title: Selenium as a Modulator of Efficacy and Toxicity of Chemotherapy and Radiation

authors: Lobb, Richard

subjects: selenium cancer

abstract: Selenium (Se) is an essential trace mineral required in maintaining health in humans. Recent research has demonstrated that Se shows promise as an agent that can reduce the harmful side-effects of chemotherapy (CT) and radiotherapy (RT), while not compromising the effectiveness of treatment. Clinical evaluations using varying doses of Se have demonstrated a significant reduction in toxicity of CT and RT. Se supplementation appears to mediate its biological effects through four main mechanisms: Se treatment promotes the death of malignant cells, but not normal cells, through the differential effects on the endoplasmic reticulum stress response; it inhibits hypoxia-induced angiogenesis which is required by tumours for their blood supply; it enhances DNA repair in normal but not malignant cells; and it reverses cellular resistance to some cytotoxic drugs. The objectives of this thesis were to evaluate the biological characteristics of the differential impact of a Se compound, methylseleninic acid (MSA), on malignant and non-malignant human cells and how that modulates the effects of cisplatin chemotherapy and/or radiation. In parallel with this, similar evaluations were undertaken in patients receiving a Se compound or placebo in conjunction with cisplatin and radiation for head and neck squamous cell carcinoma (HNSCC). MSA induced differential effects in peripheral blood mononuclear cells (PBMC) obtained from healthy individuals compared to the monocytic leukaemia THP-1 cell-line. While MSA did not change PBMC viability, it reduced that of THP-1 cells in a concentration-dependent manner. Furthermore, MSA treatment enhanced the cytotoxicity of CT and RT toward THP-1 cells without compromising the survival of PBMC. This increased sensitivity in THP-1 cells is likely to be related to significantly reduced levels of intracellular glutathione (GSH) in response to MSA. In contrast, GSH levels in PBMC rose substantially in response to MSA. Assessment of ER stress response proteins revealed that pro-survival proteins (GRP78, phospho-eIF2α, and spliced XBP-1) were upregulated in PBMC in response to MSA treatment. The malignant THP-1 cells had high levels of pro-survival proteins at baseline, which increased to a variable degree, especially caspase-8, in response to MSA. Putative pharmacodynamic markers of biological activity of Se were evaluated in plasma samples and PBMC from HNSCC patients in a randomised, placebo-controlled, double-blind phase II trial. Patients were treated with a 7-week radical course of concurrent cisplatin and RT (CRT) and were randomised to receive either selenomethionine (SLM) or matching placebo for 11 weeks, starting a week prior to CRT treatment. Because the trial is not yet complete, treatment allocation remains blinded and thus the pharmacodynamic results according to treatment with SLM or placebo cannot be made at the time of writing this thesis. However, markers of angiogenesis and the selenoprotein glutathione peroxidise 3 were measured and shown to significantly change during the course of treatment in a patient-specific manner. Lastly, ER stress markers were shown to be detected in PBMC obtained from patients during treatment. Se compounds differentially affect non-malignant and malignant cells. This results in increased therapeutic efficacy of cisplatin and RT targeting malignant cells. These effects appear to be mediated, at least in part, by modulation of intracellular GSH and ER stress response proteins

text: Selenium as a Modulator of Efficacy and Toxicity of Chemotherapy and Radiation Selenium (Se) is an essential trace mineral required in maintaining health in humans. Recent research has demonstrated that Se shows promise as an agent that can reduce the harmful side-effects of chemotherapy (CT) and radiotherapy (RT), while not compromising the effectiveness of treatment. Clinical evaluations using varying doses of Se have demonstrated a significant reduction in toxicity of CT and RT. Se supplementation appears to mediate its biological effects through four main mechanisms: Se treatment promotes the death of malignant cells, but not normal cells, through the differential effects on the endoplasmic reticulum stress response; it inhibits hypoxia-induced angiogenesis which is required by tumours for their blood supply; it enhances DNA repair in normal but not malignant cells; and it reverses cellular resistance to some cytotoxic drugs. The objectives of this thesis were to evaluate the biological characteristics of the differential impact of a Se compound, methylseleninic acid (MSA), on malignant and non-malignant human cells and how that modulates the effects of cisplatin chemotherapy and/or radiation. In parallel with this, similar evaluations were undertaken in patients receiving a Se compound or placebo in conjunction with cisplatin and radiation for head and neck squamous cell carcinoma (HNSCC). MSA induced differential effects in peripheral blood mononuclear cells (PBMC) obtained from healthy individuals compared to the monocytic leukaemia THP-1 cell-line. While MSA did not change PBMC viability, it reduced that of THP-1 cells in a concentration-dependent manner. Furthermore, MSA treatment enhanced the cytotoxicity of CT and RT toward THP-1 cells without compromising the survival of PBMC. This increased sensitivity in THP-1 cells is likely to be related to significantly reduced levels of intracellular glutathione (GSH) in response to MSA. In contrast, GSH levels in PBMC rose substantially in response to MSA. Assessment of ER stress response proteins revealed that pro-survival proteins (GRP78, phospho-eIF2α, and spliced XBP-1) were upregulated in PBMC in response to MSA treatment. The malignant THP-1 cells had high levels of pro-survival proteins at baseline, which increased to a variable degree, especially caspase-8, in response to MSA. Putative pharmacodynamic markers of biological activity of Se were evaluated in plasma samples and PBMC from HNSCC patients in a randomised, placebo-controlled, double-blind phase II trial. Patients were treated with a 7-week radical course of concurrent cisplatin and RT (CRT) and were randomised to receive either selenomethionine (SLM) or matching placebo for 11 weeks, starting a week prior to CRT treatment. Because the trial is not yet complete, treatment allocation remains blinded and thus the pharmacodynamic results according to treatment with SLM or placebo cannot be made at the time of writing this thesis. However, markers of angiogenesis and the selenoprotein glutathione peroxidise 3 were measured and shown to significantly change during the course of treatment in a patient-specific manner. Lastly, ER stress markers were shown to be detected in PBMC obtained from patients during treatment. Se compounds differentially affect non-malignant and malignant cells. This results in increased therapeutic efficacy of cisplatin and RT targeting malignant cells. These effects appear to be mediated, at least in part, by modulation of intracellular GSH and ER stress response proteins

year: 2011

title: Hypsometric and geometric controls on hydrodynamics, tidal asymmetry, and sediment connectivity in shallow estuarine systems

authors: de Ruiter, Peter Jaap

subjects: Oceanography

abstract: Estuaries and tidal basins are highly dynamic coastal systems that serve as a transition zone between the river and the ocean. The morphological evolution of these diverse environments is modulated by non-linear feedbacks between tides, meteorological forcing, and sediment transport processes. This thesis focuses on the fundamental links between these physical processes, and the geomorphologic characteristics of shallow estuarine systems, specifically: (i) how shallow basin geometries and hypsometries affect hydrodynamics and tidal asymmetry, (ii) how wind-induced currents modify velocity asymmetry in shallow basins, and (iii) defining the relationships between geometry, hypsometry, and sediment connectivity inside shallow estuarine systems. 

Linking geomorphological characteristics and tidal processes in shallow tidal basins
The links between tidal basin geometry and hypsometry, bed shear stress patterns, tidal velocity- and slack water asymmetry, and hypsometric profile shapes were explored for six shallow microtidal basins of Tauranga Harbour, New Zealand. Model results, obtained from a depth-averaged numerical model developed in Delft3D for the full estuarine system, indicated that tidal distortion increases with distance from basin entrance. A simple ratio between tidal basin width and entrance width was defined to describe the planform shape of the basin. This metric, termed the ‘basin dilation factor’ indicates whether a basin can be designated as a divergent or convergent geometry. Shallow basins with a constricted geometry and relatively deep entrance channels were found to be associated with small bed shear stress values and high rates of flood-directed tidal velocity asymmetry in the sheltered basin centres. These results suggest substantial potential for sediment deposition of larger particles. Moreover, slack water asymmetry within these basins was weakly ebb-directed, indicating a small potential for export of fine sediments. These divergent, depositional basins were found to be characterized by convex hypsometric profiles with elevated intertidal regions. Conversely, unconstricted, convergent basins were associated with larger bed shear stress values and more ebb-directed tidal velocity asymmetry within basin centres. Consequently, there was limited potential for overall sediment deposition inside these basins. The slack water asymmetry was weakly flood-dominant, suggesting limited potential for fine sediment input. The comparatively high-energy conditions within these exposed tidal basins were associated with a less convex hypsometric intertidal profile. This study highlights the impacts of specific geomorphologic basin characteristics on tidal processes in shallow estuarine systems. The ability to predict the links between tidal asymmetry and morphological changes in tide-dominated systems is beneficial for coastal management, as the morphological evolution of estuarine systems affects coastal ecosystem functioning, port and estuary navigability, and potential for coastal protection. 

Understanding the effects of wind-driven currents on velocity asymmetry in shallow tidal basins
Numerical modelling experiments were conducted for a series of idealized basins in which planform shape and bathymetry were varied. The model results were used to examine how wind-generated currents modulate horizontal velocity asymmetry patterns in shallow tidal basins. This study revealed that wind-driven currents primarily influence mean and peak flow velocities inside the basins, with a limited effect on tidal harmonics. Faster wind speeds led to more extreme horizontal velocity asymmetry (larger velocity asymmetry values), without substantially modifying overall spatial patterns of velocity asymmetry. The velocity asymmetry was found to be strongly depth-dependent, with changes to asymmetry patterns being most evident for wind speeds of 6 m/s and greater, and for wind directions parallel to the main axes of the tidal channels in the basins. Shallow intertidal regions inside the basins were characterized by a downwind-directed increase in velocity asymmetry, whereas deeper subtidal channels experienced asymmetry changes in the opposite direction. Wind event duration and timing were also found to influence the velocity asymmetry patterns. The differences between the relative size of the peak flood- and ebb directed currents were most evident for wind events with a duration of 6 hours or less that coincide with flooding tides. The results of this study highlight that hydrodynamics, sediment transport, and morphological evolution in shallow estuaries are modulated by tidal processes as well as meteorological forcing. Since anthropogenically induced climate change is expected to increase the intensity of extreme meteorological events, the ability to predict future pathways of morphological change in shallow estuarine systems, based on specific meteorological conditions as well as well-defined local tidal regimes, is vital for the management of these dynamic systems. 

An examination of sediment connectivity in a shallow estuarine system
The sediment connectivity framework was used to examine links between hydrodynamics, sediment transport pathways, and local hypsometry inside a shallow estuarine system (Tauranga Harbour, New Zealand). The estuary was divided into twenty geomorphic cells, representing tidal channels, intertidal flats, and shallow sub-basins. Depth-averaged numerical modelling simulations were carried out to quantify tide-driven sediment connectivity between the cells for five sediment grainsize classes. Connectivity matrices were developed for the different grainsize classes, based on modelled sediment mass loads. Sediment connectivity inside the estuary was found to be modulated by tidal energy, estuarine morphology (depth), sub-basin hypsometry and geometry (planform shape), and sediment characteristics. The connectivity matrices, combined with metrics such as link density and cell strength, illustrated that sediment mass loads, and hence connectivity, were largest in the high-energy environments of the deep tidal channels located in the main estuary. In the more sheltered upper estuary, and inside the shallow sub-basins, connectivity was reduced. For fine sediments (< 125 μm) connectivity was found to be substantial throughout the shallow estuarine system, with estuary-level connectivity (link density) being greater than 50%. Link density for coarser sediments (> 275 μm) was found to be ~20%, with transport pathways primarily confined to the deeper regions of the estuary. An in-depth analysis of sediment transport pathways between the shallow sub-basins emphasized that flood-dominant, divergent basins with a convex-shaped hypsometric profile mainly function as sediment sinks, whereas ebb-dominant convergent basins act as sediment sources. 
This thesis highlights the substantial dependence of tidal asymmetry, morphology, sediment transport and connectivity on hypsometry, geometry, and grainsize characteristics inside shallow estuaries. Additionally, the effects of wind-driven currents on the non-linear physical processes inside these highly dynamic environments are described. Overall, this work provides a novel elucidation of some of the relationships between geometric parameters and forcing mechanisms applicable to many shallow coastal systems.

text: Hypsometric and geometric controls on hydrodynamics, tidal asymmetry, and sediment connectivity in shallow estuarine systems Estuaries and tidal basins are highly dynamic coastal systems that serve as a transition zone between the river and the ocean. The morphological evolution of these diverse environments is modulated by non-linear feedbacks between tides, meteorological forcing, and sediment transport processes. This thesis focuses on the fundamental links between these physical processes, and the geomorphologic characteristics of shallow estuarine systems, specifically: (i) how shallow basin geometries and hypsometries affect hydrodynamics and tidal asymmetry, (ii) how wind-induced currents modify velocity asymmetry in shallow basins, and (iii) defining the relationships between geometry, hypsometry, and sediment connectivity inside shallow estuarine systems. 

Linking geomorphological characteristics and tidal processes in shallow tidal basins
The links between tidal basin geometry and hypsometry, bed shear stress patterns, tidal velocity- and slack water asymmetry, and hypsometric profile shapes were explored for six shallow microtidal basins of Tauranga Harbour, New Zealand. Model results, obtained from a depth-averaged numerical model developed in Delft3D for the full estuarine system, indicated that tidal distortion increases with distance from basin entrance. A simple ratio between tidal basin width and entrance width was defined to describe the planform shape of the basin. This metric, termed the ‘basin dilation factor’ indicates whether a basin can be designated as a divergent or convergent geometry. Shallow basins with a constricted geometry and relatively deep entrance channels were found to be associated with small bed shear stress values and high rates of flood-directed tidal velocity asymmetry in the sheltered basin centres. These results suggest substantial potential for sediment deposition of larger particles. Moreover, slack water asymmetry within these basins was weakly ebb-directed, indicating a small potential for export of fine sediments. These divergent, depositional basins were found to be characterized by convex hypsometric profiles with elevated intertidal regions. Conversely, unconstricted, convergent basins were associated with larger bed shear stress values and more ebb-directed tidal velocity asymmetry within basin centres. Consequently, there was limited potential for overall sediment deposition inside these basins. The slack water asymmetry was weakly flood-dominant, suggesting limited potential for fine sediment input. The comparatively high-energy conditions within these exposed tidal basins were associated with a less convex hypsometric intertidal profile. This study highlights the impacts of specific geomorphologic basin characteristics on tidal processes in shallow estuarine systems. The ability to predict the links between tidal asymmetry and morphological changes in tide-dominated systems is beneficial for coastal management, as the morphological evolution of estuarine systems affects coastal ecosystem functioning, port and estuary navigability, and potential for coastal protection. 

Understanding the effects of wind-driven currents on velocity asymmetry in shallow tidal basins
Numerical modelling experiments were conducted for a series of idealized basins in which planform shape and bathymetry were varied. The model results were used to examine how wind-generated currents modulate horizontal velocity asymmetry patterns in shallow tidal basins. This study revealed that wind-driven currents primarily influence mean and peak flow velocities inside the basins, with a limited effect on tidal harmonics. Faster wind speeds led to more extreme horizontal velocity asymmetry (larger velocity asymmetry values), without substantially modifying overall spatial patterns of velocity asymmetry. The velocity asymmetry was found to be strongly depth-dependent, with changes to asymmetry patterns being most evident for wind speeds of 6 m/s and greater, and for wind directions parallel to the main axes of the tidal channels in the basins. Shallow intertidal regions inside the basins were characterized by a downwind-directed increase in velocity asymmetry, whereas deeper subtidal channels experienced asymmetry changes in the opposite direction. Wind event duration and timing were also found to influence the velocity asymmetry patterns. The differences between the relative size of the peak flood- and ebb directed currents were most evident for wind events with a duration of 6 hours or less that coincide with flooding tides. The results of this study highlight that hydrodynamics, sediment transport, and morphological evolution in shallow estuaries are modulated by tidal processes as well as meteorological forcing. Since anthropogenically induced climate change is expected to increase the intensity of extreme meteorological events, the ability to predict future pathways of morphological change in shallow estuarine systems, based on specific meteorological conditions as well as well-defined local tidal regimes, is vital for the management of these dynamic systems. 

An examination of sediment connectivity in a shallow estuarine system
The sediment connectivity framework was used to examine links between hydrodynamics, sediment transport pathways, and local hypsometry inside a shallow estuarine system (Tauranga Harbour, New Zealand). The estuary was divided into twenty geomorphic cells, representing tidal channels, intertidal flats, and shallow sub-basins. Depth-averaged numerical modelling simulations were carried out to quantify tide-driven sediment connectivity between the cells for five sediment grainsize classes. Connectivity matrices were developed for the different grainsize classes, based on modelled sediment mass loads. Sediment connectivity inside the estuary was found to be modulated by tidal energy, estuarine morphology (depth), sub-basin hypsometry and geometry (planform shape), and sediment characteristics. The connectivity matrices, combined with metrics such as link density and cell strength, illustrated that sediment mass loads, and hence connectivity, were largest in the high-energy environments of the deep tidal channels located in the main estuary. In the more sheltered upper estuary, and inside the shallow sub-basins, connectivity was reduced. For fine sediments (< 125 μm) connectivity was found to be substantial throughout the shallow estuarine system, with estuary-level connectivity (link density) being greater than 50%. Link density for coarser sediments (> 275 μm) was found to be ~20%, with transport pathways primarily confined to the deeper regions of the estuary. An in-depth analysis of sediment transport pathways between the shallow sub-basins emphasized that flood-dominant, divergent basins with a convex-shaped hypsometric profile mainly function as sediment sinks, whereas ebb-dominant convergent basins act as sediment sources. 
This thesis highlights the substantial dependence of tidal asymmetry, morphology, sediment transport and connectivity on hypsometry, geometry, and grainsize characteristics inside shallow estuaries. Additionally, the effects of wind-driven currents on the non-linear physical processes inside these highly dynamic environments are described. Overall, this work provides a novel elucidation of some of the relationships between geometric parameters and forcing mechanisms applicable to many shallow coastal systems.

year: 2022

title: Utuhina Stream 2006-2020: In-stream alum dosing effects on fish and aquatic invertebrates

authors: Ling, Nicholas

abstract: This report presents the results of an on-going assessment of the fish and aquatic macroinvertebrate communities of the Utuhina Stream, Lake Rotorua, from 2006 to 2020, and an assessment of the bioavailability of aluminium in fish and kōura to satisfy Bay of Plenty Regional Council’s annual resource consent conditions 9.6, 9.8 and 9.7, respectively, for consent 65321 for the discharge of alum to the Utuhina Stream. Macroinvertebrates, fish and kōura (freshwater crayfish) were sampled from one control and two treatment reaches of the Utuhina Stream annually. Common bully (Gobiomorphus cotidianus) is the dominant species in the fish community of the Utuhina Stream. Kōura (Paranephrops planifrons) and juvenile trout were always present at all sites but variable in abundance. Differences in species abundance from year to year are most likely due to flood-related disturbances to stream bank morphology and in-stream vegetative cover or physical displacement of fish. No obvious effects of alum dosing on stream fish or macroinvertebrate communities were observed between the upstream control site and sites downstream of the alum discharge. Several other fish species were occasionally captured during sampling and the regular occurrence of juvenile koaro from 2016 to 2019 is possible evidence of this taonga species becoming established in the Utuhina. Analysis of stream macroinvertebrates also showed no consistent differences between the upstream control site and the sites downstream of the alum dosing. Overall, all sites were characterised as fair to good quality for a soft-bottomed stream. Some evidence of aluminium bioaccumulation was seen in some tissues of common bully (gills and liver) in some years, resulting from continuous alum dosing of the Utuhina Stream, but there was no evidence of bioaccumulation of aluminium in the tissues of kōura. Alum exposure in these species does not appear to affect their health or abundance in the stream.   iii Overall, continuous alum discharge does not appear to negatively impact the ecology of the lower Utuhina and improvements in the ecological condition of the Utuhina Stream will be achieved by ongoing riparian restoration and mitigation of the impacts of flood flows.

text: Utuhina Stream 2006-2020: In-stream alum dosing effects on fish and aquatic invertebrates This report presents the results of an on-going assessment of the fish and aquatic macroinvertebrate communities of the Utuhina Stream, Lake Rotorua, from 2006 to 2020, and an assessment of the bioavailability of aluminium in fish and kōura to satisfy Bay of Plenty Regional Council’s annual resource consent conditions 9.6, 9.8 and 9.7, respectively, for consent 65321 for the discharge of alum to the Utuhina Stream. Macroinvertebrates, fish and kōura (freshwater crayfish) were sampled from one control and two treatment reaches of the Utuhina Stream annually. Common bully (Gobiomorphus cotidianus) is the dominant species in the fish community of the Utuhina Stream. Kōura (Paranephrops planifrons) and juvenile trout were always present at all sites but variable in abundance. Differences in species abundance from year to year are most likely due to flood-related disturbances to stream bank morphology and in-stream vegetative cover or physical displacement of fish. No obvious effects of alum dosing on stream fish or macroinvertebrate communities were observed between the upstream control site and sites downstream of the alum discharge. Several other fish species were occasionally captured during sampling and the regular occurrence of juvenile koaro from 2016 to 2019 is possible evidence of this taonga species becoming established in the Utuhina. Analysis of stream macroinvertebrates also showed no consistent differences between the upstream control site and the sites downstream of the alum dosing. Overall, all sites were characterised as fair to good quality for a soft-bottomed stream. Some evidence of aluminium bioaccumulation was seen in some tissues of common bully (gills and liver) in some years, resulting from continuous alum dosing of the Utuhina Stream, but there was no evidence of bioaccumulation of aluminium in the tissues of kōura. Alum exposure in these species does not appear to affect their health or abundance in the stream.   iii Overall, continuous alum discharge does not appear to negatively impact the ecology of the lower Utuhina and improvements in the ecological condition of the Utuhina Stream will be achieved by ongoing riparian restoration and mitigation of the impacts of flood flows.

year: 2021-06