• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 519
  • 207
  • 122
  • 62
  • 58
  • 41
  • 23
  • 11
  • 8
  • 4
  • 3
  • 2
  • 2
  • 2
  • 1
  • Tagged with
  • 1279
  • 220
  • 166
  • 140
  • 138
  • 126
  • 120
  • 118
  • 110
  • 103
  • 102
  • 97
  • 83
  • 83
  • 81
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
31

THE EFFECT OF HYPOXIA INDUCIBLE FACTOR-1 ON THE EXPRESSION OF THE COINHIBITORY LIGANDS B7-H3 AND B7-H1 IN CANCER: RELEVANCE TO CANCER IMMUNE ESCAPE

Smallwood, Chelsea 15 August 2012 (has links)
The interactions between tumour cells and cells of the immune system are important in the natural evolution of cancer, and the acquired immune system plays an integral role in cancer immune escape. B7-H3 and B7-H1 ligands provide coinhibitory signals to T cells resulting in T cell anergy or apoptosis and their expression has been shown to increase in cancer cells. Tumour hypoxia (oxygen concentration below physiological level) is a major contributor to the spread of cancer and resistance to radiation and chemotherapy. We proposed that hypoxia results in the upregulation of the B7 molecules B7-H3 and B7-H1. Furthermore, studies in our laboratory have shown that acquisition of malignant properties in tumour cells exposed to hypoxia can be inhibited by low concentrations of nitric oxide mimetic agents such as glyceryl trinitrate (GTN). Using cultured breast and prostate cancer cells, we investigated whether the hypoxia-inducible factor HIF-1α, would mediate an upregulation of these ligands. Using a mouse model, we investigated the effect of GTN on tumour growth in vivo. For the in vitro studies, we exposed MDA-MB-231 and MCF-7 breast cancer cells and DU-145 prostate cancer cells to standard culture conditions, hypoxic conditions, or 100 μM CoCl2 (stabilizes HIF-1α) for 24 hours. Our findings indicate that B7-H3 mRNA was upregulated in hypoxia (P = 0.0101). Contrary to our hypothesis, B7-H3 protein was not upregulated in hypoxia. Interestingly, increased B7-H1 protein expression correlated with increased HIF-1α expression (r2=0.48, P<0.0001), and HIF-1α bound to the hypoxia response element (HRE) of B7-H1. These results indicate a role for HIF-1α in the upregulation of B7-H1 levels in MDA-MB-231 cells. While in vitro studies indicated no effect of GTN, a study using female BALB/c mice injected with 4T1 mammary carcinoma cells resulted in a decrease in tumour volume in the GTN treated mice. Together, these results indicate a novel role for HIF-1α in the up-regulation of B7-H1 on cancer cells, thus potentially contributing to immune escape of cancer cells and additionally, a role for GTN as a possible breast cancer therapy. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2012-08-15 11:10:06.237
32

The Role of BNIP3 in Proliferation and Hypoxia-Induced Autophagy: Implications for Cancer Therapy

Azad, Meghan Brianne 10 September 2010 (has links)
INTRODUCTION: Autophagy is a regulated degradation pathway functioning in both cell survival and cell death. Its role in cancer is controversial since autophagy can be protective or destructive to tumor cells, depending on individual genetic signatures, stage of malignancy and treatment conditions. Hypoxia is a common feature of solid tumors, correlating with poor prognosis and chemoresistance. We have investigated autophagy in hypoxic cancer cells and examined the role of the hypoxia-inducible protein, BNIP3. METHODS: Multiple cancer cell lines were exposed to chronic hypoxia (<1% O2) in the presence or absence of specific inhibitors for autophagy and apoptosis. Cell death was measured by membrane permeability assay, and autophagy was assayed by GFP-LC3 distribution, LC3 processing, electron microscopy, and acidic vacuole formation. BNIP3 was over-expressed by transient transfection, stably induced in a tetracycline-regulated expression system, or knocked down using siRNA. Whole brain morphology, cell proliferation, and hypoxic response were additionally studied in a BNIP3-null mouse model. RESULTS: Autophagic cell death was detected in hypoxic cancer cells, occurring independent of apoptosis through a mechanism involving BNIP3. BNIP3 itself induced autophagic cell death, and loss of BNIP3 protected against hypoxia-induced autophagy and cell death. Loss of BNIP3 also resulted in differential growth and cell cycle progression in vitro, and increased brain cellularity in vivo compared to wild type controls. Potential mediators of resistance to BNIP3-induced cell death were identified using a novel model of BNIP3 resistance. CONCLUSIONS: Taken together, these results support the emerging theory that autophagy represents an alternative cell death pathway that could be targeted in hypoxic and/or apoptosis-resistant tumors. We have specifically identified BNIP3 as a potential target molecule in this pathway. Finally, we have identified a possibly novel role for BNIP3 in brain development and cell cycle regulation. These findings have important clinical applications given the potential for personalized cancer therapy based on individual tumor characteristics including autophagic capacity, hypoxic status, and BNIP3 activity.
33

The Role of BNIP3 in Proliferation and Hypoxia-Induced Autophagy: Implications for Cancer Therapy

Azad, Meghan Brianne 10 September 2010 (has links)
INTRODUCTION: Autophagy is a regulated degradation pathway functioning in both cell survival and cell death. Its role in cancer is controversial since autophagy can be protective or destructive to tumor cells, depending on individual genetic signatures, stage of malignancy and treatment conditions. Hypoxia is a common feature of solid tumors, correlating with poor prognosis and chemoresistance. We have investigated autophagy in hypoxic cancer cells and examined the role of the hypoxia-inducible protein, BNIP3. METHODS: Multiple cancer cell lines were exposed to chronic hypoxia (<1% O2) in the presence or absence of specific inhibitors for autophagy and apoptosis. Cell death was measured by membrane permeability assay, and autophagy was assayed by GFP-LC3 distribution, LC3 processing, electron microscopy, and acidic vacuole formation. BNIP3 was over-expressed by transient transfection, stably induced in a tetracycline-regulated expression system, or knocked down using siRNA. Whole brain morphology, cell proliferation, and hypoxic response were additionally studied in a BNIP3-null mouse model. RESULTS: Autophagic cell death was detected in hypoxic cancer cells, occurring independent of apoptosis through a mechanism involving BNIP3. BNIP3 itself induced autophagic cell death, and loss of BNIP3 protected against hypoxia-induced autophagy and cell death. Loss of BNIP3 also resulted in differential growth and cell cycle progression in vitro, and increased brain cellularity in vivo compared to wild type controls. Potential mediators of resistance to BNIP3-induced cell death were identified using a novel model of BNIP3 resistance. CONCLUSIONS: Taken together, these results support the emerging theory that autophagy represents an alternative cell death pathway that could be targeted in hypoxic and/or apoptosis-resistant tumors. We have specifically identified BNIP3 as a potential target molecule in this pathway. Finally, we have identified a possibly novel role for BNIP3 in brain development and cell cycle regulation. These findings have important clinical applications given the potential for personalized cancer therapy based on individual tumor characteristics including autophagic capacity, hypoxic status, and BNIP3 activity.
34

Understanding CD8 T cell function under the tumour environment condition hypoxia

Townsend, Katelin N. 03 August 2012 (has links)
As CD8 T cells migrate to tumour sites, they experience conditions of low oxygen or hypoxia, in the tumour environment. Hypoxia results due to the rapid proliferation of tumour cells which deplete essential nutrients such as oxygen as they expand beyond normal vasculature. Hypoxia can cause attenuated immune responses due to the resultant signalling events and metabolic changes initiated in CD8 T cells under these conditions. CD8 T cells are important mediators of anti-tumour activity as they directly kill tumour cells, and are associated with increased survival outcomes in cancer patients. Therefore, I sought to determine the impact of low oxygen on CD8 T cell function. In addition, I investigated the role for autophagy, a cell survival process induced by nutrient depletion, in T cells under hypoxia. The first chapter of this thesis outlines the effects of the hypoxic tumour environment and the known roles for autophagy in T cells. In the second chapter, the role of hypoxia and hypoxia-induced autophagy will be explored in CD8 T cells and the impact on cell function assessed using a transgenic mouse model. The importance of hypoxia for T cell activity clinically will be examined in Chapter 3. High-grade serous ovarian tumours will be evaluated for their oxygenation levels and immune status and correlations with patient survival will be assessed. These results are important for understanding how CD8 T cells function during pathophysiological oxygen conditions found in tumours and reveal hypoxia as a new relevant inducer of autophagy in T cells. Ultimately, these results highlight the need for further research discoveries which promote T cell function during conditions of low oxygen in tumours. Such future discoveries may be combined with therapies which boost or enhance immune responses, allowing more optimal tumour treatments to improve patient survival. / Graduate
35

Hypoxia Suppresses DNA Repair: Implications for Cancer Progression and Treatment

Chan, Norman 14 February 2011 (has links)
Acute and chronic hypoxia exists within the microenvironment of solid tumours and drives therapy resistance, genetic instability and metastasis. Despite its importance in solid tumour progression, very little is known regarding the functional consequences of hypoxia-mediated changes in the expression of DNA repair proteins. I studied the relationship between hypoxia and DNA repair using a prolonged chronic hypoxic gas treatment model in a variety of human tumour cell lines to mimic the dynamic state of proliferation and DNA repair in cells distant from the tumour blood vasculature. I observed decreased expression of homologous recombination (HR) and base excision repair (BER) proteins due to a novel mechanism involving decreased protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O2 as measured by the DR-GFP reporter system and functional BER was impaired as assessed with a functional glycosylase assay. This decrease in protein expression and function resulted in increased sensitivity to the DNA damaging agents MMC, cisplatin, H2O2 and MMS. Additionally, chronically hypoxic cells were relatively radiosensitive (OER = 1.37) when compared to acutely hypoxic or anoxic cells (OER = 1.96 - 2.61). As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, I evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. I observed increased clonogenic killing in HR-deficient hypoxic cells following inhibition or depletion of PARP1. PARP-inhibited hypoxic cells accumulated γH2AX foci consistent with an accumulation of collapsed replication forks. Additionally, tumour xenografts exposed to PARP1 inhibition showed increased γH2AX and cleaved caspase-3 expression in hypoxic subregions with suppressed RAD51 protein expression and decreased ex vivo clonogenic survival. I conclude that persistent down-regulation of DNA repair components by the microenvironment could result in faulty DNA repair with significant implications for therapeutic response and genetic instability in human cancers. Specifically, hypoxic cells may be sensitized to PARP inhibitors and other agents targeting repair pathways down-regulated by hypoxia as a consequence of microenvironment-mediated “contextual synthetic lethality”.
36

Mechanisms and evolution of hypoxia tolerance in family Cottidae

Mandic, Milica 05 1900 (has links)
A comparative phylogenetically independent contrast (PIC) analysis was employed to investigate the adaptive role of traits involved in hypoxia tolerance in sculpins, a group of closely related fish species that live in the nearshore marine environment. I demonstrated that there was a tight correlation between critical oxygen (O₂) tension (P-crit) and the distribution of species across an environmental gradient. Species of sculpins with the lowest P-crit inhabit the 0₂ variable intertidal zone, while species with higher P-crit inhabit the O₂ stable subtidal zone. Low P-crit values in sculpins were associated with enhanced O₂ extraction capacity, with three principal traits accounting for 83% of the variation in P-crit: low routine O₂ consumption rate (MO2 ), high mass specific gill surface area and high whole cell hemoglobin-oxygen (Hb-0₂) binding affinity. Variation in whole cell Hb-O₂ binding affinity was strongly correlated with the intrinsic affinity of Hb for O₂ and not to differences in the concentration of the allosteric Hb modulators ATP and GTP. When environmental O₂ dropped below a species' P-crit, some species of sculpins behaviorally responded to the severe hypoxia by performing aquatic surface respiration (ASR) and aerial emergence. Although intertidal sculpins consistently performed these behaviors, the clustering of these species into a single phylogenetic Glade did not allow us to draw conclusions regarding the relationship between ASR, aerial emergence and P-crit using PIC analysis. Three species of sculpins, which were chosen because of their low, medium and high P-crit values, exhibited dramatically varied mortality rates when exposed to severe hypoxia equivalent to 40% of their respective P-crit. Although ATP turnover rates were similar between the three species in the initial two hours of hypoxia exposure, the differences in the ability of the three species to survive severe hypoxia appeared to be associated with the concentration of on-board liver glycogen and the degree of liver glycogen depletion. However, when liver glycogen was assessed in twelve species of sculpins at normoxia and compared with P-crit, there was nosignificant PIC correlation between P-crit and liver glycogen. Overall, I have shown that there is a clear relationship between P-crit and the distribution of sculpins along the nearshore environment and that this is primarily related to differences in O₂ extraction capacity. When O₂ tensions are well below their P-crit, there are dramatic differences in behavioral, physiological and biochemical responses among these species of sculpins.
37

Sublethal effects of diel fluctuations in dissolved oxygen saturation on freshwater fishes from tropical Queensland /

Flint, Nicole. January 2005 (has links)
Thesis (Ph.D. ) - James Cook University, 2005. / Typescript (photocopy) Bibliography: leaves 162-178, 193-198.
38

Effects of hypoxia on development of the digestive system and metabolism in zebrafish (Danio rerio)

Matozel, Michelle. January 2009 (has links)
Thesis (M.S.)--University of Akron, Dept. of Biology, 2009. / "May, 2009." Title from electronic thesis title page (viewed 8/2/2009) Advisor, Brian Bagatto; Committee members, Francisco Moore, Richard Londraville, Qin Liu; Department Chair, Monte Turner; Dean of the College, Chand Midha; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.
39

Oxybuoy constructing a real-time inexpensive hypoxia monitoring platform /

Nor, Rizal Mohd. January 2009 (has links)
Thesis (M.S.)--Kent State University, 2009. / Title from PDF t.p. (viewed April 7, 2010). Advisor: Mikhail Nesterenko. Keywords: Sensor Networks; Hypoxia; Embedded Devices; Satellite Communication; Optical Dissolved Oxygen Sensor. Includes bibliographical references (p. 30-34).
40

Hypoxia-inducible factor-1α and the Control of Hypoxic Ventilatory and Metabolic Responses in Mice and African Naked Mole Rats

Borecky, Lisa 23 July 2018 (has links)
Hypoxia-inducible factors (HIFs) are a highly conserved group of transcriptional regulators responsible for cellular and systemic O2 homeostasis in animals. However, how HIFs are involved in basic adaptive ventilatory and metabolic responses to acute and chronic hypoxia remains incompletely characterized. Naked mole rats are among the most hypoxia tolerant mammals identified. As opposed to the typical hyperventilatory response of most adult mammals, naked mole rats exhibit a unique decline in ventilation, matching their substantial decrease in metabolic rate. Naked mole rats therefore provide an excellent model in which to investigate adaptations to hypoxic ventilatory and metabolic responses (HVR and HMR, respectively). Interestingly, naked mole rats possess a mutation within the von Hippel-Lindau (VHL) binding domain—a protein necessary for proteasomal degradation of HIF subunits in normal O2 concentrations—suggesting they retain elevated baseline expression of HIF and thus an upregulation of downstream gene targets. In designing our experiment, we focused on sustained hypoxia and HIF1, which is typically the first responder subunit upon exposure to low O2 stress. We sought to determine how increased HIF1 expression might contribute to the distinct HVR and HMR of naked mole rats, first by confirming the observed VHL mutation translates into increased HIF1 protein expression via immunoblotting. HIF1 protein expression was found to be 3-fold higher in naked mole rat brain than mouse brain and 4-fold higher than in mouse liver tissue (p < 0.05). We then investigated how elevated HIF1 levels might contribute to the HVR and HMR by treating naked mole rats with two different HIF1 inhibitors (either echinomycin; 0.5 and 1.0 mg kg-1, or PX-478; 80.0 mg kg-1) and subsequently examined changes in ventilatory and metabolic parameters in awake animals exposed to sustained hypoxia (7% O2; 1 hour). In control naked mole rats, minute ventilation (V̇E) reversibly decreased by 32% in hypoxia (1298.3 ± 188.5 to 882.6 ± 117.0 mL min-1 kg-1) because of changes in both breathing frequency (fR) and tidal volume (VT). Conversely, the HVR was not significantly affected in any of our three treatment groups however, normoxic ventilation increased in naked mole rats treated with low dose echinomycin (0.5 mg kg-1) by 72% (from 1298.3 ± 188.5 to 2239.5 ± 221.1 mL min-1 kg-1). Consistent with previous findings, metabolic rate in control naked mole rats decreased 70% (from 40.1 ± 5.0 to 11.9 ± 0.9 mL O2 min-1 kg-1). Again, treatment with our pharmacological agents did not significantly alter this response but did result in a 43% decrease in basal metabolic rate (V̇O2 and V̇CO2) in both high-dose echinomycin and PX-478 treated naked mole rats (40.1 ± 5.0 to 22.5 ± 3.6 and 23.0 ± 1.88 mL O2 min-1 kg-1 respectively, p < 0.05), dulling the magnitude of the HMR. As a result of unmatched changes in V̇E and V̇O2, HIF1 deficient naked mole rats treated with both low-dose echinomycin and PX-478 experienced an atypical increase in their air convection requirement (ACR; V̇E:V̇O2-1) in hypoxia (from 77.4 ± 11.3 to 159.2 ± 34.63 and 123.5 ± 35.5 respectively, p < 0.05), resembling a hyperventilation response closer to that of hypoxia-intolerant mammals. To further determine how increased HIF1 availability affects the HMR and HVR, we administered hypoxia-intolerant mice with a pharmacological HIF1 agonist (3,4- EDHB; 180 mg kg-1) and used identical experimental design to measure downstream ventilatory and metabolic responses. Mice exhibit similar reductions in metabolic rate during hypoxic exposure (from 60.3 ± 2.4 to 21.8 ± 1.8 mL O2 min-1 kg-1, p < 0.05) but experience a 30% increase in fR (from 157.5 ± 9.5 to 200.4 ± 10.8 breaths min-1, p < 0.05). In contrast, mice treated with EDHB and to exposed 7% O2 exhibited a 20% increase in fR (200.4 ± 10.8 to 236.5 ± 14.1 breaths min-1, p < 0.05) and a 30% reduction in the magnitude of their HMR (from 38.5 ± 2.8 to 27.8 ± 3.6 ΔV̇O2). No other significant trends were observed in any of the other parameters measured. We conclude metabolic and ventilatory control in naked mole rats and mice may partially depend on increased HIF1 expression.

Page generated in 0.0743 seconds