Global Epidemiology of Lung Cancer.

While lung cancer has been the leading cause of cancer-related deaths for many years in the United States, incidence and mortality statistics - among other measures - vary widely worldwide. The aim of this study was to review the evidence on lung cancer epidemiology, including data of international scope with comparisons of economically, socially, and biologically different patient groups. In industrialized nations, evolving social and cultural smoking patterns have led to rising or plateauing rates of lung cancer in women, lagging the long-declining smoking and cancer incidence rates in men. In contrast, emerging economies vary widely in smoking practices and cancer incidence but commonly also harbor risks from environmental exposures, particularly widespread air pollution. Recent research has also revealed clinical, radiologic, and pathologic correlates, leading to greater knowledge in molecular profiling and targeted therapeutics, as well as an emphasis on the rising incidence of adenocarcinoma histology. Furthermore, emergent evidence about the benefits of lung cancer screening has led to efforts to identify high-risk smokers and development of prediction tools. This review also includes a discussion on the epidemiologic characteristics of special groups including women and nonsmokers. Varying trends in smoking largely dictate international patterns in lung cancer incidence and mortality. With declining smoking rates in developed countries and knowledge gains made through molecular profiling of tumors, the emergence of new risk factors and disease features will lead to changes in the landscape of lung cancer epidemiology

Computational modeling of TC0583 as a putative component of the Chlamydia muridarum V-type ATP synthase complex and assessment of its protective capabilities as a vaccine antigen.

Numerous Chlamydia trachomatis proteins have been identified as potential subunit vaccines, of which the major outer-membrane protein (MOMP) has, so far, proven the most efficacious. Recently, subunit A of the V-type ATP synthase (ATPase; TC0582) complex was shown to elicit partial protection against infection. Computational modeling of a neighboring gene revealed a novel subunit of the V-type ATPase (TC0583). To determine if this newly identified subunit could induce protection and/or enhance the partial protection provided by subunit A alone, challenge studies were performed using a combination of these recombinant proteins. The TC0583 subunit alone and concurrently with TC0582, was used to vaccinate BALB/c mice utilizing CpG-1826 and Montanide ISA 720 VG as adjuvants. Vaccinated animals were challenged intranasally with Chlamydia muridarum and the course of the infection was followed. Mice immunized with individual antigens showed minimal alleviation of body weight reduction; however, mice immunized with TC0583 and TC0582 in combination, displayed weight loss levels close to those observed with MOMP. Importantly, immunization with a combination of recombinant subunit proteins reduced chlamydial inclusion forming units by approximately a log-fold. These protection levels support that, these highly conserved Chlamydia proteins, in combination with other antigens, may serve as potential vaccine candidates

Consistent avoidance of human disturbance over large geographical distances by a migratory bird

Recent work on animal personalities has demonstrated that individuals may show consistent behaviour across situations and contexts. These studies were often carried out in one location and/or during short time intervals. Many animals, however, migrate and spend their life in several geographically distinct locations, and they may either adopt behaviours specific to the local environment or keep consistent behaviours over ecologically distinct locations. Long-distance migratory species offer excellent opportunities to test whether the animals maintain their personalities over large geographical scale, although the practical difficulties associated with these studies have hampered such tests. Here, we demonstrate for the first time consistency in disturbance tolerance behaviour in a long-distance migratory bird, using the common crane Grus grus as an ecological model species. Cranes that hatched in undisturbed habitats in Finland choose undisturbed migratory stop-over sites in Hungary, 1300–2000 km away from their breeding ground. This is remarkable, because these sites are not only separated by large distances, they also differ ecologically: the breeding sites are wooded bogs and subarctic tundra, whereas the migratory stop-over sites are temperate zone alkaline grasslands. The significance of our study goes beyond evolutionary biology and behavioural ecology: local effects on behaviour may carry over large distances, and this hitherto hidden implication of habitat selection needs to be incorporated into conservation planning

Chlamydia trachomatis CT771 (nudH) is an asymmetric Ap4A hydrolase

Asymmetric diadenosine 5′,5′″-P1,P4-tetraphosphate (Ap4A) hydrolases are members of the Nudix superfamily that asymmetrically cleave the metabolite Ap4A into ATP and AMP while facilitating homeostasis. The obligate intracellular mammalian pathogen Chlamydia trachomatis possesses a single Nudix family protein, CT771. As pathogens that rely on a host for replication and dissemination typically have one or zero Nudix family proteins, this suggests that CT771 could be critical for chlamydial biology and pathogenesis. We identified orthologs to CT771 within environmental Chlamydiales that share active site residues suggesting a common function. Crystal structures of both apo- and ligand-bound CT771 were determined to 2.6 Å and 1.9 Å resolution, respectively. The structure of CT771 shows a αβα-sandwich motif with many conserved elements lining the putative Nudix active site. Numerous aspects of the ligand-bound CT771 structure mirror those observed in the ligand-bound structure of the Ap4A hydrolase from Caenorhabditis elegans. These structures represent only the second Ap4A hydrolase enzyme member determined from eubacteria and suggest that mammalian and bacterial Ap4A hydrolases might be more similar than previously thought. The aforementioned structural similarities, in tandem with molecular docking, guided the enzymatic characterization of CT771. Together, these studies provide the molecular details for substrate binding and specificity, supporting the analysis that CT771 is an Ap4A hydrolase (nudH)

Orally Active MMP-1 Sparing α-tetrahydropyranyl and α-piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP’s-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds

MMP-13 Selective α-sulfone Hydroxamates: a Survey of P1\u27 Heterocyclic Amide Isosteres

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows \u3e400-fold selectivity versus MMP-8 and \u3e600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented

A differential method for bounding the ground state energy

For a wide class of Hamiltonians, a novel method to obtain lower and upper bounds for the lowest energy is presented. Unlike perturbative or variational techniques, this method does not involve the computation of any integral (a normalisation factor or a matrix element). It just requires the determination of the absolute minimum and maximum in the whole configuration space of the local energy associated with a normalisable trial function (the calculation of the norm is not needed). After a general introduction, the method is applied to three non-integrable systems: the asymmetric annular billiard, the many-body spinless Coulombian problem, the hydrogen atom in a constant and uniform magnetic field. Being more sensitive than the variational methods to any local perturbation of the trial function, this method can used to systematically improve the energy bounds with a local skilled analysis; an algorithm relying on this method can therefore be constructed and an explicit example for a one-dimensional problem is given.Comment: Accepted for publication in Journal of Physics

DoOP: Databases of Orthologous Promoters, collections of clusters of orthologous upstream sequences from chordates and plants

DoOP (http://doop.abc.hu/) is a database of eukaryotic promoter sequences (upstream regions) aiming to facilitate the recognition of regulatory sites conserved between species. The annotated first exons of human and Arabidopsis thaliana genes were used as queries in BLAST searches to collect the most closely related orthologous first exon sequences from Chordata and Viridiplantae species. Up to 3000 bp DNA segments upstream from these first exons constitute the clusters in the chordate and plant sections of the Database of Orthologous Promoters. Release 1.0 of DoOP contains 21 061 chordate clusters from 284 different species and 7548 plant clusters from 269 different species. The database can be used to find and retrieve promoter sequences of a given gene from various species and it is also suitable to see the most trivial conserved sequence blocks in the orthologous upstream regions. Users can search DoOP with either sequence or text (annotation) to find promoter clusters of various genes. In addition to the sequence data, the positions of the conserved sequence blocks derived from multiple alignments, the positions of repetitive elements and the positions of transcription start sites known from the Eukaryotic Promoter Database (EPD) can be viewed graphically

Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports That Menaquinone Synthesis Occurs through the Futalosine Pathway

BACKGROUND: Specific pathways and components for respiration in Chlamydia are poorly understood. RESULTS: The C. trachomatis hypothetical protein CT263 crystal structure displays strong structural similarity with 5′-methylthioadenosine nucleosidase enzymes. CONCLUSION: Bioinformatic analyses and enzymatic characterization of CT263 suggest menaquinone biosynthesis proceeds through the futalosine pathway in Chlamydiaceae. SIGNIFICANCE: Unique structural aspects of the CT263 active site can be leveraged to modify existing transition state inhibitors

Chlamydia trachomatis protein CT009 is a structural and functional homolog to the key morphogenesis component RodZ and interacts with division septal plane localized MreB

This is the peer reviewed version of the following article: Kemege, K. E., Hickey, J. M., Barta, M. L., Wickstrum, J., Balwalli, N., Lovell, S., Battaile, K. P. and Hefty, P. S. (2015), Chlamydia trachomatis protein CT009 is a structural and functional homolog to the key morphogenesis component RodZ and interacts with division septal plane localized MreB. Molecular Microbiology, 95: 365–382. doi:10.1111/mmi.12855, which has been published in final form at http://doi.org/10.1111/mmi.12855. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Cell division in Chlamydiae is poorly understood as apparent homologs to most conserved bacterial cell division proteins are lacking and presence of elongation (rod shape) associated proteins indicate non-canonical mechanisms may be employed. The rod-shape determining protein MreB has been proposed as playing a unique role in chlamydial cell division. In other organisms, MreB is part of an elongation complex that requires RodZ for proper function. A recent study reported that the protein encoded by ORF CT009 interacts with MreB despite low sequence similarity to RodZ. The studies herein expand on those observations through protein structure, mutagenesis, and cellular localization analyses. Structural analysis indicated that CT009 shares high level of structural similarity to RodZ, revealing the conserved orientation of two residues critical for MreB interaction. Substitutions eliminated MreB protein interaction and partial complementation provided by CT009 in RodZ deficient E. coli. Cellular localization analysis of CT009 showed uniform membrane staining in Chlamydia. This was in contrast to the localization of MreB, which was restricted to predicted septal planes. MreB localization to septal planes provides direct experimental observation for the role of MreB in cell division and supports the hypothesis that it serves as a functional replacement for FtsZ in Chlamydia