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The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.

During drug development, tissue samples serve as indicators of disease activity and pharmacodynamic responses. Reliable non-invasive measures of drug target engagement will facilitate identification of promising new treatments. Here we develop and validate a novel bi-transgenic mouse model of myotonic dystrophy type 1 (DM1) in which expression of either DsRed or GFP is determined by alternative splicing of an upstream minigene that is mis-regulated in DM1. Using a novel in vivo fluorescence spectroscopy system, we show that quantitation of the DsRed/GFP ratio provides an accurate estimation of splicing outcomes in muscle tissue of live mice that nearly doubles throughput over conventional fluorescence imaging techniques. Serial in vivo spectroscopy measurements in mice treated with a C16 fatty acid ligand conjugated antisense (LICA) oligonucleotide reveal a dose-dependent therapeutic response within seven days, confirm a several-week duration of action, and demonstrate a two-fold greater target engagement as compared to the unconjugated parent oligonucleotide. Myotonic dystrophy type 1 (DM1) is associated with aberrant transcript splicing. Here, the authors develop a transgenic mouse model expressing a bi-chromatic reporter system that allows non-invasive monitoring of splicing of a transcript altered in DM1 in vivo, and show that it allows for evaluation of the therapeutic response to treatment with antisense oligonucleotides.

Oxygen transport imposes a possible constraint on the brain's ability to sustain variable metabolic demands, but oxygen diffusion in the cerebral cortex has not yet been observed directly. We show that concurrent two-photon fluorescence imaging of endogenous nicotinamide adenine dinucleotide (NADH) and the cortical microcirculation exposes well-defined boundaries of tissue oxygen diffusion in the mouse cortex. The NADH fluorescence increases rapidly over a narrow, very low pO2 range with a p50 of 3.4±0.6 mm Hg, thereby establishing a nearly binary reporter of significant, metabolically limiting hypoxia. The transient cortical tissue boundaries of NADH fluorescence exhibit remarkably delineated geometrical patterns, which define the limits of tissue oxygen diffusion from the cortical microcirculation and bear a striking resemblance to the ideal Krogh tissue cylinder. The visualization of microvessels and their regional contribution to oxygen delivery establishes penetrating arterioles as major oxygen sources in addition to the capillary network and confirms the existence of cortical oxygen fields with steep microregional oxygen gradients. Thus, two-photon NADH imaging can be applied to expose vascular supply regions and to localize functionally relevant microregional cortical hypoxia with micrometer spatial resolution.

Mitochondria play critical roles in meeting cellular energy demand, in cell death, and in reactive oxygen species (ROS) and stress signaling. Most Caenorhabditis elegans loss-of-function ( lf ) mutants in nuclear-encoded components of the respiratory chain are non-viable, emphasizing the importance of respiratory function. Chromophore-Assisted Light Inactivation (CALI) using genetically-encoded photosensitizers provides an opportunity to determine how individual respiratory chain components contribute to physiology following acute lf . As proof-of-concept, we expressed the ‘singlet oxygen generator’ miniSOG as a fusion with the SDHC subunit of respiratory complex II, encoded by mev-1 in C. elegans, using Mos1-mediated Single Copy Insertion. The resulting mev-1:: miniSOG transgene complemented mev-1 mutant phenotypes in kn1 missense and tm1081 ( lf ) deletion mutants. Complex II activity was inactivated by blue light in mitochondria from strains expressing active miniSOG fusions, but not those from inactive fusions. Moreover, light-inducible phenotypes in vivo demonstrated that complex II activity is important under conditions of high energy demand, and that specific cell types are uniquely susceptible to loss of complex II. In conclusion, miniSOG-mediated CALI is a novel genetic platform for acute inactivation of respiratory chain components. Spatio-temporally controlled ROS generation will expand our understanding of how the respiratory chain and mitochondrial ROS influence whole organism physiology.

Staphylococcus aureus can cause disease at most body sites, with illness ranging from asymptomatic infection to death. The increasing prevalence of antibiotic-resistant strains results in treatment failures and high mortality rates. S. aureus acquires resistance to antibiotics through multiple mechanisms, often by genetic variation that alters antimicrobial targets. Staphylococcus aureus is an opportunistic pathogen with a clinical spectrum ranging from asymptomatic skin colonization to invasive infections. While traditional antibiotic therapies can be effective against S. aureus , the increasing prevalence of antibiotic-resistant strains results in treatment failures and high mortality rates. Photodynamic inactivation (PDI) is an innovative and promising alternative to antibiotics. While progress has been made in our understanding of the bacterial response to PDI, major gaps remain in our knowledge of PDI tolerance, the global cellular response, and adaptive genomic mutations acquired as a result of PDI. To address these gaps, S. aureus HG003 and isogenic mutants with mutations in agr , mutS , mutL , and mutY exposed to single or multiple doses of PDI were assessed for survival and tolerance and examined by global transcriptome and genome analyses to identify regulatory and genetic adaptations that contribute to tolerance. Pathways in inorganic ion transport, oxidative response, DNA replication recombination and repair, and cell wall and membrane biogenesis were identified in a global cellular response to PDI. Tolerance to PDI was associated with superoxide dismutase and the S. aureus global methylhydroquinone (MHQ)-quinone transcriptome network. Genome analysis of PDI-tolerant HG003 identified a nonsynonymous mutation in the quinone binding domain of the transcriptional repressor QsrR, which mediates quinone sensing and oxidant response. Acquisition of a heritable QsrR mutation through repeated PDI treatment demonstrates selective adaption of S. aureus to PDI. PDI tolerance of a qsrR gene deletion in HG003 confirmed that QsrR regulates the S. aureus response to PDI. IMPORTANCE Staphylococcus aureus can cause disease at most body sites, with illness ranging from asymptomatic infection to death. The increasing prevalence of antibiotic-resistant strains results in treatment failures and high mortality rates. S. aureus acquires resistance to antibiotics through multiple mechanisms, often by genetic variation that alters antimicrobial targets. Photodynamic inactivation (PDI), which employs a combination of a nontoxic dye and low-intensity visible light, is a promising alternative to antibiotics that effectively eradicates S. aureus in human infections when antibiotics are no longer effective. In this study, we demonstrate that repeated exposure to PDI results in resistance of S. aureus to further PDI treatment and identify the underlying bacterial mechanisms that contribute to resistance. This work supports further analysis of these mechanisms and refinement of this novel technology as an adjunctive treatment for S. aureus infections.

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. [PUBLICATION ABSTRACT]

Viewing the Future in the Past is a collection of essays that represents a wide range of authors, loci, and subjects that together demonstrate the value and necessity of looking at environmental problems as a long-term process that involves humans as a causal factor. Editors H. Thomas Foster, II, Lisa M. Paciulli, and David J. Goldstein argue that it is increasingly apparent to environmental and earth sciences experts that humans have had a profound effect on the physical, climatological, and biological earth. Consequently, they suggest that understanding any aspect of the earth within the last ten thousand years means understanding the density and activities of Homo sapiens. The essays reveal the ways in which archaeologists and anthropologists have devised methodological and theoretical tools and applied them to pre-Columbian societies in the New World and ancient sites in the Middle East. Some of the authors demonstrate how these tools can be useful in examining modern societies. The contributors provide evidence that past and present ecosystems, economies, and landscapes must be understood through the study of human activity over millennia and across the globe.

Historical forests in the Southeastern Mixed Forest province of the United States have been less researched than other regions using historical tree surveys. We used 81,000 tree records from surveys during the 1800s to quantify composition of this ecological province. Upland oaks and pines comprised about 75% of all trees, with relatively equal composition. Oak composition may have comprised ≥ 45% to the northern and eastern sides of the province. Hickories were about 10% of composition and a few species were present at 1% to 2% composition. Currently, pine has increased to 49% composition; loblolly pine was 46% of all trees. Upland oaks decreased to 8% composition. Paralleling other historically oak- or pinedominated regions, fire-intolerant species increased to 40% of composition, particularly early-successional sweetgum. Historical oak-pine forests mostly have converted to loblolly pine plantations and broadleaf forests in this region. A large extent of the eastern United States historically was dominated by oak or pine forests, which likely were open old growth forests due to a frequent, low-to-moderate severity fire regime that reduced tree densities and infrequently disturbed overstory trees. Open old growth forests should be recognized as distinct ecosystems with unique characteristics, ecological functioning, and associated management practices.

Apalachicola was a Hitchitee community that was considered the capital of the Creek Nation during the seventeenth and eighteenth century in the Southeastern United States. The role of this community in the formation of the southeastern political and cultural geography is paramount because of their coalescence with emigrant Muscogee people. In this article, I synthesize 10 years of research at the site and clarify the population history of this community. The research demonstrates the formation of the Creek culture area in the material record. Pottery surface decoration becomes measurably homogenous and I interpret this pattern as a result of that cultural development.

In this paper I review risk management and horticultural production among the Muscogee Creek of southeastern North America (1715–1825) in an attempt to understand decisions about land use. The z-score model and the marginal value theorem are developed, incorporating the effects of population growth among consumers and confounding variables that result from long-term resource consumption. The study calculated the annual productivity of horticultural fields of the Muscogee town of Cussetuh between 1715 and 1825 and found that the native people were not maximizing long-term average maize yield. The Cussetuh ceased using their horticultural fields sooner than a marginal value model would predict, which is consistent with the z-score model of a risk-sensitive consumer. I discuss implications of the finding that the Southeastern Native Americans were risk sensitive.