Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

Managing Flow Regimes and Landscapes Together: Hydrospatial Analysis for Evaluating Spatiotemporal Floodplain Inundation Patterns with Restoration and Climate Change Implications

Riverine landscapes are shaped by dynamic and complex interactions between streamflow and floodplain landforms, and these physical processes drive productive and diverse freshwater ecosystems. However, human activities have fundamentally altered river-floodplain processes and degraded ecosystems. Flow regime variability has been homogenized and floodplains disconnected from rivers due to dams, diversions, levee building, and land use change. Reconciling competing demands to support ecosystems and resilience to future change is a core scientific and management challenge. This dissertation describes spatiotemporal dynamics of floodplain environments, introducing a method for flood regime classification and establishing a methodological approach for hydrospatial analysis to quantify and evaluate the response of floodplain inundation patterns and related physical habitat to restoration and flow regime change under climate change. It is motivated by the need to develop process-based and landscapescale strategies to better manage flow regimes and landscapes together, such as coordinated levee-removal floodplain restoration and environmental flow allocations. River restoration literature is synthesized herein to examine trajectories from form-based to process-based approaches, recognize that highly modified large rivers may require coordinated physical habitat restoration and environmental flows implementation, and suggest opportunities for improved integration of restoration strategies. A river’s flood regime drives a variety of different physical and ecological functions. Characterizing different floods of a flood regime informs understanding of climate and watershed processes and the management of natural floodplain dynamics. Following cluster analysis approaches used in flow regime classification, a flood regime typology was developed for the Cosumnes River, the only major unregulated river of the west slope Sierra Nevada, California, USA. A primary contribution of this study is the establishment of flood regime classification that moves beyond typical flood frequency analysis to address a range of ecologically-relevant flood characteristics, including duration and timing. Rehabilitating freshwater ecosystems of highly modified rivers under a changing future requires improved understanding and quantification of land-water interactions. Despite ecological implications, quantification of spatiotemporal variability is rare, particularly for management applications. An approach for evaluating spatiotemporal floodplain inundation patterns, or the hydrospatial regime, is presented in several studies. Physical inundation characteristics and associated habitat were quantified in space and time, and responses to restoration and climate change induced flow scenarios were evaluated and compared. The multi-metric approach is demonstrated for a recent levee-removal restoration site along the lower Cosumnes River. The novel hydrospatial analytical approach developed and presented herein applies twodimensional hydrodynamic modeling and spatial analysis to quantitatively summarize, in space and time, a range of ecologically-relevant physical metrics relating to inundation extent, depth, velocity, frequency, -iiiduration, timing, rate of change, connectivity, and heterogeneity. Comparison of metrics before and after levee-removal restoration on the Cosumnes River floodplain showed that while inundation extent greatly increased with restoration, responses varied in space and time and were different for different metrics. Changes in metrics were most substantial at intermediate flood flows. Subsequently, habitat criteria for a native floodplain fish species, Sacramento splittail (Pogonichthys macrolepidotus), were applied to the physical metrics. Findings suggest that restoration nearly doubled overall habitat availability, though benefits varied considerably in space and time. Flow-habitat relationships were nonlinear and not oneto- one, indicating habitat availability mediated by the physical complexity of the floodplain. Finally, floodplain responses to climate change induced streamflow scenarios were compared and the relative impacts of levee-removal restoration across the scenarios were evaluated. Results reflected the balance of increasing extreme winter flooding and declining spring flooding under future climate change scenarios. Magnitude and direction of change depended on the climate change scenario and metric. Levee removal had the general effect of dampening climate change impacts, though the relative impacts of climate change scenarios were greater than that of restoration in some cases. This body of work presents a new methodology to analyze flow-landscape interactions, and in turn contributes to understanding of flow-ecology relationships, susceptibility to anthropogenic change, and improvements to water and land management. Several broad implications emerge from this research. It demonstrates the capacity of a riverine landscape to serve different functions at different times and supports improved management toward variable conditions. Another contribution is advancing the use of hydraulic metrics over hydrologic metrics for better connections between physical processes and ecological functions. Further, the approach allows for ecologically-relevant criteria that are spatially and temporally dependent to be evaluated explicitly (e.g., duration, connectivity, temporal sequence of flood events). Findings show that, for habitat evaluation within complex floodplain environments, habitat availability is not likely to be a simple function of flow. Floodplain hydrospatial regime responses to climate change will be mediated by flow-landscape interactions, with the potential for physical restoration activities to mitigate impacts of climate change. Despite highly modified physical processes, climate change, and freshwater diversity and productivity declines globally, there is great capacity to better balance human and ecosystem requirements. This dissertation expands scientific understanding of and informs management toward dynamic and heterogeneous riverine landscapes that support functional and resilient ecosystems

Managing Flow Regimes and Landscapes Together: Hydrospatial Analysis for Evaluating Spatiotemporal Floodplain Inundation Patterns with Restoration and Climate Change Implications

Riverine landscapes are shaped by dynamic and complex interactions between streamflow and floodplain landforms, and these physical processes drive productive and diverse freshwater ecosystems. However, human activities have fundamentally altered river-floodplain processes and degraded ecosystems. Flow regime variability has been homogenized and floodplains disconnected from rivers due to dams, diversions, levee building, and land use change. Reconciling competing demands to support ecosystems and resilience to future change is a core scientific and management challenge. This dissertation describes spatiotemporal dynamics of floodplain environments, introducing a method for flood regime classification and establishing a methodological approach for hydrospatial analysis to quantify and evaluate the response of floodplain inundation patterns and related physical habitat to restoration and flow regime change under climate change. It is motivated by the need to develop process-based and landscapescale strategies to better manage flow regimes and landscapes together, such as coordinated levee-removal floodplain restoration and environmental flow allocations. River restoration literature is synthesized herein to examine trajectories from form-based to process-based approaches, recognize that highly modified large rivers may require coordinated physical habitat restoration and environmental flows implementation, and suggest opportunities for improved integration of restoration strategies. A river’s flood regime drives a variety of different physical and ecological functions. Characterizing different floods of a flood regime informs understanding of climate and watershed processes and the management of natural floodplain dynamics. Following cluster analysis approaches used in flow regime classification, a flood regime typology was developed for the Cosumnes River, the only major unregulated river of the west slope Sierra Nevada, California, USA. A primary contribution of this study is the establishment of flood regime classification that moves beyond typical flood frequency analysis to address a range of ecologically-relevant flood characteristics, including duration and timing. Rehabilitating freshwater ecosystems of highly modified rivers under a changing future requires improved understanding and quantification of land-water interactions. Despite ecological implications, quantification of spatiotemporal variability is rare, particularly for management applications. An approach for evaluating spatiotemporal floodplain inundation patterns, or the hydrospatial regime, is presented in several studies. Physical inundation characteristics and associated habitat were quantified in space and time, and responses to restoration and climate change induced flow scenarios were evaluated and compared. The multi-metric approach is demonstrated for a recent levee-removal restoration site along the lower Cosumnes River. The novel hydrospatial analytical approach developed and presented herein applies twodimensional hydrodynamic modeling and spatial analysis to quantitatively summarize, in space and time, a range of ecologically-relevant physical metrics relating to inundation extent, depth, velocity, frequency, -iiiduration, timing, rate of change, connectivity, and heterogeneity. Comparison of metrics before and after levee-removal restoration on the Cosumnes River floodplain showed that while inundation extent greatly increased with restoration, responses varied in space and time and were different for different metrics. Changes in metrics were most substantial at intermediate flood flows. Subsequently, habitat criteria for a native floodplain fish species, Sacramento splittail (Pogonichthys macrolepidotus), were applied to the physical metrics. Findings suggest that restoration nearly doubled overall habitat availability, though benefits varied considerably in space and time. Flow-habitat relationships were nonlinear and not oneto- one, indicating habitat availability mediated by the physical complexity of the floodplain. Finally, floodplain responses to climate change induced streamflow scenarios were compared and the relative impacts of levee-removal restoration across the scenarios were evaluated. Results reflected the balance of increasing extreme winter flooding and declining spring flooding under future climate change scenarios. Magnitude and direction of change depended on the climate change scenario and metric. Levee removal had the general effect of dampening climate change impacts, though the relative impacts of climate change scenarios were greater than that of restoration in some cases. This body of work presents a new methodology to analyze flow-landscape interactions, and in turn contributes to understanding of flow-ecology relationships, susceptibility to anthropogenic change, and improvements to water and land management. Several broad implications emerge from this research. It demonstrates the capacity of a riverine landscape to serve different functions at different times and supports improved management toward variable conditions. Another contribution is advancing the use of hydraulic metrics over hydrologic metrics for better connections between physical processes and ecological functions. Further, the approach allows for ecologically-relevant criteria that are spatially and temporally dependent to be evaluated explicitly (e.g., duration, connectivity, temporal sequence of flood events). Findings show that, for habitat evaluation within complex floodplain environments, habitat availability is not likely to be a simple function of flow. Floodplain hydrospatial regime responses to climate change will be mediated by flow-landscape interactions, with the potential for physical restoration activities to mitigate impacts of climate change. Despite highly modified physical processes, climate change, and freshwater diversity and productivity declines globally, there is great capacity to better balance human and ecosystem requirements. This dissertation expands scientific understanding of and informs management toward dynamic and heterogeneous riverine landscapes that support functional and resilient ecosystems

Data from: Coupling landscapes and river flows to restore highly modified rivers

Modifications to landscapes and flow regimes of rivers have altered the function, biodiversity, and productivity of freshwater ecosystems globally. Reestablishing geomorphological and hydrological conditions necessary to sustain ecosystems is a central challenge for restoration within highly altered systems. Meeting this challenge requires simultaneously addressing multiple and interacting stressors within the context of irreversible changes and socio‐economic constraints. Traditionally, river restoration approaches either physically change the landscape or channel (channel‐floodplain manipulation) or adjust hydrology (environmental flows), and such actions are often independent. We juxtapose these two subfields of river restoration, which have undergone parallel transformations, from goals of reproducing static representations of form and flow regime to goals of reestablishing processes. The parallel transformations have generated shared ideas, which point to benefits of coupling channel‐floodplain manipulation and environmental flow actions to achieve process‐based goals. Such coupling supports comprehensive river restoration efforts aimed at supporting resilient ecosystems within human dominated landscapes in a nonstationary climate. We identify four elements of coupled approaches for restoring highly modified rivers: (1) identify physical and ecological process potential given interactive effects of altered landscapes and flows; (2) consider capacity for sustaining identified processes under potential future change; (3) model alternatives for coupled restoration actions to support identified processes; and (4) evaluate alternatives using metrics representing integrative effects of coupled actions. We suggest these emergent elements contribute to the development of standard practices for restoring highly modified rivers and encourage an increasing number and quality of coupled applications

Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells.

Cells isolated from many types of human cancers express heparin-binding growth factors (HBGFs) that drive tumor growth, metastasis, and angiogenesis. The heparan sulfate proteoglycan glypican-1 (GPC1) is a coreceptor for HBGFs. Here we show that both cancer cell-derived and host-derived GPC1 are crucial for efficient growth, metastasis, and angiogenesis of human and mouse cancer cells. Thus downregulation of GPC1 in the human pancreatic cancer cell line PANC-1, using antisense approaches, resulted in prolonged doubling times and decreased anchorage-independent growth in vitro as well as attenuated tumor growth, angiogenesis, and metastasis when these cells were transplanted into athymic mice. Moreover, athymic mice that lacked GPC1 exhibited decreased tumor angiogenesis and metastasis following intrapancreatic implantation with either PANC-1 or T3M4 human pancreatic cancer cells and fewer pulmonary metastases following intravenous injection of murine B16-F10 melanoma cells. In addition, hepatic endothelial cells isolated from these mice exhibited an attenuated mitogenic response to VEGF-A. These data indicate that cancer cell- and host-derived GPC1 are crucial for full mitogenic, angiogenic, and metastatic potential of cancer cells. Thus targeting GPC1 might provide new avenues for cancer therapy and for the prevention of cancer metastasis

Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells

Cells isolated from many types of human cancers express heparin-binding growth factors (HBGFs) that drive tumor growth, metastasis, and angiogenesis. The heparan sulfate proteoglycan glypican-1 (GPC1) is a coreceptor for HBGFs. Here we show that both cancer cell–derived and host-derived GPC1 are crucial for efficient growth, metastasis, and angiogenesis of human and mouse cancer cells. Thus downregulation of GPC1 in the human pancreatic cancer cell line PANC-1, using antisense approaches, resulted in prolonged doubling times and decreased anchorage-independent growth in vitro as well as attenuated tumor growth, angiogenesis, and metastasis when these cells were transplanted into athymic mice. Moreover, athymic mice that lacked GPC1 exhibited decreased tumor angiogenesis and metastasis following intrapancreatic implantation with either PANC-1 or T3M4 human pancreatic cancer cells and fewer pulmonary metastases following intravenous injection of murine B16-F10 melanoma cells. In addition, hepatic endothelial cells isolated from these mice exhibited an attenuated mitogenic response to VEGF-A. These data indicate that cancer cell– and host-derived GPC1 are crucial for full mitogenic, angiogenic, and metastatic potential of cancer cells. Thus targeting GPC1 might provide new avenues for cancer therapy and for the prevention of cancer metastasis