+publisher:"Penn State University" +contributor:("Richard Robert Young, Committee Member")

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1. Ryland, Lindsay Kate. DIFFERENTIAL MECHANISMS OF CELL DEATH INDUCTION VIA DELIVERY OF THERAPEUTIC NANOLIPOSOMAL CERAMIDE IN LEUKEMIAS .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12511

► Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative malignancy that involves blood, bone marrow and spleen infiltration. Clinically, LGL leukemia can manifest as a… (more)

▼ Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative malignancy that involves blood, bone marrow and spleen infiltration. Clinically, LGL leukemia can manifest as a chronic lymphocytosis or as an aggressive leukemia that is fatal within a short period of time. A segment of LGL leukemia patients are unresponsive to immunosuppressive therapy and currently there is no known curative treatment for this disease. Another hematological malignancy, chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults in Western countries and accounts for approximately 30% of all diagnosed leukemia cases. Around 95% of all CLL cases involve clonal expansion and abnormal proliferation of neoplastic B lymphocytes in lymphoid organs, bone marrow and peripheral blood. Similar to LGL leukemia, CLL is also incurable with current therapies. Therefore, this represents a need for new therapeutic approaches for treatment of these diseases. Recent advances in nanotechnology have illustrated the feasibility of generating nanoliposomes that encapsulate hydrophobic compounds, like ceramide, to facilitate treatment of LGL leukemia and CLL. Ceramide is an anti-proliferative sphingolipid metabolite that has been shown to selectively induce cell death in cancer cells. However, the use of ceramide as a chemotherapeutic agent is limited due to hydrophobicity. While it is understood how nanoliposomal ceramide induces cell death in several types of cancers and hematological malignancies, the effect of nanoliposomal ceramide treatment in LGL leukemia and CLL remains unclear. In this study, we investigate the differential mechanisms of cell death induction following nanoliposomal C6-ceramide treatment in both LGL leukemia and CLL. We show that nanoliposomal C6-ceramide displays minimal cytotoxicity in normal donors‟ peripheral blood mononuclear cells (PBMCs) and is a well-tolerated therapy during in vivo treatment in these leukemia models. To further examine this mechanism of selectivity, we utilize CLL as a cancer model which has an increased dependency on glycolysis. As most tumors exhibit a preferential switch to glycolysis, as described in the “Warburg effect,” we hypothesize that ceramide nanoliposomes selectively target this activated glycolytic pathway in cancer. We demonstrate that nanoliposomal ceramide inhibits both the RNA and protein expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an intermediate enzyme in the glycolytic pathway, which is overexpressed in a subset of CLL patients. Taken together, our results suggest that C6-ceramide nanoliposomes preferentially inhibit the enhanced metabolism of glucose in leukemic CLL cells, which results in induction of cell death. We conclude that selective inhibition of the glycolytic pathway in CLL cells with nanoliposomal C6-ceramide could potentially be an effective therapy for this leukemia by targeting the Warburg effect. In addition, we conclude that nanoliposomal C6-ceramide could also be an effective therapy for patients with LGL leukemia.… Advisors/Committee Members: Mark Kester, Dissertation Advisor/Co-Advisor, Mark Kester, Committee Chair/Co-Chair, Thomas Loughran, Committee Member, Hong Gang Wang, Committee Member, Jin Ming Yang, Committee Member, Richard Robert Young, Committee Member.

Subjects/Keywords: sphingolipid; ceramide; nanoliposome; chronic lymphocytic leukemia

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APA (6^th Edition):

Ryland, L. K. (2011). DIFFERENTIAL MECHANISMS OF CELL DEATH INDUCTION VIA DELIVERY OF THERAPEUTIC NANOLIPOSOMAL CERAMIDE IN LEUKEMIAS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12511

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ryland, Lindsay Kate. “DIFFERENTIAL MECHANISMS OF CELL DEATH INDUCTION VIA DELIVERY OF THERAPEUTIC NANOLIPOSOMAL CERAMIDE IN LEUKEMIAS .” 2011. Thesis, Penn State University. Accessed February 26, 2021. https://submit-etda.libraries.psu.edu/catalog/12511.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ryland, Lindsay Kate. “DIFFERENTIAL MECHANISMS OF CELL DEATH INDUCTION VIA DELIVERY OF THERAPEUTIC NANOLIPOSOMAL CERAMIDE IN LEUKEMIAS .” 2011. Web. 26 Feb 2021.

Vancouver:

Ryland LK. DIFFERENTIAL MECHANISMS OF CELL DEATH INDUCTION VIA DELIVERY OF THERAPEUTIC NANOLIPOSOMAL CERAMIDE IN LEUKEMIAS . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Feb 26]. Available from: https://submit-etda.libraries.psu.edu/catalog/12511.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ryland LK. DIFFERENTIAL MECHANISMS OF CELL DEATH INDUCTION VIA DELIVERY OF THERAPEUTIC NANOLIPOSOMAL CERAMIDE IN LEUKEMIAS . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12511

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

2. Young, Megan Marie. The Role Of Sphingosine Kinase In The Crosstalk Between Apoptosis, Autophagy And Endocytosis.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/27408

► Autophagy is a catabolic process in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and delivered to lysosomes for degradation and recycling. Autophagy… (more)

▼ Autophagy is a catabolic process in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and delivered to lysosomes for degradation and recycling. Autophagy functions to maintain homeostasis through the removal of cellular damage and generation of nutrients. Although autophagy and the cell death pathway of apoptosis utilize fundamentally distinct machinery to regulate cell fate, the two pathways are joined through an intricate network of molecular crosstalk. Sphingolipids represent a class of bioactive lipids that regulate various cellular processes, including apoptosis and autophagy, and thus may serve as novel regulators of the crosstalk between the two pathways. Here, we demonstrate that modulation of sphingolipid metabolism using the pan-sphingosine kinase 1/2 inhibitor, SKI-I, induces the assembly of an intracellular death-inducing signaling complex (iDISC) on autophagosomal membranes for the activation of caspase-8 and induction of apoptosis. Mechanistically, we show that the iDISC consists of two arms that recruit pro-caspase-8 to the autophagosomal membrane for oligomerization and self-activation: 1) Atg12-Atg5:FADD:caspase-8 and 2) LC3-II:p62:caspase-8. To further dissect the role of sphingosine kinase in iDISC-mediated cell death, we identified several sphingosine kinase 1 (Sphk1)-selective inhibitors to test in our system. Unexpectedly, we observed that the sphingosine-based inhibitor SK1i, but not the small molecule inhibitor PF-543, induces massive cellular vacuolization and enlargement of late endosomes and amphisomes. Notably, the loss of Sphk1 suppresses vacuolization by SK1i, and SK1i-induced endocytic vesicles fail to acquire late endosomal markers in Sphk1-deficient cells. As SK1i inhibits Sphk1 activity and the protein localizes to the enlarged vacuoles during treatment, we hypothesize that Sphk1 promotes membrane fusion independent of enzymatic activity. Furthermore, we demonstrate that the LC3 conjugation machinery and lysosome biogenesis regulate the clearance of the enlarged late endosomes. Collectively, these studies suggest that inhibition of sphingosine kinase alters autophagosomal and endosomal membrane dynamics and intracellular trafficking to regulate cell fate. Future studies will aid in identifying specific sphingolipid metabolites and/or proteins required for iDISC-dependent cell death as well as mechanistic insight into Sphk1 function in endosome trafficking. We believe that this knowledge will be critical for the implementation of autophagy-dependent apoptosis as a novel approach to enhance chemotherapeutic efficacy. Advisors/Committee Members: Hong Gang Wang, Dissertation Advisor/Co-Advisor, Hong Gang Wang, Committee Chair/Co-Chair, Mark Kester, Committee Chair/Co-Chair, Jin Ming Yang, Committee Member, Lisa M Shantz, Committee Member, Richard Robert Young, Committee Member.

Subjects/Keywords: autophagy; apoptosis; endocytosis; iDISC; sphingosine kinase; sphingosine; sphingolipid; SK1i; SKI-I; late endosome

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APA (6^th Edition):

Young, M. M. (2015). The Role Of Sphingosine Kinase In The Crosstalk Between Apoptosis, Autophagy And Endocytosis. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/27408

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Young, Megan Marie. “The Role Of Sphingosine Kinase In The Crosstalk Between Apoptosis, Autophagy And Endocytosis.” 2015. Thesis, Penn State University. Accessed February 26, 2021. https://submit-etda.libraries.psu.edu/catalog/27408.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Young, Megan Marie. “The Role Of Sphingosine Kinase In The Crosstalk Between Apoptosis, Autophagy And Endocytosis.” 2015. Web. 26 Feb 2021.

Vancouver:

Young MM. The Role Of Sphingosine Kinase In The Crosstalk Between Apoptosis, Autophagy And Endocytosis. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Feb 26]. Available from: https://submit-etda.libraries.psu.edu/catalog/27408.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Young MM. The Role Of Sphingosine Kinase In The Crosstalk Between Apoptosis, Autophagy And Endocytosis. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/27408

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

3. Crampsie, Melissa Ashley. INVESTIGATION OF THE MECHANISM OF ACTION OF ISOTHIOCYANATE DERIVED ISOSELENOCYANATES AND THE CHEMOPREVENTIVE POTENTIAL OF PHENYLBUTYL ISOSELENOCYANATE .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12391

► Goals of Dissertation Research Lung cancer is currently the leading cause of cancer deaths among men and women and has a survival rate of only… (more)

▼ Goals of Dissertation Research Lung cancer is currently the leading cause of cancer deaths among men and women and has a survival rate of only 16%. Because nearly 90% of lung cancer cases are attributed to smoking tobacco and tobacco related lung cancer has a latency period of 20-30 years from time of exposure to invasive disease, intervention before invasive disease with a chemical agent, termed chemoprevention, is a well suited approach for this particular disease. Research suggests that many natural compounds, often found in the human diet, have chemopreventive properties and are actively being explored and/or can make excellent lead compounds. Our lab, using rational drug design techniques, developed a novel isoselenocyanate compound known as phenylbutyl isoselenocyanate (ISC-4) based on naturally occurring compounds found in cruciferous vegetables. The central hypothesis of this research was that ISC-4, based on its design, would function as a potent and effective anti-cancer agent and could be used as a chemopreventive agent. Specific Aims Specific Aim 1: To determine the effects of replacing the sulfur atom of a panel of phenyl alkyl isothiocyanates with selenium to form a new panel of phenyl alkyl isoselenocyanates (Chapter 2). A structure activity study was performed on the panel of parent isothiocyanate compounds and the resulting panel of isoselenocyanate compounds to determine if mechanistic characteristics were retained and to ascertain a reason for increased activity. Specific Aim 2: Testing the hypothesis that ISC-4 has potential as a chemopreventive agent (Chapter 3). This drug was found to potently target and inhibit carcinogen bioactivation by cytochrome P450 enzymes, including the tobacco specific nitrosamine procarcinogen, N-nitrosyl ketone (NNK). When bioactivated, NNK can lead to mutations in DNA and ultimately result in tumorigenesis. A series of experiments were conducted to assess chemopreventive properties including bioavailability, anti-initiation, and DNA adduct studies, all of which were needed as proof of concept before performing an animal bioassay. Specific Aim 3: Testing ISC-4 as a chemopreventive agent in a lung cancer chemoprevention bioassay (Chapter 4). Using an A/J mouse model, ISC-4 at varying doses and along with its sulfur analog PBITC were tested for the ability to inhibit NNK induced lung tumorigenesis over a 24 week period of time. Original Breakthroughs and Findings Isoselenocyanate (ISC) compounds were actually found to have increased activity with cellular thiols compared to their corresponding sulfur analogs leading to the hypothesis that specific protein modifications and redox activity in the cell are responsible for the increased activities seen with the ISC compounds. As Phase I cytochrome P450s were identified early as a significant protein target of ISC-4, the cancer chemopreventive properties of this compound were explored. ISC-4 was found to be orally bioavailable, able to transcriptionally induce Phase II detoxification enzymes, and inhibit DNA adduct… Advisors/Committee Members: Shantu G Amin, Dissertation Advisor/Co-Advisor, Shantu G Amin, Committee Chair/Co-Chair, Arun Kumar Sharma, Committee Chair/Co-Chair, Kelly J Karpa, Committee Member, Bogdan Prokopczyk, Committee Member, Gary H Perdew, Committee Member, Richard Robert Young, Committee Member.

Subjects/Keywords: ISC-4; lung cancer; chemoprevention

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APA (6^th Edition):

Crampsie, M. A. (2011). INVESTIGATION OF THE MECHANISM OF ACTION OF ISOTHIOCYANATE DERIVED ISOSELENOCYANATES AND THE CHEMOPREVENTIVE POTENTIAL OF PHENYLBUTYL ISOSELENOCYANATE . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12391

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Crampsie, Melissa Ashley. “INVESTIGATION OF THE MECHANISM OF ACTION OF ISOTHIOCYANATE DERIVED ISOSELENOCYANATES AND THE CHEMOPREVENTIVE POTENTIAL OF PHENYLBUTYL ISOSELENOCYANATE .” 2011. Thesis, Penn State University. Accessed February 26, 2021. https://submit-etda.libraries.psu.edu/catalog/12391.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Crampsie MA. INVESTIGATION OF THE MECHANISM OF ACTION OF ISOTHIOCYANATE DERIVED ISOSELENOCYANATES AND THE CHEMOPREVENTIVE POTENTIAL OF PHENYLBUTYL ISOSELENOCYANATE . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Feb 26]. Available from: https://submit-etda.libraries.psu.edu/catalog/12391.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Crampsie MA. INVESTIGATION OF THE MECHANISM OF ACTION OF ISOTHIOCYANATE DERIVED ISOSELENOCYANATES AND THE CHEMOPREVENTIVE POTENTIAL OF PHENYLBUTYL ISOSELENOCYANATE . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12391

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

4. Jones, Nathan Richard. Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism.

Degree: 2012, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/13184

► There is a complex interplay between genetic and environmental factors that determine inter-individual differences in disease disposition and therapeutic response. Drug metabolism pathways have been… (more)

▼ There is a complex interplay between genetic and environmental factors that determine inter-individual differences in disease disposition and therapeutic response. Drug metabolism pathways have been a major focus of pharmacogenetic studies because inter-individual differences in the expression and activity of these enzymes may cause clinically significant effects on the kinetic properties of various drugs. Because of their role in the metabolism of chemical toxins and carcinogens, genetic differences in drug metabolizing enzymes are also associated with risk of diseases such as cancer. There are many factors governing inter-individual variation in drug-metabolizing enzymes including SNPs, epigenetics, alternative splicing events, transcriptional regulation, and post-translational modifications. UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and excretion of endogenous and xenobiotic compounds including drugs and carcinogens. UGT enzymes mediate the phase II conjugation of glucuronic acid to their substrates, thereby increasing substrate polarity and facilitating their excretion. Variations in UGT genes are associated with altered drug metabolism and cancer risk. Some of the genetic factors underlying these associations have been discovered, but often there is wide variability in phenotype within a given genotype. The liver is the organ most commonly associated with metabolism, and most UGTs are expressed in the human liver. Expression in extrahepatic tissues has been less well characterized, even though tissues that form a barrier with the environment, such as aerodigestive and gastrointestinal tract tissues represent an important first line of defense against exposures to xenobiotic compounds. A better understanding of the inter-individual variability and relative abundance of UGT gene expression in different tissues is important as this helps determine the physiological relevance of each UGT enzyme. While many previous studies have used qualitative reverse transcription polymerase chain reaction (RT-PCR) for determining which UGT genes are expressed in different tissues, some quantitative analysis of UGT expression has been performed In studies described in this thesis dissertation, real-time PCR was used to quantify the expression of 16 UGT enzymes in multiple specimens of various normal human tissues including lung, liver, larynx, brain, tongue, floor of mouth, tonsil, esophagus, endometrium, and pancreas. Substantial inter-individual variability in expression was observed in both hepatic and extrahepatic tissues. In extrahepatic tissues, unpredictable expression patterns were frequently observed, in which UGT enzymes expressed in some individuals were not expressed in others. In the liver, there was a high degree of correlation between the expression levels of many UGT enzymes within the same individual, suggesting a common mechanism of transcriptional regulation. The hepatic expression of UGTs is known to be transcriptionally regulated by ligand-activated and… Advisors/Committee Members: Philip Lazarus, Ph D, Dissertation Advisor/Co-Advisor, Philip Lazarus, Ph D, Committee Chair/Co-Chair, Jong Kak Yun, Committee Member, John Peter Richie Jr., Committee Member, Thomas E Spratt, Committee Member, Richard Robert Young, Committee Member.

Subjects/Keywords: UDP-glucuronosyltransferase; expression; transcriptional regulation; alternative splicing; pharmacogenetics

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APA (6^th Edition):

Jones, N. R. (2012). Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13184

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Jones, Nathan Richard. “Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism.” 2012. Thesis, Penn State University. Accessed February 26, 2021. https://submit-etda.libraries.psu.edu/catalog/13184.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Jones NR. Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Feb 26]. Available from: https://submit-etda.libraries.psu.edu/catalog/13184.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Jones NR. Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/13184

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

5. Dick, Taryn Eve. A promising anti-cancer agent that functions as a dual target inhibitor of SphK1 and microtubule dynamics.

Degree: 2016, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/29574

► An extensive amount of data points to sphingosine kinase 1 (SphK1) and aberrant regulation of sphingolipids as important components of tumorigenesis. We previously developed SKI-178… (more)

▼ An extensive amount of data points to sphingosine kinase 1 (SphK1) and aberrant regulation of sphingolipids as important components of tumorigenesis. We previously developed SKI-178 as a novel small molecule, SphK1-selective inhibitor that is cytotoxic toward a broad panel of cancer cell lines. Nonetheless, the mechanism underlying SKI-178 induced apoptotic cell death had not yet been elucidated. Therefore, the overarching goal of this research study was to uncover the detailed mechanism-of-action (MOA) of SKI-178 induced apoptosis. Using human acute myeloid leukemia (AML) cell lines as a model, we present evidence that SKI-178 induces prolonged mitosis followed by apoptotic cell death through the intrinsic apoptotic cascade. We further demonstrate that the sustained activation of cyclin-dependent kinase 1 (CDK1) during SKI-178 mediated prolonged mitosis leads to the simultaneous phosphorylation of pro-survival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. Based on evidence in the literature suggesting a link between SphK1 activity and mitotic arrest, we originally attributed much of the MOA to SphK1 inhibition. However, in light of recent reports claiming that SphK1 inhibition alone is not sufficient to induce apoptotic cell death; we considered the possibility that SKI-178 may have additional targets that contribute to its cytotoxicity. Based on the striking similarly between the MOA of SKI-178 and various agents that disrupt microtubules, we considered the possibility that SKI-178, in addition to being a SphK1 selective inhibitor, also affects normal microtubule dynamics. We hypothesize that SKI-178 mediated apoptosis is due to its ability to work as a microtubule targeting agent (MTA), and that its concomitant inhibition of SphK1 sensitizes cells to this effect. Herein we present evidence that SKI-178 does indeed function as MTA, preventing the polymerization of the microtubule network. Furthermore, we demonstrate that independent of SKI-178, inhibition of SphK1 alone sensitizes cells to vincristine, a MTA known for its ability to disrupt microtubule polymerization. We also definitively confirm that in cells, SKI-178 is able to directly target engage both SphK1 and tubulin proteins at concentrations known to induce apoptotic cell death in a panel of cancer cell lines. Moreover, multi-drug resistance, mediated by multidrug resistant protein-1 and/or pro-survival Bcl-2 family member over-expression, did not affect the sensitivity of cells to SKI-178. Together, these results establish SKI-178 as a dual target inhibitor with promising chemotherapeutic potential for a wide variety of cancer types including those know to be multi-drug resistant. Advisors/Committee Members: Jong Kak Yun, Dissertation Advisor/Co-Advisor, Jong Kak Yun, Committee Chair/Co-Chair, Victor J Ruiz Velasco, Committee Member, Shantu G Amin, Committee Member, Dhimant Desai, Committee Member, Richard Robert Young, Committee Member, Jeremy Andrew Hengst, Special Member.

Subjects/Keywords: Sphingosine Kinase; Cyclin-dependent kinase 1; cell cycle arrest; mitotic arrest; mitotic cell death; microtubules

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APA (6^th Edition):

Dick, T. E. (2016). A promising anti-cancer agent that functions as a dual target inhibitor of SphK1 and microtubule dynamics. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/29574

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Dick, Taryn Eve. “A promising anti-cancer agent that functions as a dual target inhibitor of SphK1 and microtubule dynamics.” 2016. Thesis, Penn State University. Accessed February 26, 2021. https://submit-etda.libraries.psu.edu/catalog/29574.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Dick, Taryn Eve. “A promising anti-cancer agent that functions as a dual target inhibitor of SphK1 and microtubule dynamics.” 2016. Web. 26 Feb 2021.

Vancouver:

Dick TE. A promising anti-cancer agent that functions as a dual target inhibitor of SphK1 and microtubule dynamics. [Internet] [Thesis]. Penn State University; 2016. [cited 2021 Feb 26]. Available from: https://submit-etda.libraries.psu.edu/catalog/29574.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Dick TE. A promising anti-cancer agent that functions as a dual target inhibitor of SphK1 and microtubule dynamics. [Thesis]. Penn State University; 2016. Available from: https://submit-etda.libraries.psu.edu/catalog/29574

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

6. Doshi, Ushma Atul. Molecular Mechanisms of Nanoliposomal C6-ceramide-induced Cell Death in Chronic Lymphocytic Leukemia.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/27515

► Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia in Western countries. Despite a high incidence, its pathogenesis is still poorly understood,… (more)

▼ Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia in Western countries. Despite a high incidence, its pathogenesis is still poorly understood, hence limiting treatment strategies. Furthermore, since CLL is predominantly a disease of the elderly, numerous therapeutic strategies are unsuitable due to limited physical fitness of the patient. Therefore, the CLL remains incurable for most patients. Further research is needed to develop novel therapeutic strategies. Ceramide is a ‘tumor suppressor’ sphingolipid known to regulate differentiation, senescence and cell cycle arrest. While a large body of work reveals the mechanism of nanoliposomal ceramide (CNL)-induced cell death in several types of cancers, the effect in CLL remains unclear. This study investigates the effect of CNL in CLL and deciphers the key signaling mechanisms mediating CNL-induced cell death. We have shown that CNL selectively induces cell death in CLL cells by targeting the Warburg effect through reducing levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), with no detrimental effects on normal peripheral blood mononuclear cells. Additionally, CNL treatment results in tumor regression in an in vivo murine model of CLL. Several reports in the literature have shown that signal transducer and activator of transcription 3 (STAT3) is constitutively phosphorylated on serine-727 in CLL and that STAT3 might be a therapeutic target in this disease. We demonstrate that CNL suppresses STAT3 phosphorylation at both tyrosine-705 and serine-727 by inhibiting multiple upstream kinases that include Bruton’s tyrosine kinase, mitogen-activated protein kinase kinase and protein kinase C. This suppression in STAT3 phosphorylation and the subsequent downregulation of STAT3 transcriptional activity mediates CNL-induced cell death in CLL. Recent work in the literature has uncovered that STAT3 phosphorylated at serine-727 associates with mitochondrial components and regulates the respiratory chain. Overactivation of mitochondrial STAT3 phosphorylated at serine-727 confers viability and stress protection to CLL cells. Our initial results demonstrate that CNL treatment reduces mitochondrial STAT3 levels, which might also be critical to the cell death induction. Taken together, our results suggest that inhibition of glycolytic respiration and inhibition of STAT3 transcriptional activity are key signaling mechanisms of CNL-induced cell death in CLL cells. Additionally, we also speculate that inhibition of STAT3-dependent mitochondrial respiration is also critical for induction of cell death by CNL treatment. We conclude that CNL could potentially be an effective therapy for CLL. Overall, this work emphasizes targeting the sphingolipid pathway and development of sphingolipids-based therapeutics for cancer. Advisors/Committee Members: Dr Mark Kester, Dissertation Advisor/Co-Advisor, Charles H Lang, Committee Chair/Co-Chair, Dr Thomas Loughran, Committee Member, Hong Gang Wang, Committee Member, David F Claxton, Special Member, Jin Yang, Committee Member, Richard Robert Young, Committee Member.

Subjects/Keywords: chronic lymphocytic leukemia; ceramide; Warburg effect; STAT3; cell death

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Doshi, U. A. (2015). Molecular Mechanisms of Nanoliposomal C6-ceramide-induced Cell Death in Chronic Lymphocytic Leukemia. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/27515

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Doshi, Ushma Atul. “Molecular Mechanisms of Nanoliposomal C6-ceramide-induced Cell Death in Chronic Lymphocytic Leukemia.” 2015. Thesis, Penn State University. Accessed February 26, 2021. https://submit-etda.libraries.psu.edu/catalog/27515.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Doshi, Ushma Atul. “Molecular Mechanisms of Nanoliposomal C6-ceramide-induced Cell Death in Chronic Lymphocytic Leukemia.” 2015. Web. 26 Feb 2021.

Vancouver:

Doshi UA. Molecular Mechanisms of Nanoliposomal C6-ceramide-induced Cell Death in Chronic Lymphocytic Leukemia. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Feb 26]. Available from: https://submit-etda.libraries.psu.edu/catalog/27515.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Doshi UA. Molecular Mechanisms of Nanoliposomal C6-ceramide-induced Cell Death in Chronic Lymphocytic Leukemia. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/27515

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

7. Kordel, Richard. EXPLORING THE ELECTRONIC CLASSROOM AS A LEARNING SYSTEM .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8386

► ABSTRACT The purpose of this study is to examine the system that is comprised of teachers, students, content and media, with a focus on the… (more)

▼ ABSTRACT The purpose of this study is to examine the system that is comprised of teachers, students, content and media, with a focus on the specific consequences of using computers as teaching aids, and to explore the factors that may lead to an understanding of those consequences. I will explore the idea that far from being a passive information delivery and communication tool, the act of moving information onto a computer adds to, subtracts from, and changes the nature of information presentation, comprehension and communication. That change can be situated in the nature of the medium itself, or in how the students and teachers interact with that medium, or in the teachers and students themselves. Hopefully, this study will lead to a more careful consideration on the part of educators of how, in the best of circumstances, the computer has been incorporated into education as a useful research and communication tool, and in the worst, of how education has been compromised by the indiscriminate use of computers. Looking forward it is my hope that this research can serve to guide practice within the evolving field of educational technology. In this paper I will seek answers to the following research questions: - What role does the presentation and communication of information on a computer screen play in how students and teachers interpret and react to the information? - What happens to the learning system when teaching and learning transaction is filtered through the medium of the computer? Specifically, what happens: o in the content of discussions? o in the conduct of discussions? iv o in how students and teachers conceptualize knowledge? o in how students and teachers envision the purpose of education? - What role do student and teacher background attitudes, personality type, information processing style and self-perceived computer competency play in how those students and teachers perceive discussions, conceptualize knowledge, and perceive purpose of education? These research questions are viewed as being inter-related and part of a complete system. Implicit in these questions is an applied research orientation which assumes there is a way to improve teaching and learning through an understanding of how the use of computers affects students, teachers and information Advisors/Committee Members: Patricia Angelica Cranton, Committee Chair/Co-Chair, Daniele D Flannery, Committee Member, William Dryden Milheim, Committee Member, Richard Robert Young, Committee Member.

Subjects/Keywords: information presentation; electronic education; learning systems; mental models

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APA (6^th Edition):

Kordel, R. (2008). EXPLORING THE ELECTRONIC CLASSROOM AS A LEARNING SYSTEM . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8386

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kordel, Richard. “EXPLORING THE ELECTRONIC CLASSROOM AS A LEARNING SYSTEM .” 2008. Thesis, Penn State University. Accessed February 26, 2021. https://submit-etda.libraries.psu.edu/catalog/8386.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kordel, Richard. “EXPLORING THE ELECTRONIC CLASSROOM AS A LEARNING SYSTEM .” 2008. Web. 26 Feb 2021.

Vancouver:

Kordel R. EXPLORING THE ELECTRONIC CLASSROOM AS A LEARNING SYSTEM . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Feb 26]. Available from: https://submit-etda.libraries.psu.edu/catalog/8386.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kordel R. EXPLORING THE ELECTRONIC CLASSROOM AS A LEARNING SYSTEM . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8386

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Open Access Theses and Dissertations