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You searched for +publisher:"Temple University" +contributor:("Golemis, Erica;"). Showing records 1 – 3 of 3 total matches.

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Temple University

1. Nemani, Neeharika. Molecular Determinant of Mitochondrial Shape Change.

Degree: PhD, 2018, Temple University

Biomedical Sciences

Mitochondria shape cytosolic Ca2+ (cCa2+) transients. Ca2+ entry into the mitochondria is driven by the highly negative mitochondrial membrane potential and through a highly selective channel, the Mitochondrial Calcium Uniporter (MCU). Mitochondrial Ca2+ (mCa2+) is utilized by the matrix dehydrogenases for maintaining cellular bioenergetics. The TCA cycle-derived NADH and FADH2 are mCa2+ dependent thus, feed into the electron transport chain (ETC) to generate ATP. Either loss of mCa2+ or metabolite uptake by the mitochondria results in a bioenergetic crisis and mitochondrial dysfunction. Reciprocally, sudden elevation of cCa2+ under conditions of stroke or ischemia/reperfusion injury (I/R) drives excessive mCa2+ overload that in turn leads to the opening of a large channel, the mitochondrial permeability transition pore (PTP) that triggers necrotic cell death. Thus, Ca2+ and metabolite equilibrium is essential to maintain a healthy mitochondrial pool. Our laboratory has previously showed that loss of mCa2+ uptake leads to decreased ATP generation and cell survival through autophagy. Although metabolite scarcity also results in similar reduction in ATP generation, the molecular mechanisms by which metabolites control mitochondrial ion homeostasis remain elusive. Deprivation of glucose or supplementation of mitochondrial pyruvate carrier (MPC) transport blocker UK5099 and or carnitine-dependent fatty acid blocker etomoxir triggered an increase in the expression of MICU1, a regulator of the mitochondrial calcium uniporter (MCU) but not the MCU core subunit. Consistently, either RNAi-mediated deletion of MPC isoforms or dominant negative human mutant MPC1 R97W showed significant induction of MICU1 protein abundance and inhibition of MCU-mediated mCa2+ uptake. Moreover, TCA cycle substrate-dependent MICU1 expression is under the control of EGR1 transcriptional regulation. Reciprocally, the MICU1 dependent inhibition of mCa2+ uptake exhibited lower NADH production and oxygen consumption and ATP production. The reduction of mitochondrial pyruvate by MPC knockdown is linked to higher production of mitochondrial ROS and elevated autophagy markers. These studies reveal an unexpected regulation of MCU-mediated mCa2+ flux machinery involving major TCA cycle substrate availability and possibly MICU1 to control cellular switch between glycolysis and oxidative phosphorylation. While mCa2+ is required for energy generation, sustained elevation of mCa2+ results in mitochondrial swelling and necrotic death. Hence, it was thought that preventing mCa2+ overload can be protective under conditions of elevated cCa2+. Contrary to this, mice knocked-out for MCU, that demonstrated no mCa2+ uptake and hence no mitochondrial swelling, however failed protect cells from I/R- mediated cell death. MCU-/- animals showed a similar infarct size comparable to that of control animals, suggesting that prevention of MCU-mediated mCa2+ overload alone is not sufficient to protect cells from Ca2+ -induced necrosis. The absence of mCa2+…

Advisors/Committee Members: Goldfinger, Lawrence;, Muniswamy, Madesh, Golemis, Erica A., Tian, Ying, Gallo, Gianluca;.

Subjects/Keywords: Molecular biology; Biochemistry;

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APA (6th Edition):

Nemani, N. (2018). Molecular Determinant of Mitochondrial Shape Change. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,511170

Chicago Manual of Style (16th Edition):

Nemani, Neeharika. “Molecular Determinant of Mitochondrial Shape Change.” 2018. Doctoral Dissertation, Temple University. Accessed October 27, 2020. http://digital.library.temple.edu/u?/p245801coll10,511170.

MLA Handbook (7th Edition):

Nemani, Neeharika. “Molecular Determinant of Mitochondrial Shape Change.” 2018. Web. 27 Oct 2020.

Vancouver:

Nemani N. Molecular Determinant of Mitochondrial Shape Change. [Internet] [Doctoral dissertation]. Temple University; 2018. [cited 2020 Oct 27]. Available from: http://digital.library.temple.edu/u?/p245801coll10,511170.

Council of Science Editors:

Nemani N. Molecular Determinant of Mitochondrial Shape Change. [Doctoral Dissertation]. Temple University; 2018. Available from: http://digital.library.temple.edu/u?/p245801coll10,511170


Temple University

2. Wagner, Jessica Michelle. Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues.

Degree: PhD, 2018, Temple University

Cancer Biology & Genetics

ONC201 is a novel compound that upregulates endogenous TNF-Related Apoptosis-Inducing Ligand (TRAIL), in tumor and normal cells, restoring autocrine and paracrine anti-tumor activity within tumor cells, and upregulates the DR5 gene by activating the integrated stress response, inducing eIF2-alpha-dependent ATF4 and CHOP [1-3]. ONC201 also demonstrates potent anti-tumor effects on colorectal cancers [4, 5]. ONC201 presented a promising oral bioavailability, wide distribution throughout the body, and ability to cross the blood-brain barrier. Further, the unique ability of its TRAIL-and-DR5-based signaling to induce apoptosis in cancer cells and not normal cells adds to its appeal as an anti-cancer therapeutic and prompted clinical development [1-4, 6]. ONC201 has successfully completed an FDA advanced Phase I/II clinical trial in advanced aggressive refractory solid tumors. Results indicated that ONC201 is well-tolerated and recommended a phase II dose of 625 mg orally every 3 weeks. Several Phase I/II clinical trials are enrolling in multiple solid tumors and hematological malignancies [7, 8]. Chapter two of this study provides evidence that ONC201 dose intensification demonstrates an increased pharmacodynamic effect and an increasing anti-tumor efficacy in vivo while having a safe toxicity profile upon weekly dosing. This data influenced the Phase II clinical trials, which have now been adjusted to include weekly dosing. Given the potential anti-metastatic effects of TRAIL signaling and the role of TRAIL in the immune surveillance of cancer, we hypothesized that ONC201 would suppress metastatic tumor development and engage the immune system in its anti-cancer activity. We also establish that ONC201 provides an important anti-metastatic effect in CRC that should be pursued in both pre-clinical and clinical studies. Tail vein and surgical CRC models demonstrate that ONC201 inhibits the number and size of metastases. Evidence has shown that TRAIL can also inhibit cancer metastasis by possibly inducing cell death or TRAIL-sensitization in the primary tumor when cells undergo extravasation upon detachment from the primary tumor [9-11]. While we show that TRAIL plays a role in ONC201’s ability to inhibit migration/invasion in vitro, further investigation of the role of TRAIL in vivo is necessary. Our data indicates that ONC201 promotes a pro-immune response in CRC subcutaneous tumors with increased NK cells that play a role in ONC201’s efficacy in syngeneic models. Since activated natural killer cells express TRAIL, we established that ON201 can activate and induce TRAIL expression in NK cells [12, 13]. As we did not find any immune infiltrates in the metastases, we suggest that the effect of the micro-environment or in more clinically-relevant models with stromal environments should be pursued. Chapter 3 of this of thesis demonstrates the characterization of ONC201’s core structure and development of ONC201 analogues including their mechanistic differences and potential in vivo efficacy and…

Advisors/Committee Members: El-Deiry, Wafik S.;, Grana-Amat, Xavier, Golemis, Erica, Haines, Dale, Yang, Xiaolu;.

Subjects/Keywords: Biology; Pharmacology;

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APA (6th Edition):

Wagner, J. M. (2018). Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,499420

Chicago Manual of Style (16th Edition):

Wagner, Jessica Michelle. “Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues.” 2018. Doctoral Dissertation, Temple University. Accessed October 27, 2020. http://digital.library.temple.edu/u?/p245801coll10,499420.

MLA Handbook (7th Edition):

Wagner, Jessica Michelle. “Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues.” 2018. Web. 27 Oct 2020.

Vancouver:

Wagner JM. Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues. [Internet] [Doctoral dissertation]. Temple University; 2018. [cited 2020 Oct 27]. Available from: http://digital.library.temple.edu/u?/p245801coll10,499420.

Council of Science Editors:

Wagner JM. Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues. [Doctoral Dissertation]. Temple University; 2018. Available from: http://digital.library.temple.edu/u?/p245801coll10,499420


Temple University

3. Michael, James. Regulation of Ras signaling and oncogenesis by plasma membrane microdomains.

Degree: PhD, 2016, Temple University

Cell Biology

In this study, we assessed the contributions of plasma membrane (PM) microdomain targeting to the functions of H-Ras and R-Ras. These paralogues have identical effector-binding regions, but variant C-terminal targeting domains (tDs) which are responsible for lateral microdomain distribution: activated H-Ras targets to lipid ordered/disordered (Lo/Ld) domain borders, and R-Ras to Lo domains (rafts). We hypothesized that PM distribution regulates Ras effector interactions and downstream signaling. We used tD swap mutants, and assessed effects on signal transduction, cell proliferation, transformation, and tumorigenesis. R-Ras harboring the H-Ras tD (R-Ras-tH) interacted with Raf, and induced Raf and ERK phosphorylation similar to H-Ras. R-Ras-tH stimulated proliferation and transformation in vitro, and these effects were blocked by both MEK and PI3K inhibition. Conversely, the R-Ras tD suppressed H-Ras-mediated Raf activation and ERK phosphorylation, proliferation, and transformation. Thus, Ras access to Raf at the PM is sufficient for MAPK activation and is a principal component of Ras mitogenesis and transformation. Fusion of the R-Ras extended N-terminal domain to H-Ras had no effect on proliferation, but inhibited transformation and tumor progression, indicating that the R-Ras N-terminus also contributes negative regulation to these Ras functions. PI3K activation was tD-independent; however, H-Ras was a stronger activator of PI3K than R-Ras, with either tD. PI3K inhibition nearly ablated transformation by R-Ras-tH, H-Ras, and H-Ras-tR, whereas MEK inhibition had a modest effect on Ras-tH-driven transformation but no effect on H-Ras-tR transformation. R-Ras-tH supported tumor initiation, but not tumor progression. Whereas H-Ras-tR-induced transformation was reduced relative to H-Ras, tumor progression was robust and similar to H-Ras. H-Ras tumor growth was moderately suppressed by MEK inhibition, which had no effect on H-Ras-tR tumor growth. In contrast, PI3K inhibition markedly suppressed tumor growth by H-Ras and H-Ras-tR, indicating that sustained PI3K signaling is a critical pathway for H-Ras-driven tumor progression, independent of microdomains. In the second phase of the study, we investigated the combinatorial use of two drugs currently either in active use as anti-cancer agents (Rapamycin) or in clinical trials (OTX008), as a novel strategy to inhibit H-Ras-driven tumor progression. H-Ras anchored to the plasma membrane shuttles from the lipid ordered (Lo) domain to the lipid ordered/lipid disordered border upon activation, and retention of H-Ras at these sites requires Galectin-1 (Gal-1). We have previously found that genetically-mediated Lo sequestration of H-Ras inhibited MAPK signaling but not PI3K activation. Here we show that inhibition of Gal-1 with OTX008 sequestered H-Ras in the Lo domain, blocked H-Ras-mediated MAPK signaling, and attenuated H-Ras-driven tumor progression in mice. H-Ras-driven tumor growth was also attenuated by treatment with mTOR inhibitor Rapamycin, and this…

Advisors/Committee Members: Goldfinger, Lawrence;, Rizzo, Victor, Abood, Mary Ellen, Grana-Amat, Xavier, Golemis, Erica;.

Subjects/Keywords: Cellular biology

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

APA (6th Edition):

Michael, J. (2016). Regulation of Ras signaling and oncogenesis by plasma membrane microdomains. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,377230

Chicago Manual of Style (16th Edition):

Michael, James. “Regulation of Ras signaling and oncogenesis by plasma membrane microdomains.” 2016. Doctoral Dissertation, Temple University. Accessed October 27, 2020. http://digital.library.temple.edu/u?/p245801coll10,377230.

MLA Handbook (7th Edition):

Michael, James. “Regulation of Ras signaling and oncogenesis by plasma membrane microdomains.” 2016. Web. 27 Oct 2020.

Vancouver:

Michael J. Regulation of Ras signaling and oncogenesis by plasma membrane microdomains. [Internet] [Doctoral dissertation]. Temple University; 2016. [cited 2020 Oct 27]. Available from: http://digital.library.temple.edu/u?/p245801coll10,377230.

Council of Science Editors:

Michael J. Regulation of Ras signaling and oncogenesis by plasma membrane microdomains. [Doctoral Dissertation]. Temple University; 2016. Available from: http://digital.library.temple.edu/u?/p245801coll10,377230

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