups (designated here as A–C). In this study, the recombination pattern of EV-C species sub-group B that contains types CVA-21, CVA-24, EV-C95, EV-C96 and EV-C99 was determined using partial 5′UTR and VP1 sequences of enterovirus strains isolated during poliovirus surveillance and previously published complete genome sequences. Several inter-typic recombination events were detected. Furthermore, the analyses suggested that inter-typic recombination events have occurred mainly within the distinct sub-groups of EV-C species. Only sporadic recombination events between EV-C species sub-group B and other EV-C sub-groups were detected. In addition, strict recombination barriers were inferred for CVA-21 genotype C and CVA-24 variant strains. These results suggest that the frequency of inter-typic recombinations, even within species, may depend on the phylogenetic position of the given viruses.     

Mouse epidermal growth factor concentrations are altered by gonadectomy and treatments with estradiol and progesterone

In adult male and female mice we compared the epidermal growth factor (EGF) concentrations after gonadectomy and studied the effects of postgonadectomy treatments with estradiol and progesterone. In gonadectomized mice the mean concentration of EGF in the submandibular salivary gland (SMG) was (7-fold) higher in the females than the males. In the kidneys the males had (1.3-fold) higher levels of EGF than the females. Yet, gonadectomized males had higher plasma EGF levels and females higher urinary EGF concentrations. Estradiol treatment clearly decreased the EGF concentration in the SMG and increased it in urine and kidneys. Progesterone decreased male kidney EGF. Combined treatment with estradiol and progesterone increased the EGF concentration in the male urine and SMG, and decreased it in male kidneys.     

Long-term effects of ionising radiation on the brain: cause for concern?

There is no clear evidence proving or disproving that ionising radiation is causally linked with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. However, it is known that high doses of ionising radiation to the head (20–50 Gy) lead to severe learning and memory impairment which is characteristical for Alzheimer’s. The cumulative doses of ionising radiation to the Western population are accruing, mostly due to the explosive growth of medical imaging procedures. Children are in particular prone to ionising radiation as the molecular processes within the brain are not completely finished. Furthermore, they have a long lifespan under risk. We wish to open a debate if such low doses of radiation exposure may lead to delayed long-term cognitive and other defects, albeit at a lower frequency than those observed during application of high doses. Further, we want to sensitise the society towards the risks of ionising radiation. To achieve these aims, we will recapitulate the known symptoms of Parkinson’s and Alzheimer’s on the molecular level and incorporate data of mainly low- and moderate-ionising radiation (<5 Gy). Thus, we want to highlight in general the potential similarities of both the neurodegenerative and radiation-induced pathways. We will propose a mechanistic model for radiation-induced neurodegeneration pointing out mitochondria as a key element. This includes effects of oxidative stress and neuroinflammation—all fundamental players of neurodegenerative diseases.     

Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

Background and methods

Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects.

Results

We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand.

Conclusions

Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies.     

Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation

Accidental nuclear scenarios lead to environmental contamination of unknown level. Immediate radiation‐induced biological responses that trigger processes leading to adverse health effects decades later are not well understood. A comprehensive proteomic analysis provides a promising means to identify and quantify the initial damage after radiation exposure. Early changes in the cardiac tissue of C57BL/6 mice exposed to total body irradiation were studied, using a dose relevant to both intentional and accidental exposure (3 Gy gamma ray). Heart tissue protein lysates were analyzed 5 and 24 h after the exposure using isotope‐coded protein labeling (ICPL) and 2‐dimensional difference‐in‐gel‐electrophoresis (2‐D DIGE) proteomics approaches. The differentially expressed proteins were identified by LC‐ESI‐MS‐MS. Both techniques showed similar functional groups of proteins to be involved in the initial injury. Pathway analyses indicated that total body irradiation immediately induced biological responses such as inflammation, antioxidative defense, and reorganization of structural proteins. Mitochondrial proteins represented the protein class most sensitive to ionizing radiation. The proteins involved in the initial damage processes map to several functional categories involving cardiotoxicity. This prompts us to propose that these early changes are indicative of the processes that lead to an increased risk of cardiovascular disease after radiation exposure.     

Differential Roles of Fibroblast Growth Factor Receptors (FGFR) 1, 2 and 3 in the Regulation of S115 Breast Cancer Cell Growth

Fibroblast growth factors (FGFs) regulate the growth and progression of breast cancer. FGF signaling is transduced through FGF receptors 1–4, which have oncogenic or anti-oncogenic roles depending on the ligand and the cellular context. Our aim was to clarify the roles of FGFR1–3 in breast cancer cell growth in vitro and in vivo. Pools of S115 mouse breast cancer cells expressing shRNA against FGFR1, 2 and 3 were created by lentiviral gene transfer, resulting in cells with downregulated expression of FGFR1, FGFR2 or FGFR3 (shR1, shR2 and shR3 cells, respectively) and shLacZ controls. FGFR1-silenced shR1 cells formed small, poorly vascularized tumors in nude mice. Silencing of FGFR2 in shR2 cells was associated with strong upregulation of FGFR1 expression and the formation of large, highly vascularized tumors compared to the control tumors. Silencing FGFR3 did not affect cell survival or tumor growth. Overexpressing FGFR2 in control cells did not affect FGFR1 expression, suggesting that high FGFR1 expression in shR2 cells and tumors was associated with FGFR2 silencing by indirect mechanisms. The expression of FGFR1 was, however, increased by the addition of FGF-8 to starved shLacZ or MCF-7 cells and decreased by the FGFR inhibitor PD173074 in shR2 cells with an elevated FGFR1 level. In conclusion, our results demonstrate that FGFR1 is crucial for S115 breast cancer cell proliferation and tumor growth and angiogenesis, whereas FGFR2 and FGFR3 are less critical for the growth of these cells. The results also suggest that the expression of FGFR1 itself is regulated by FGF-8 and FGF signaling, which may be of importance in breast tumors expressing FGFs at a high level.     

FGF‐8b induces growth and rich vascularization in an orthotopic PC‐3 model of prostate cancer

Fibroblast growth factor 8 (FGF‐8) is expressed at an increased level in a high proportion of prostate cancers and it is associated with a poor prognosis of the disease. Our aim was to study the effects of FGF‐8b on proliferation of PC‐3 prostate cancer cells and growth of PC‐3 tumors, and to identify FGF‐8b‐associated molecular targets. Expression of ectopic FGF‐8b in PC‐3 cells caused a 1.5‐fold increase in cell proliferation in vitro and a four‐ to fivefold increase in the size of subcutaneous and orthotopic prostate tumors in nude mice. Tumors expressing FGF‐8b showed a characteristic morphology with a very rich network of capillaries. This was associated with increased spread of the cancer cells to the lungs as measured by RT‐qPCR of FGF‐8b mRNA. Microarray analyses revealed significantly altered, up‐ and downregulated, genes in PC‐3 cell cultures (169 genes) and in orthotopic PC‐3 tumors (61 genes). IPA network analysis of the upregulated genes showed the strongest association with development, cell proliferation (CRIP1, SHC1), angiogenesis (CCL2, DDAH2), bone metastasis (SPP1), cell‐to‐cell signaling and energy production, and the downregulated genes associated with differentiation (DKK‐1, VDR) and cell death (CYCS). The changes in gene expression were confirmed by RT‐qPCR. In conclusion, our results demonstrate that FGF‐8b increases the growth and angiogenesis of orthotopic prostate tumors. The associated gene expression signature suggests potential mediators for FGF‐8b actions on prostate cancer progression and metastasis. J. Cell. Biochem. 107: 769–784, 2009. © 2009 Wiley‐Liss, Inc.     

Arsenic in the aetiology of cancer

Arsenic, one of the most significant hazards in the environment affecting millions of people around the world, is associated with several diseases including cancers of skin, lung, urinary bladder, kidney and liver. Groundwater contamination by arsenic is the main route of exposure. Inhalation of airborne arsenic or arsenic-contaminated dust is a common health problem in many ore mines. This review deals with the questions raised in the epidemiological studies such as the dose-response relationship, putative confounders and synergistic effects, and methods evaluating arsenic exposure. Furthermore, it describes the metabolic pathways of arsenic, and its biological modes of action. The role of arsenic in the development of cancer is elucidated in the context of combined epidemiological and biological studies. However, further analyses by means of molecular epidemiology are needed to improve the understanding of cancer aetiology induced by arsenic.