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Purpose:Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics.Experimental Design:Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined.Results:The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; γH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744.Conclusions:These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.

Ocean warming is increasing the incidence, scale, and severity of global-scale coral bleaching and mortality, culminating in the third global coral bleaching event that occurred during record marine heatwaves of 2014-2017. While local effects of these events have been widely reported, the global implications remain unknown. Analysis of 15,066 reef surveys during 2014-2017 revealed that 80% of surveyed reefs experienced significant coral bleaching and 35% experienced significant coral mortality. The global extent of significant coral bleaching and mortality was assessed by extrapolating results from reef surveys using comprehensive remote-sensing data of regional heat stress. This model predicted that 51% of the world’s coral reefs suffered significant bleaching and 15% significant mortality, surpassing damage from any prior global bleaching event. These observations demonstrate that global warming’s widespread damage to coral reefs is accelerating and underscores the threat anthropogenic climate change poses for the irreversible transformation of these essential ecosystems.

Clinical trials of biodynamic digital holography in human esophageal cancer and canine B-cell lymphoma, performed within 24 hours of biopsy acquisition, have an accuracy of 90% identifying patients resistant to their prescribed chemotherapy. Translation of this biomedical optical technology to clinical laboratory services has the potential to transform personalized cancer care.

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

A critical need in the management of public and non-urban private lands in the United States and elsewhere is assessing the efficacy of different management alternatives under different environmental and land use scenarios. One type of tool that would be extremely valuable is large-scale ecological simulation models designed to project effects of alternative climatic, usage, and management scenarios on ecological resources. A modeling challenge in this type of application is to link mechanistic simulations of small-scale ‘ecosystem’ processes to large-scale ‘landscape’ processes to provide more realistic and exhaustive projections of effects and ramifications of management alternatives. The Ecological DYnamics Simulation model (EDYS) is a general ecosystem simulation model that mechanistically implements relevant processes in ecosystem dynamics, including: climatic inputs, soil water and nutrient dynamics, plant uptake and growth by species, herbivory, fire, contaminants, physical disturbance, and management activities. In the EDYS model, ecological processes simulated in plot-level ecosystem cells are scaled up to the landscape level using a grid-based representation of the spatial extent of that ecosystem across the landscape. A significant practical challenge in applying complex ecological models is compilation of appropriate input data from a wide-variety of print and on-line media. A semi-automated database is currently under development, which will compile, organize, and format data sets to facilitate future EDYS applications. Another challenge is linking different types of models, each of which is specialized to simulate particular aspects of ecosystem and landscape dynamics. As so many different types of organizations are presently involved in model development and resource management, ownership of models and datasets will increasingly become an issue in their distribution and use among different types of land managers.

Grid-based models such as cellular automata are useful tools for investigating spatial dynamics in ecological systems. Quantitative measures have been proposed for characterizing static spatial patterns, but techniques for examining the dynamics of spatial pattern are less developed. I present an adaptation of Hamiltonian free energy equations to predict numbers of state changes resulting from different ecological mechanisms in spatial automata models. The three terms in the Hamiltonian estimate the number of grid cells changing state due to spontaneous state changes, to interactions among cells, and to heterogeneity in the behavior of different cells in the grid. PComp is a simple competition model in which each cell in the grid can be occupied by a single individual plant. The simulation calculates the Hamiltonian at each time step to indicate how many of the observed changes in cell occupancy are due to basic colonization and death rates, crowding effects, dispersal from adjacent cell, and differences in substrate suitability.

Grid-based automata models have been widely applied in simulating ecological process and spatial patterns at all spatial scales. In this paper, we present methods for calculating the effects of number of states, size of the neighborhood, means of tallying neighborhood states, and choice of deterministic or stochastic rules on the complexity and tractability of spatial automata models. We use as examples Conway's Game of Life and models for successional dynamics in a mesquite savanna landscape in south Texas. The number of possible neighborhood state configurations largely determines the complexity of automata models. The number of different configurations in Life, a two-state, deterministic, voting-rule model with an eight-cell Moore neighborhood is 18. A similar model for the seven-state savanna system would have 21,021 different neighborhood configurations. For stochastic models, the number of possible state transitions is the number of neighborhood configurations times the number of possible cell states. A stochastic, unique neighbor model for the savanna system with a Moore neighborhood and seven possible states would have 282,475,249 possible neighborhood-based state transitions. Stochastic models with an eight-cell Moore neighborhood are probably most appropriate for ecological applications. The best options for minimizing the complexity of ecological models are using voting rather than unique neighbor transition rules, reducing the number of possible states, and implementing ecologically-based heuristics to simplify the transition rule table.

We apply a resource integration approach to address increasing crop and forage production in a semi-arid agroecosystem in northwestern China. A holistic modeling approach was employed to study improvement in agricultural practices with respect to ecosystem conservation. Using a proposed rotational scheme for winter wheat and alfalfa production, portions of arable land are allocated for raising animal forage in order to improve soil productivity. Animal manures are returned to the soil to stabilize the structure further and to maintain fertility. Regional climate and topography are included in the simulation model. A series of 40-yr simulation runs for ravine tablelands and hilly topography were conducted to investigate model behavior. Long-term application of nitrogen fertilizer as an alternative management practice was evaluated using the model, but detrimental effects on primary and secondary production from such a practice were predicted by simulation results. The impact of population pressure on agricultural systems was also considered.

Length‐limit regulations and promotion of catch‐and‐release fishing have become increasingly important management approaches for recreational fisheries. We review‐studies on catch‐and‐release (hooking) mortality gathered from the existing fisheries literature and from a survey of fisheries management agencies in all 50 states, the U.S. government, all Canadian provinces, and selected academic and research institutions. We identified hooking mortality estimates for 32 taxa. Most studies dealt with salmonids, centrarchids (especially black basses, Micropterus spp.), and percids (especially walleye, Stizostedion vitreum). Within and among species, differences in percent mortality were reported in association with bait type (artificial vs. natural), hook type (number of hooks, hook size, and barbs), season/ temperature, water depth (depressurization), anatomical location of hook wound, and individual size. Although most hooking mortalities occur within 24 h, the use of initial plus delayed mortality ...

We evaluated the ability of three condition indices-condition factor (K), relative condition (Kn ), and relative weight (Wr )–to estimate annual growth rates of largemouth bass Micropterus salmoides and white crappies Pomoxis annularis collected during standardized autumn electrofishing and trap-net surveys of Texas reservoirs. Multiple-regression models for estimation of length increments from initial length (at the start of the growing season) and condition indices had R 2 values of 0.63–0.76 for largemouth bass and 0.46–0.83 for white crappie. However, these models are not useful for indirect estimation ofgrowth rates because growth must be known (initial length equals length at capture minus estimated annual growth). Models based on length at capture and condition indices had R 2 values of 0.22–0.68 for largemouth bass and less than 0.45 for white crappie. The low precision of models based on length at capture indicates that condition provides a weak basis for indirect estimation of growth ra...

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

Standard-weight (Ws ) curves for 22 fish species in Texas were derived from statewide length and weight data by means of log-transformed regressions of 75th-percentile weights for 10-mm total length classes. When curves for 12 of the species were compared with standard-weight curves published or used elsewhere, they were significantly different in each case. These results indicate that regional standard-weight curves may be appropriate for managing some species.

An understanding of ecological processes at multiple scales is important in making sound evaluations of the effects of management practices for natural resources. Hierarchical approaches to these processes should be able to link these processes across multiple scales into simulation models of community and landscape dynamics (Urban et al. 1987; Pickett et al. 1987). In recent years, considerable progress has been made in landscape ecological analysis of spatial patterns in order to make inferences on spatial processes (Cale et al. 1989; Turner 1990; Turner and Gardner 1991), and on hierarchically structured landscapes in particular (Lavorel et al. 1993). A complementary approach is to examine processes to determine their effects on resulting spatial patterns; this is the approach taken in simulation modeling of landscapes (Gardner et al. 1987; Gardner and O'Neill 1991). “Because landscape ecology explicitly considers spatial heterogeneity, it follows that models of population dynamics in a landscape context, even those that include only simple dynamics, are analytically intractable. A possible alternative is the use of simulation models” (Fahrig 1991). Both approaches are valuable in establishing the connections between pattern and process at all spatial scales.