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Core Binding Factor Leukemia Hijacks T-Cell Prone Pu.1 Antisense Promoter [Preprint], E. van der Kouwe, Lucio H. Castilla, D. G. Tenen, P. B. Staber 2020 Medical University of Vienna

Core Binding Factor Leukemia Hijacks T-Cell Prone Pu.1 Antisense Promoter [Preprint], E. Van Der Kouwe, Lucio H. Castilla, D. G. Tenen, P. B. Staber

University of Massachusetts Medical School Faculty Publications

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of the hematopoietic master regulator PU.114. PU.1 gene expression is regulated through enhancer-promoter interactions within a topologically associated domain (TAD)5,6. PU.1 levels increase during myeloid differentiation while failure to do so results in myeloid leukemia7. In contrast, T-cell differentiation requires PU.1 to be completely switched off810. Little is known about the precise mechanisms of PU.1 repression, physiological as in T-cell differentiation, or pathological as in leukemia. Here we ...


Rapamycin Treatment Correlates Changes In Primary Cilia Expression With Cell Cycle Regulation In Epithelial Cells, Maha Jamal, Ane C.F. Nunes, Nosratola D. Vaziri, Ramani Ramchandran, Robert L. Bacallao, Andromeda M. Nauli, Surya M. Nauli 2020 Chapman University

Rapamycin Treatment Correlates Changes In Primary Cilia Expression With Cell Cycle Regulation In Epithelial Cells, Maha Jamal, Ane C.F. Nunes, Nosratola D. Vaziri, Ramani Ramchandran, Robert L. Bacallao, Andromeda M. Nauli, Surya M. Nauli

Pharmacy Faculty Articles and Research

Primary cilia are sensory organelles that regulate cell cycle and signaling pathways. In addition to its association with cancer, dysfunction of primary cilia is responsible for the pathogenesis of polycystic kidney disease (PKD) and other ciliopathies. Because the association between cilia formation or length and cell cycle or division is poorly understood, we here evaluated their correlation in this study. Using Spectral Karyotyping (SKY) technique, we showed that PKD and the cancer/tumorigenic epithelial cells PC3, DU145, and NL20-TA were associated with abnormal ploidy. We also showed that PKD and the cancer epithelia were highly proliferative. Importantly, the cancer epithelial ...


Yap1 Withdrawal In Hepatoblastoma Drives Therapeutic Differentiation Of Tumor Cells To Functional Hepatocyte-Like Cells, Jordan L. Smith, Tomas Rodriguez, Haiwei Mou, Suet-Yan Kwan, Henry E. Pratt, Xiao-Ou Zhang, Yueying Cao, Shun-Qing Liang, Deniz M. Ozata, Tianxiong Yu, Qiangzong Yin, Max Hazeltine, Zhiping Weng, Erik J. Sontheimer, Wen Xue 2020 University of Massachusetts Medical School

Yap1 Withdrawal In Hepatoblastoma Drives Therapeutic Differentiation Of Tumor Cells To Functional Hepatocyte-Like Cells, Jordan L. Smith, Tomas Rodriguez, Haiwei Mou, Suet-Yan Kwan, Henry E. Pratt, Xiao-Ou Zhang, Yueying Cao, Shun-Qing Liang, Deniz M. Ozata, Tianxiong Yu, Qiangzong Yin, Max Hazeltine, Zhiping Weng, Erik J. Sontheimer, Wen Xue

University of Massachusetts Medical School Faculty Publications

BACKGROUND and AIMS: Despite surgical and chemotherapeutic advances, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and beta-Catenin co-activation occurs in 80% of children's HB; however, a lack of conditional genetic models precludes tumor maintenance exploration. Thus, the need for a targeted therapy remains unmet. Given the predominance of YAP1 and beta-Catenin activation in HB, we sought to evaluate YAP1 as a therapeutic target in HB.

APPROACH and RESULTS: We engineered the first conditional HB murine model using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1(S127A) , constitutive ...


From Tank To Treatment: Modeling Melanoma In Zebrafish, William Tyler Frantz, Craig J. Ceol 2020 University of Massachusetts Medical School

From Tank To Treatment: Modeling Melanoma In Zebrafish, William Tyler Frantz, Craig J. Ceol

Open Access Publications by UMMS Authors

Melanoma is the deadliest form of skin cancer and one of few cancers with a growing incidence. A thorough understanding of its pathogenesis is fundamental to developing new strategies to combat mortality and morbidity. Zebrafish-due in large part to their tractable genetics, conserved pathways, and optical properties-have emerged as an excellent system to model melanoma. Zebrafish have been used to study melanoma from a single tumor initiating cell, through metastasis, remission, and finally into relapse. In this review, we examine seminal zebrafish studies that have advanced our understanding of melanoma.


The Anti-Proliferative Effects Of Methotrexate And Novel Ucp1162 On Acute Myeloid Leukemia Cell Lines, Jacqueline Klepinger, Charles Giardina, Didem Ozcan 2020 University of Connecticut, Storrs

The Anti-Proliferative Effects Of Methotrexate And Novel Ucp1162 On Acute Myeloid Leukemia Cell Lines, Jacqueline Klepinger, Charles Giardina, Didem Ozcan

Honors Scholar Theses

Cancer cells proliferate at rapid rates due to the aberrant activity of proteins involved in regulating the cell cycle. This characteristic allows mutated cancer cells to spread and metastasize, causing lesions to form throughout the body. Two treatment conditions, one classical antifolate methotrexate (MTX) and non-classical, novel antifolate UCP1162, were tested on a panel of acute myeloid leukemia (AML) cell lines to determine if UCP1162 has higher anti-proliferative activity. High dose MTX is used as a first line chemotherapy in common childhood malignancies such as acute lymphoid leukemia (ALL). Methotrexate is excluded from acute myeloid leukemia (AML) treatments based on ...


Yap1/Taz Drives Ependymoma-Like Tumour Formation In Mice, Noreen Eder, Federico Roncaroli, Marie-Charlotte Dolmart, Stuart Horswell, Felipe Andreiuolo, Helen R. Flynn, Andre T. Lopes, Suzanne Claxton, John-Paul Kilday, Lucy Collinson, Junhao Mao, Torsten Pietsch, Barry Thompson, Ambrosius P. Snijders, Sila K. Ultanir 2020 The Francis Crick Institute

Yap1/Taz Drives Ependymoma-Like Tumour Formation In Mice, Noreen Eder, Federico Roncaroli, Marie-Charlotte Dolmart, Stuart Horswell, Felipe Andreiuolo, Helen R. Flynn, Andre T. Lopes, Suzanne Claxton, John-Paul Kilday, Lucy Collinson, Junhao Mao, Torsten Pietsch, Barry Thompson, Ambrosius P. Snijders, Sila K. Ultanir

Open Access Publications by UMMS Authors

YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1's negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of ...


Role Of Tissue Microenvironment In Recruiting Macrophages During Apoptosis-Induced Proliferation, Neha Diwanji 2020 University of Massachusetts Medical School

Role Of Tissue Microenvironment In Recruiting Macrophages During Apoptosis-Induced Proliferation, Neha Diwanji

GSBS Dissertations and Theses

Apoptosis-induced compensatory proliferation (AiP) is a mechanism that maintains tissue homeostasis after stress-induced cell death. During AiP, apoptotic cells induce proliferation of the neighboring surviving cells to compensate for tissue loss. AiP is important for wound healing and tissue regeneration in several model organisms. Additionally, AiP is an important feature of tumorigenesis and tumor relapse as it contributes to tumor repopulation following radiation or chemotherapy. Using an overgrowth tumor model (“undead tissue”) in Drosophila melanogaster, we determined that the initiator caspase Dronc promotes generation of extracellular Reactive Oxygen Species (ROS), which drive activation of the stress kinase JNK and downstream ...


Glucose Metabolism Of Breast Cancer Sub-Clones That Preferentially Metastasize To The Lungs And Bone, Anna G. Skubiz 2020 University of Mississippi

Glucose Metabolism Of Breast Cancer Sub-Clones That Preferentially Metastasize To The Lungs And Bone, Anna G. Skubiz

Honors Theses

Malignant breast cancers exhibit preferential metastasis to bone and lung (1). While changes in gene expression in lung-specific (LM) and bone-specific metastasis (BoM) lines derived from the MDA-MB-231 breast cancer line have been identified, few metabolic genes are differentially expressed; thus it is unknown if tissue-specific metabolic reprogramming occurs. Two hallmarks of cancer cells are an altered metabolic phenotype characterized by enhanced conversion of glucose to lactate in spite of adequate oxygen availability for complete mitochondrial oxidation of this substrate (referred to as aerobic glycolysis or the Warburg effect) and a greater dependence on glutamine. These changes in primary tumor ...


Breast Cancer Sub-Clones That Metastasize To Lung And Bone Exhibit Different Metabolic Preferences, Mollie Merrell 2020 University of Mississippi

Breast Cancer Sub-Clones That Metastasize To Lung And Bone Exhibit Different Metabolic Preferences, Mollie Merrell

Honors Theses

Metastasis is responsible for the majority of cancer related deaths. In breast cancer the lungs and bones are the major sites for metastasis. Previous studies used the metastatic aggressive MDA-MB-231 breast cancer line to isolate sub-clones that preferentially invade the lungs (LM line) or bones (BoM line). While genes associated with the tissue specific metastasis have been identified, it is unknown if metabolic adaptations contribute to the growth of the LM and BoM lines in their respective organs. The goal of this study was to test the hypothesis that the LM and BoM lines exhibit differences in glucose and glutamine ...


Inter-Individual Variation In Response To Estrogen And Implications For Breast Cancer Risk, Amye L. Black 2020 University of Massachusetts Amherst

Inter-Individual Variation In Response To Estrogen And Implications For Breast Cancer Risk, Amye L. Black

Doctoral Dissertations

Breast cancer is the second leading cause of cancer related death among women and the most prevalent cancer type in women worldwide. Many risk factors for breast cancer are related to estrogen exposure and all involve prolonged or high levels of estrogen exposure. However, estrogen exposure during early pregnancy reduces breast cancer risk by up to 50%. Estrogen’s paradoxical role in both contributing to and reducing breast cancer risk is still not understood. We hypothesized that a subset of women may be more sensitive to estrogen exposure, and the following experiments were designed to test this hypothesis and determine ...


Cell Proliferation And Viability Inhibition By Resveratrol On Breast Cancer Cell Lines, Kyle Ford Gordon Jr 2020 University of Mississippi

Cell Proliferation And Viability Inhibition By Resveratrol On Breast Cancer Cell Lines, Kyle Ford Gordon Jr

Honors Theses

Antioxidants are well-known for their various health benefits. They are able to protect cells from being damaged by free radicals that are produced by vital biochemical processes. It has long been known that antioxidants are important in our everyday health, but their potential as disease preventers and potential therapeutic agents is a relatively new field of study. Resveratrol, a natural polyphenol and well-known antioxidant, is found in plants, fruits, and products derived from them, like red wine. Resveratrol has been shown to have various properties, including antiaging, anti-aggregation of platelets, anti-inflammatory, and anticancer activities. Because of their many health benefits ...


Design Of A 3d Printed Bioreactor For Bone Cancer Research, Brooklyn K. VanDerWolde, Katelyn Hillson 2020 South Dakota State University

Design Of A 3d Printed Bioreactor For Bone Cancer Research, Brooklyn K. Vanderwolde, Katelyn Hillson

The Journal of Undergraduate Research

Bone cancer is an aggressive disease and has peak occurrence during physiological stimulation of growth and aging. Astronauts who undergo long-term space missions also acquire an increased risk of bone tissue degeneration and cancer. Few in-vitro models currently exist capable of reproducing the complex microenvironment of bone tissue to support multicellular activity in a three-dimensional structure. This limits the ability to understand disease progression and develop suitable treatment strategies. Therefore, developing a bone tissue model and an associated bioreactor is critical to understand the risks associated with cancer progression and improve treatment and preventions related to those risks. The goal ...


Neurocognitive Risk Factors And Current Intervention Strategies For Survivors Of Pediatric Acute Lymphoblastic Leukemia, Abigail Taber 2020 Liberty University

Neurocognitive Risk Factors And Current Intervention Strategies For Survivors Of Pediatric Acute Lymphoblastic Leukemia, Abigail Taber

Senior Honors Theses

The improved survival rate for pediatric cancer patients is one of the greatest triumphs of recent medicine, but the late effects faced by these survivors have been uncovered through this new population of survivors. Many survivors of pediatric acute lymphoblastic leukemia (ALL) experience cognitive deficits in areas such as attention, memory, processing speed, and academic achievement following cancer treatment. Recent research has pointed to chemotherapeutic agents, host risk factors, and genetic predispositions as perpetrators of these deficits, although other factors are also under investigation. Consequently, the search for appropriate interventions for the amelioration of these deficits has dominated the literature ...


Impact Of Epa And Dha Supplementation And 15-Lox-1 Expression On Colitis And Colitis-Associated Colorectal Cancer, Jonathan Jaoude 2020 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Impact Of Epa And Dha Supplementation And 15-Lox-1 Expression On Colitis And Colitis-Associated Colorectal Cancer, Jonathan Jaoude

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Inflammatory bowel disease (IBD) patients not only suffer from colitis but also from increased morbidity and mortality of colitis-associated colorectal cancer (CAC). The enzyme 15-lipoxygenase-1 (15-LOX-1) is crucial to converting omega-3 fatty acid derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to resolvins, potent anti-inflammatory products. 15-LOX-1 effects on the conversion of EPA and DHA to resolvins that subsequently exert anti-inflammatory and anti-tumorigenic effects have received little attention. To address this knowledge gap, we hypothesize that 15-LOX-1 expression in colonic epithelial cells is essential for resolvin biosynthesis from EPA and DHA to modulate immunophenotype, limit inflammation, promote resolution, and help ...


Microglia-Neuron Interactions In A Mouse Model Of Low Grade Neuroepithelial Tumors, Veolette Hanna 2020 University of Connecticut

Microglia-Neuron Interactions In A Mouse Model Of Low Grade Neuroepithelial Tumors, Veolette Hanna

Honors Scholar Theses

Microglia are the macrophages of the brain and spinal cord, playing an important role in the immune response to disease states of the nervous system. This study conducts an investigation on the activity of microglia in response to low grade neuroepithelial tumors. Using mouse models and microglial markers, a qualitative and quantitative analysis of microglia activation, migration, and invasion within the brain cortex during early stages of tumor development was conducted. It was found that the presence of a low grade neuroepithelial tumor in the cortex of one hemisphere of the brain causes significant microglia activation in comparison to the ...


Exosomal Communication By Metastatic Osteosarcoma Cells Modulates Alveolar Macrophages To An M2 Tumor-Promoting Phenotype And Inhibits Tumoricidal Functions, Kerri Wolf 2020 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Exosomal Communication By Metastatic Osteosarcoma Cells Modulates Alveolar Macrophages To An M2 Tumor-Promoting Phenotype And Inhibits Tumoricidal Functions, Kerri Wolf

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Osteosarcoma metastasizes to the lung, and there is a link between the predominance of tumor promoting immunosuppressive M2 macrophages in the metastases and poor patient survival. By contrast, M1macrophage predominance correlates with longer survival. M2 macrophages can be induced by various stimuli in the tumor microenvironment, including exosomes, which are 40- to 150-nm vesicles that are involved in intercellular communication and contribute to tumor progression and immune evasion. Recognizing that tumor cells can influence the tumor microenvironment to make it more permissive and because of the link between M2 dominance and curtailed patient survival, we evaluated the effect of ...


Effects Of Penfluridol On Integrin-Fak Signaling And Tumor Cell Killing In Combination With Oncolytic Hsv In Glioblastoma, Mitra Nair 2020 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Effects Of Penfluridol On Integrin-Fak Signaling And Tumor Cell Killing In Combination With Oncolytic Hsv In Glioblastoma, Mitra Nair

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Integrins are known to play an important role in activating multiple intracellular pathways, one of which is focal adhesion kinase (FAK). Phosphorylation of FAK can lead to the activation of various downstream signaling pathways that can increase tumor cell growth and proliferation, making it an ideal target for cancer therapeutics. Due to the fact that many FAK inhibitors are limited in their penetration of the blood brain barrier, we investigated the use of Penfluridol, an antipsychotic drug known to attenuate integrin expression at a transcriptional level, in combination with oncolytic herpes simplex I virus (oHSV) in a glioblastoma model. We ...


Heterogeneous Nuclear Ribonucleoprotein K (Hnrnp K) Overexpression And Its Interaction With Runx1 Rna In Acute Myeloid Leukemia, Marisa Aitken 2020 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Heterogeneous Nuclear Ribonucleoprotein K (Hnrnp K) Overexpression And Its Interaction With Runx1 Rna In Acute Myeloid Leukemia, Marisa Aitken

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is an often devastating hematologic malignancy with 5-year overall survival lingering near 20%. Acquiring a deeper understanding of molecular underpinnings of leukemogenesis will provide a basis for developing more effective therapeutic strategies for patients with AML.

Here, we identified overexpression of hnRNP K as a recurrent abnormality in a subset (~20%) of AML patients. High levels of this RNA-binding protein associated with inferior clinical outcomes in de novo AML. Thus, to evaluate its putative oncogenic capacity in myeloid disease, we overexpressed hnRNP K in murine hematopoietic stem and progenitor cells isolated from fetal liver cells (FLCs ...


Receptor Tyrosine Kinases-Mediated Acquired Parp Inhibitor Resistance In Breast Cancer, MEI-KUANG CHEN 2020 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Receptor Tyrosine Kinases-Mediated Acquired Parp Inhibitor Resistance In Breast Cancer, Mei-Kuang Chen

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Leveraging compromised DNA damage repair (DDR) pathways commonly found in tumor cells, a classic strategy in cancer therapy is inducing excessive DNA damage to cause cancer cell death. Small molecule poly(ADP-ribose) polymerase (PARP) inhibitors (PARP-is) have been approved for clinical use in treating breast cancer and ovarian cancer patients bearing DDR-deficient tumors with mutations in breast cancer susceptibility genes (BRCAm). However, accumulating evidences show that both intrinsic and acquired resistances to PARP-is exist in clinic and pre-clinical animal models. Therefore, I developed panels of cells with acquired PARP-is resistance from PARP-is-sensitive triple negative breast cancer (TNBC) cell lines ...


Size-Dependent Inhibitory Effects Of Antibiotic Nanocarriers On Filamentation Of E. Coli, Preeyaporn Songkiatisak, Feng Ding, Pavan Kumar Cherukuri, Xiao-Hong Nancy Xu 2020 Old Dominion University

Size-Dependent Inhibitory Effects Of Antibiotic Nanocarriers On Filamentation Of E. Coli, Preeyaporn Songkiatisak, Feng Ding, Pavan Kumar Cherukuri, Xiao-Hong Nancy Xu

Chemistry & Biochemistry Faculty Publications

Multidrug membrane transporters exist in both prokaryotic and eukaryotic cells and cause multidrug resistance (MDR), which results in an urgent need for new and more effective therapeutic agents. In this study, we used three different sized antibiotic nanocarriers to study their mode of action and their size-dependent inhibitory effects against Escherichia coli (E. coli). Antibiotic nanocarriers (AgMUNH–Oflx NPs) with 8.6 × 102, 9.4 × 103 and 6.5 × 105 Oflx molecules per nanoparticle (NP) were prepared by functionalizing Ag NPs (2.4 ± 0.7, 13.0 ± 3.1 and 92.6 ± 4.4 nm) with a ...


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