Radiotherapy of benign disorders

The radiation oncologist's primary concern is treatment of patients with malignant tumors but sometimes faces on occasion rare, non malignant disorders. The scarcity of disease incidence is reflected by the paucity of references for these diseases in the literature. This minimal exchange of information may make research and analysis difficult, tedious and not easily directed. Even with recognition of the risks of late skin injury, carcinogenesis, leukemogenesis and genetic damage from all ionizing radiation, radiation therapy also continues to be accepted treatment for benign diseases that do not respond to other methods of therapy. The purpose of this paper is to provide a short overview of the radiotherapy of most frequent benign disorders.     

Modelling the introduction and spread of non‐native species: international trade and climate change drive ragweed invasion

Biological invasions are a major driver of global change, for which models can attribute causes, assess impacts and guide management. However, invasion models typically focus on spread from known introduction points or non‐native distributions and ignore the transport processes by which species arrive. Here, we developed a simulation model to understand and describe plant invasion at a continental scale, integrating repeated transport through trade pathways, unintentional release events and the population dynamics and local anthropogenic dispersal that drive subsequent spread. We used the model to simulate the invasion of Europe by common ragweed (Ambrosia artemisiifolia), a globally invasive plant that causes serious harm as an aeroallergen and crop weed. Simulations starting in 1950 accurately reproduced ragweed's current distribution, including the presence of records in climatically unsuitable areas as a result of repeated introduction. Furthermore, the model outputs were strongly correlated with spatial and temporal patterns of ragweed pollen concentrations, which are fully independent of the calibration data. The model suggests that recent trends for warmer summers and increased volumes of international trade have accelerated the ragweed invasion. For the latter, long distance dispersal because of trade within the invaded continent is highlighted as a key invasion process, in addition to import from the native range. Biosecurity simulations, whereby transport through trade pathways is halted, showed that effective control is only achieved by early action targeting all relevant pathways. We conclude that invasion models would benefit from integrating introduction processes (transport and release) with spread dynamics, to better represent propagule pressure from native sources as well as mechanisms for long‐distance dispersal within invaded continents. Ultimately, such integration may facilitate better prediction of spatial and temporal variation in invasion risk and provide useful guidance for management strategies to reduce the impacts of invasion.     

Malthusian Parameters as Estimators of the Fitness of Microbes: A Cautionary Tale about the Low Side of High Throughput

The maximum exponential growth rate, the Malthusian parameter (MP), is commonly used as a measure of fitness in experimental studies of adaptive evolution and of the effects of antibiotic resistance and other genes on the fitness of planktonic microbes. Thanks to automated, multi-well optical density plate readers and computers, with little hands-on effort investigators can readily obtain hundreds of estimates of MPs in less than a day. Here we compare estimates of the relative fitness of antibiotic susceptible and resistant strains of E. coli, Pseudomonas aeruginosa and Staphylococcus aureus based on MP data obtained with automated multi-well plate readers with the results from pairwise competition experiments. This leads us to question the reliability of estimates of MP obtained with these high throughput devices and the utility of these estimates of the maximum growth rates to detect fitness differences.     

Evolution of the nucleotide sequence of influenza virus RNA segment 7 during drift of the H3N2 subtype

The complete genetic information contained in the influenza virus RNA segment 7 of the A/Bangkok/ $\text{1}\text{79}$ (H3N2) strain has been cloned by in vitro synthesis of the complementary dsDNA and its insertion into plasmid pBR322. The nucleotide sequence of the viral RNA segment has been determined from the cDNA insert. It is 1027 nucleotides long, and contains two open reading frames, as shown for other influenza virus strains. When compared with the previously published sequence for the A/Udorn/72 (H3N2) strain, 15 nucleotide exchanges are observed, most of them silent mutations, and only two causing amino acid changes in each of the M1 and M2 protein sequences.     

Estrogen-mediated up-regulation of the Ca-dependent constitutive nitric oxide synthase in the rat aorta and heart

The role of endogenous estrogens has been studied in the regulation of the Ca-dependent constitutive nitric oxide synthase (cNOS) enzyme activity in aortic and cardiac tissues of the rat. The activity of cNOS enzyme was measured by the citrulline assay in the abdominal aorta and in the left ventricle of the heart obtained from male, sham-operated female and ovariectomized female Wistar rats. Estrogen replacement therapy (17-beta-estradiol, 20-100 microg/kg/day, s.c.) has been performed in ovariectomized rats over two weeks. We found that cNOS activity was higher in the aorta and heart of female rats compared to males. Ovariectomy decreased cNOS activity in both tissues to that level what could be observed in males. Estrogen supplementation caused a dose-dependent elevation of cNOS enzyme activity in cardiac and aortic tissues, where the higher dose (100 microg) completely restored cNOS enzyme activity to the levels found in females. We concluded that endogenous estrogens up-regulate the activity of the cNOS isoenzymes in the rat aorta and heart.     

Re-Mind the Gap! Insertion – Deletion Data Reveal Neglected Phylogenetic Potential of the Nuclear Ribosomal Internal Transcribed Spacer (ITS) of Fungi

Rapidly evolving, indel-rich phylogenetic markers play a pivotal role in our understanding of the relationships at multiple levels of the tree of life. There is extensive evidence that indels provide conserved phylogenetic signal, however, the range of phylogenetic depths for which gaps retain tree signal has not been investigated in detail. Here we address this question using the fungal internal transcribed spacer (ITS), which is central in many phylogenetic studies, molecular ecology, detection and identification of pathogenic and non-pathogenic species. ITS is repeatedly criticized for indel-induced alignment problems and the lack of phylogenetic resolution above species level, although these have not been critically investigated. In this study, we examined whether the inclusion of gap characters in the analyses shifts the phylogenetic utility of ITS alignments towards earlier divergences. By re-analyzing 115 published fungal ITS alignments, we found that indels are slightly more conserved than nucleotide substitutions, and when included in phylogenetic analyses, improved the resolution and branch support of phylogenies across an array of taxonomic ranges and extended the resolving power of ITS towards earlier nodes of phylogenetic trees. Our results reconcile previous contradicting evidence for the effects of data exclusion: in the case of more sophisticated indel placement, the exclusion of indel-rich regions from the analyses results in a loss of tree resolution, whereas in the case of simpler alignment methods, the exclusion of gapped sites improves it. Although the empirical datasets do not provide to measure alignment accuracy objectively, our results for the ITS region are consistent with previous simulations studies alignment algorithms. We suggest that sophisticated alignment algorithms and the inclusion of indels make the ITS region and potentially other rapidly evolving indel-rich loci valuable sources of phylogenetic information, which can be exploited at multiple taxonomic levels.     

Effect of the Gas6 c.834+7G>A Polymorphism and the Interaction of Known Risk Factors on AMD Pathogenesis in Hungarian Patients

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26–0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30–393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98–12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD.     

Expression pattern of Filamin-240 in Drosophila blood cells

The expression pattern of Filamin-240 was studied in subsets of Drosophila blood cells by means of immunofluorescent staining and Western blot analysis with use of an antibody specific to a "filamin-folding domain", a consensus motif profile generated from the 20 existing filamin repeats. Expression of Filamin-240 is restricted to lamellocytes - a special blood cell type of the cellular immune response - and is involved in the regulation of lamellocyte development. In the cher1 homozygous larvae, which lack Filamin-240 protein, a vigorous lamellocyte differentiation occurs which is further enhanced upon in vivo immune challenge by a parasitic wasp, Leptopilina boulardi. By introducing a full-length transgene encoding the Drosophila Filamin-240 protein into the cher1 Filamin-deficient homozygous mutant, the mutant blood cell phenotype was rescued. These data demonstrate that the expression of Filamin-240 is strictly lamellocyte specific in Drosophila blood cells and that the protein is a suppressor of lamellocyte development.     

Structural determinants of tissue tropism and in vivo pathogenicity for the parvovirus minute virus of mice

Two strains of the parvovirus minute virus of mice (MVM), the immunosuppressive (MVMi) and the prototype (MVMp) strains, display disparate in vitro tropism and in vivo pathogenicity. We report the crystal structures of MVMp virus-like particles (MVMp(b)) and native wild-type (wt) empty capsids (MVMp(e)), determined and refined to 3.25 and 3.75 A resolution, respectively, and their comparison to the structure of MVMi, also refined to 3.5 A resolution in this study. A comparison of the MVMp(b) and MVMp(e) capsids showed their structures to be the same, providing structural verification that some heterologously expressed parvovirus capsids are indistinguishable from wt capsids produced in host cells. The structures of MVMi and MVMp capsids were almost identical, but local surface conformational differences clustered from symmetry-related capsid proteins at three specific domains: (i) the icosahedral fivefold axis, (ii) the "shoulder" of the protrusion at the icosahedral threefold axis, and (iii) the area surrounding the depression at the icosahedral twofold axis. The latter two domains contain important determinants of MVM in vitro tropism (residues 317 and 321) and forward mutation residues (residues 399, 460, 553, and 558) conferring fibrotropism on MVMi. Furthermore, these structural differences between the MVM strains colocalize with tropism and pathogenicity determinants mapped for other autonomous parvovirus capsids, highlighting the importance of common parvovirus capsid regions in the control of virus-host interactions.