Browsing by Subject "cancer"
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Item 1998 Minnesota State Survey: Results and Technical Report.(Minnesota Center for Survey Research (MCSR), 1999) Minnesota Center for Survey ResearchItem 2000 Minnesota State Survey--Part II: Results and Technical Report.(Minnesota Center for Survey Research (MCSR), 2000) Minnesota Center for Survey ResearchItem Biophysical and structural studies of small molecule, protein, and nucleic-acid interactions with BET bromodomain-containing proteins(2022-06) Kalra, PrakritiBromodomains are ∼110 amino acid structural motifs that recognize specific protein sequences containing acetylated lysines. Many bromodomain modules are found within multidomain proteins that can both interact with chromatin and recruit enzymatic activity. The presence of multiple domains within a single protein leads to context-dependent and selective functions via multivalent protein−protein and protein−nucleic-acid interactions along with enzymatic function. The bromodomain and extra-terminal (BET) domain family has four proteins: BRD2, BRD3, BRD4, and the testis-specific BRDT. Each protein minimally consists of two tandem N-terminal bromodomains (BD1 and BD2) and an extra-terminal domain. The BET proteins have been shown to bind multiple acetylated lysines on histone tails and acetylated regions of various transcription factors. Given their significant role in disease, including cancer, cardiovascular, neurological, and inflammatory diseases, BET bromodomains are a well-studied drug target class. First-generation inhibitors retain high affinities for both the BD1 and BD2 domains of BET proteins. Due to their pan-inhibition of BET bromodomains, it is difficult to segregate the roles of individual BET proteins from each other. Recently, domain-selective inhibitors have been found to have different phenotypic responses and reduced toxicity as compared to the pan-BET inhibitors. Thus, isoform and domain-specific inhibitors will help to dissect the individual roles of each BET bromodomain, and thus new biophysical tools are required to discover them. As BET proteins regulate different cellular processes, it is essential to unravel their chromatin-binding determinants for designing better therapeutic modalities. Recently, epigenetic reader domains have also been found to harbor double-stranded (ds)DNA-binding activity, which is as functionally critical as histone association. Thus, using a suite of biophysical and structural studies, we have explored the dsDNA recognition of the N-terminal bromodomain of the Bromodomain and Extra-Terminal (BET) protein, BRD4. Through these studies, we have inferred that the disordered region connecting the BDs might be playing a significant role in mediating high-affinity interactions with chromatin’s repeatingunit, the nucleosome. These studies also highlight the importance of exploring the multi-domain interactions beyond just the bromodomains in regulating the structure and function of BET proteins. A particular example is the investigation of phosphorylation of disordered regions in BRD4 to regulate the protein’s chromatin recognition and gene-specific function. In this dissertation, I have described various biophysical and structural studies to elucidate the protein, small molecule, and nucleic-acid interactions with multi-domain BET proteins. Chapter 1 discusses various biophysical and structural techniques previously used for studying multi-domain BET proteins and highlights an area for further research in the field. Chapter 2 describes the application of protein-observed fluorine (PrOF) NMR to the tandem bromodomains of BRD4 and BRDT to quantify the selectivity of their interactions with acetylated histones as well as small molecules. This is the first report from the Pomerantz lab on PrOF NMR applied to multi-domain proteins as prior studies have focused on individual bromodomains only. We further determined the selectivity profile of a new class of ligands,1,4-acylthiazepanes, and found them to have ~3−10-fold selectivity for the C-terminal bromodomain of both BRD4 and BRDT. An extension of the previous chapter, chapter 3 focuses on the development of biophysical methods, including AlphaScreen competitive-inhibition assay and structural biology efforts on unraveling the BD2-selectivity of 1,4-acylthiazepanes. It also contains a section on a collaborative screening effort of a second library of 3D fragments to discover newer domain-selective scaffolds. Chapter 4 explores the dsDNA recognition of the N-terminal bromodomain of the Bromodomain and Extra-Terminal (BET) protein, BRD4. Using NMR-based assays, gel-shift assays, and competitive-inhibition assays, we established the binding surface of dsDNA and found it to be largely overlapping with the acetylated-histone (KAc) binding site. Rather than engaging in electrostatic contacts, we found dsDNA to interact competitively within the KAc-binding pocket. These interactions are distinct from the highly homologous BET bromodomain, BRDT. Together, these studies help establish a binding model for dsDNA interactions with BRD4 bromodomains and elucidate the chromatin recognition mechanisms of the BRD4 protein for regulating gene expression.Chapter 5 builds upon chapter 4 and the application of cryo-electron microscopy (cryo-EM) to study the interactions between the tandem domains of BRD4 and BRDT with unmodified nucleosomes. It also describes my efforts toward establishing a structural and quantitative picture of the “phospho-switch mechanism” to regulate BRD4’s native structure and function. Lastly, the appendix chapter explores a genetic code expansion strategy and a cysteine bio-conjugation approach to include alternative 19F NMR probes for protein-observed 19F NMR. These probes bearing a trifluoromethyl (-CF3) group will be useful for studying larger multi-domain bromodomain-containing proteins.Item Cardiovascular Disease In Cancer Survivors(2023) Polter, ElizabethOver 18 million cancer survivors are living in the United States. Cancer survivors are at high risk for numerous adverse events, including cardiovascular disease (CVD). As the community of cancer survivors grows, there is a need to disentangle the complex causal relationships between cancer and CVD.In our first two manuscripts, we investigated two potential causes of CVD in cancer survivors. Manuscript 1 evaluated the associations between cancer, T-Cell immunosenescence (immune system aging), and CVD using data from the Health and Retirement Study. Prevalent cancer was strongly associated with T-cell immunosenescence, with stronger associations among participants who received chemotherapy and radiation. However, T-cell Immunosenescence was not prospectively associated with CVD or cancer. For Manuscript 2, we used the Marketscan® administrative healthcare claims databases to estimate the cardiovascular risk associated with the use of two hormone therapies, aromatase inhibitors (with ovarian suppression) and tamoxifen in premenopausal female breast cancer survivors. Although CVD events were rare in this population, enrollees who used aromatase inhibitors with ovarian suppression had an elevated risk of CVD compared to those who used tamoxifen. Finally, Manuscript 3 assessed the performance of the Pooled Cohort Equations (PCEs), risk prediction tools used to estimate ten-year cardiovascular risk and prescribe interventions. Analyses included cancer survivors and cancer-free participants in the Atherosclerosis Risk in Communities Study. Although the PCEs overestimated CVD risk in each group, we found no evidence that prediction differed by cancer history. Together, these findings provide insights that can be used to improve cardiovascular healthcare and prevention for cancer survivors.Item Characterization of Glioblastoma and T Cell Migration in Brain Tissue(2023-07) Anderson, SarahGlioblastoma (GBM) is an aggressive malignant brain tumor with extremely low 5-year survival rates. One key characteristic of the disease is the ability of glioblastoma cells to migrate rapidly and spread throughout healthy brain tissue. To develop treatments that effectively target cell migration, it is important to understand the fundamental mechanism driving cell migration in brain tissue. In the first part of this dissertation, we utilized confocal imaging to measure traction dynamics and migration speeds of glioblastoma cells in mouse organotypic brain slices to identify that the cells are using a motor-clutch mode of migration. In addition, both integrins and CD44, as well as myosin motors, were found to play an important role in constituting the adhesive clutch. In developing a treatment that targets migration of glioblastoma cells, it is critical to take into account how this could impact T cell migration and the resulting ability of T cells to kill cancer cells. A hallmark of glioblastoma is the suppression of the immune response, allowing the tumor to grow and spread faster, and infiltration of cytotoxic CD8+ T cells into the tumor has been shown to be an important indicator of disease progression and survival. In the second part of this dissertation, we use mouse organotypic brain slices co-cultured with CD8+ T cells to image migrating CD8+ T cells in healthy brain tissue in response to cell migration targeting drugs and antibodies. We find an increase in migration speed in response to targeting CD44, which is a critical deviation between cancer cell and T cell phenotype, implicating CD44 as a potential target for improving glioma outcomes by slowing cancer cell migration and speeding up CD8+ T cells.Item Discrimination and Depressive Symptom Trajectories of Middle-aged and Older Adults with Chronic Diseases(2021-07) Yoon, Young JiDepression is a serious health concern for adults who have been diagnosed with cancer or diabetes. In addition to the challenges associated with chronic disease management, perceived discrimination has been identified as a factor that increases the risk of depressive symptoms. However, empirical evidence using longitudinal data to test the association between perceived discrimination and depressive symptoms of those with cancer or diabetes is limited. Using Andersen’s Behavioral Model and the Theory of Fundamental Causes as guiding frameworks, this three-paper dissertation study presents a scoping review (Study 1) and two quantitative studies (Studies 2 and 3) to investigate the association between perceived discrimination and depressive symptoms among middle-aged and older adults with a cancer history or diabetes. In Study 1, an assessment of 23 peer-reviewed journal articles provides strong empirical evidence for statistically significant direct or indirect relationships between discrimination/stigma and depressive symptoms. In Studies 2 and 3, latent growth modeling using data from the Health and Retirement Study indicates that cancer survivors had an increasing linear trajectory of depressive symptoms and people with diabetes had a decreasing linear trajectory of depressive symptoms over a 4-year period (Study 2: 2010–2014, Study 3: 2014-2018). Findings from these studies support the need for social workers and other members of the health care team to offer tailored assessment and treatment approaches to address depressive symptoms for cancer survivors and people with diabetes, especially those who may perceive discrimination based on their race, ethnicity, socioeconomic status, culture, language, and having a medical diagnosis. Implications for future investigations are discussed.Item Drug development and novel combination strategies with phytochemicals for precision medicine in cancer(2017-08) Shin, Seung HoPrecision medicine refers to matching the most accurate and effective treatment to each individual, and has the potential to manage diseases. In cancer, however, developing drug candidates and finding effective combination strategies are in great demand. Here, we present a framework covering drug development against a specific oncoprotein, effective combinations of drug and natural compounds, and a physiologically-achievable chemoprevention strategy. First, HI-B1 is synthesized and identified as a direct β-catenin inhibitor. A colon cancer patient-derived xenograft (PDX) model with a high level of β-catenin is sensitive to HI-B1. Second, a combination of aspirin with a ginger extract shows synergistic effect. Combining a ginger extract with aspirin treatment can significantly reduce the effective dose of aspirin while retaining its therapeutic effects in PDX mouse models. Third, multiple phytochemicals at low doses accumulatively inhibit one key protein to exert their chemopreventive and therapeutic effects. Natural ERK2 inhibitors are discovered using chemoinformatics, crystallography, cell biology and biochemistry. Each outcome could be used in a precision oncology workflow to help prevent and treat cancer efficiently.Item The effects of lexical and discourse-based hedging in news stories of cancer screening and treatment on cancer-related behavioral beliefs and trust towards cancer scientists(2021-07) Wang, LeHedging, a way to convey scientific uncertainty, could manifest in two different ways: lexical hedging (expression of uncertainty through linguistic elements such as “might,” “may,” and “likely”) and discourse-based hedging (expression of uncertainty through disclosing experimental weaknesses, lack of generalizability of study results, and so forth). Previous studies in cancer communication documented some positive effects of hedging on variables pertaining to cancer prevention and control, but they focused on discourse-based hedging. To assess and compare the effects of the two different types of hedging on people’s cancer-related behavioral beliefs and trust towards cancer scientists, an online survey experiment was conducted. No significant effects of hedging on beliefs or trust were found. The associations among variables of interests, including behavioral beliefs, trust, attitude, and behavioral intention, were examined, and the potential moderating role of research literacy was explored. Implications of the study’s results are discussed.Item The Effects of Tamoxifen on Mammary Organoids from Young and Old MMTV-c-neu Mice(2020-12) Troness, BenjaminTamoxifen, an estrogen antagonist, can prevent ER-positive tumor development in women at risk of developing breast cancer. Mouse studies demonstrate that tamoxifen can prevent ER-negative tumors if administered to young mice. This project examined the differences in cell populations and progenitor activity between mammary organoids from young and old MMTV-c-neu mice, treated with or without tamoxifen. Tamoxifen-treatment increased the proportion of luminal, colony-forming cells in 2D but decreased the proportions of basal and CD61-positive, luminal progenitor cells in young and old mouse organoids. Tamoxifen tended to increase the proportions of CD61-negative, luminal cells in old organoids but reduced this population in young mouse organoids. In 3D cultures, tamoxifen increased the number of luminal-like colonies produced by old, but not young, mouse organoid cells. These results suggest that aging renders the CD61-negative, luminal cell population resistant to tamoxifen and that this population should be targeted for the prevention of ER-negative tumors.Item Firebird(2025-04-01) Allen, Justin D.Firebird, Justin’s most recent work, confronts the fallibility of memory and the deeply human behaviors caused by the loss of a loved one. In this case, the work finds an entry point to talk about these themes through the loss of Justin’s dad to melanoma in 2009. The work examines how the ripple of his dad’s life continues to reach out in curious and unexpected ways. Using an unlikely entry point (the scientific study of the cosmos) and a playful sense of humor, Justin begins to unravel what happens to the mind and body when it encounters such heavy loss. From this central point, the work expands in many directions and asks questions such as: What stories are we supposed to tell about our loved ones who have passed? What is the role of our loved ones' possessions after they've gone? Why does loss feel so different to every person? What does it mean to carry on a "legacy"?Item A Flexible Simulator for Oncolytic Viral Therapy(2015-05) Berg, DavidDevelopments in recombinant DNA technology have given researchers the ability to modify viruses so that they are highly selective towards cancer cells. Engineered viruses have successfully treated cancer in human trials. In an effort to better understand viral population dynamics in a temporal context, researchers have turned to mathematical models. Some of these viruses spread only by contact between virus-infected and uninfected tumor cells. Therefore, mathematical models that usually assume populations are well-mixed may not apply. This thesis describes a computational approach to modeling viral population dynamics that takes into account the spatial nature of viral spread by contact.Item Genetic Engineering of Primary Human Natural Killer (NK) Cells for Enhanced Cancer Immunotherapy(2021-06) Pomeroy, EmilyNatural killer (NK) cells are a critical component of the innate immune system due to their ability to kill a variety of target cells, including cancer cells. This innate anti-tumor phenotype has driven intense interest in the use of NK cells for cancer immunotherapy, but this has seen limited success in the clinic. Enhancing NK cell cytotoxicity by augmenting activating signals or eliminating inhibitory signals could significantly improve NK-based cancer immunotherapy. We have developed highly efficient methods for editing the genome of human NK cells. Specifically, to target inhibitory signals for elimination, we have developed methods for CRISPR-Cas9-based gene knockout. We have also created platforms for delivery of activating signals using either CRISPR-Cas9 in combination with recombinant adeno-associated virus (rAAV) and a non-viral approach for engineering using DNA transposons. We targeted relevant genes (ADAM17 and PDCD1) for knockout and delivering activating receptors CD16a and a CD19-specific chimeric antigen receptor (CAR). Importantly, we show direct functional consequences of engineering steps, using preclinical in vitro and in vivo models. Furthermore, we demonstrate the clinical scalability of all methods. The focus of this work was to develop methods for engineering primary human NK cells, with the goal of creating clinical products to treat human disease. Future work will focus on combining approaches to generate NK cells expertly equipped to kill cancer.Item Gluconeogenic FBP1 plays a key metabolic role in activated T cells(2017-07) Bapat, AditiFructose bisphosphatase-1 (FBP1) is a rate limiting enzyme in gluconeogenesis that converts fructose-1,6-bisphosphate (F1,6BP) to fructose-6-phosphate (F6P). It is active in liver, kidney and skeletal muscle cells. This study suggests that FBP1 plays a novel non-gluconeogenic role in T cells. Targeted metabolomics using [13C]-6-glucose revealed a labeling pattern of F6P in stimulated CD3+ T cells that could only have resulted from FBP1 enzymatic activity. Following stimulation, T cells expressed a 27kD form of FBP1, in addition to the full-length 37kD protein. The hypothesis that T cells utilize an alternative translational start site to express a shorter, constitutively active, form is being tested. Future studies will also test the hypothesis that FBP1 activity increases carbon flux into the pentose phosphate pathway (PPP), to facilitate increased production of reducing agent and co-factor, NADPH, in preparation for proliferation. This research could contribute significantly to our understanding of T cell physiology and cancer cell metabolism.Item Interview with Shelley Chou(University of Minnesota, 1999-07-12) Chou, Shelley N.; Pflaum, Ann M.Ann Pflaum interviews Dr. Shelley Chou, former vice-president for Health Sciences and head of the Department of Neurosurgery.Item My Easy Year: Breast Cancer, Narrative Reckoning, and the Art of Creating a Dissertation(2023-01) Shopa, AmandaA serious illness acts as a break to one’s routine and wrecks a life’s narrative (Frank, 2013). A serious illness can force one to examine the weave of their life—past, present, and future—in unexpected ways (Lorde, 1980/2020). I learned this firsthand when, late in my doctoral studies, I was diagnosed with breast cancer after a routine mammogram screening. The diagnosis, treatment, and on-going side effects left me with one question: How am I supposed to get through this (creating a dissertation) after going through that (cancer)? To answer that question, I turned to arts-based research practices (Leavy, 2015; Loveless, 2019; Springgay & Irwin, 2005). In this non-traditional “braided” dissertation (Miller, 2021), I use creative writing (personal stories, journal entries, and doctor’s charting notes), textile arts (knitting, felting, weaving, and quilting), and photographic practices (black-and-white darkroom work and the cyanotype process) to examine my past, present, and future. At the same time, I incorporate research and theory from medical sociology to ground my personal experience in a larger cultural context. I explore the illness narratives I tell (Frank, 2013) and consider how they align with or resist American breast cancer culture and the expectation that women are made “better” by having cancer (Ehrenreich, 2001; Sulik, 2011). I argue that there is no conclusion to breast cancer, even though the broader culture may call for one. Ultimately, this dissertation resists dominant breast cancer culture and adds nuance and complexity to breast cancer stories. It also demonstrates how artistic practices and academic research can be used to make sense of the existential crisis that a serious illness can trigger in one’s life.Item Myeloid derived suppressor cells in dogs with cancer: phenotype, function and clinical implications(2014-06) Goulart, Michelle RodriguesMyeloid-derived suppressor cells comprise phenotypically heterogeneous population of myeloid cells at different stages of differentiation endowed with potent immunosuppressive activity. Abnormal accumulation of MDSC in tumor models and cancer patients produce profound immune suppression, severely impairing T cell antitumor immunity, contributing to angiogenesis, cell invasion and metastasis, and constitute a major hurdle in achieving successful immunebased therapies. Understanding the mechanism that drives MDSC expansion and enhances function in humans and dogs is crucial for the development of efficacious immunotherapy. Studies in dogs with several tumor types, including sarcoma, carcinomas, mast cell tumors and gliomas confirmed MDSC expansion in the peripheral blood of dog cancer patients. MDSC have been identified in dogs using the combination of three-marker phenotype CD11b+CD14-MHCII-cells for granulocytic and CD11b+CD14+MHCII-cells for monocytic subsets. Granulocytic MDSC accumulated in the peripheral blood of dogs with advanced sarcoma, carcinomas and mast cell tumors, co-purified with peripheral blood mononuclear cell (PBMC) fraction and expressed polymorphic mononuclear morphology. This subset of cells showed the ability to efficiently inhibit T cell proliferation and IFN-γ secretion of autologous T cells, as well as allogenic T cells from healthy dogs, and expressed ARG1, iNOS2, TGF-β and IL-10. Monocytic MDSC also demonstrated potent ability to suppress T cell proliferation and preferentially accumulated in the peripheral blood of dogs with glioma. Elevated levels of arginase activity found in the serum of dogs with glioma could potentially be due to the presence of elevated numbers of MDSC. Evaluation of the anti-mouse Gr1 antibody for MDSC staining and identification revealed that does not cross react and therefore is not suitable for canine cells.Item Perceptions of COVID-19 and Health Survey in the United States, Cross-sectional study April 2020(2020-10-12) Vogel, Rachel I; Lou, Emil; Mburu, E. Waruiru; Thomaier, Lauren; Hui, Jane YC; Nelson, Heather H; Teoh, Deanna; Brown, Katherine; Blaes, Anne; Holtan, Shernan; Jewett, Patricia; Parsons, Helen; isak0023@umn.edu; Vogel, Rachel ICross-sectional anonymous online survey among individuals with and without cancer in the United States during the initial phase of the COVID-19 pandemic (April 3, 2020 – April 11, 2020). NOTE: To protect the identity of participants, the variables dem_1, dem_3, and dem_17 - which correspond to exact age, transgender status, and state of residence - have been removed from this public data set. Please contact the principal investigator if you require the full data set with these variables included for your research.Item Reconceptualizing Cancer: The development of new models and frameworks(2018-12) Liu, KatherineCancer research secures an enormous amount of money each year, and researchers are generally quite productive with that money. The trend over the recent years has been for cancer biologists to focus on understanding the early stages of cancer and through a molecular and mechanistic framework. This gets translated into clinical applications through implementation of preventive and screening practices and early treatments. This work is important and has undoubtedly saved many lives. However, metastasis (the spread of cancer throughout the body) is the pathogenic aspect of cancer, and the cause of most cancer-related deaths. We have little ability to successfully treat cancers once they have reached this stage. Thus, this dissertation offers three novel models (two conceptual models and one empirical model) that facilitate the shift of attention away from the elucidation of tumor initiation and early stage cancers to the investigation of metastatic cancers. This shift to metastatic cancers involves more than a temporal shift in the cancer progression. That is, part of my argument is that we cannot simply apply the same conceptual frameworks and methods used to study tumorigenesis but to metastatic cells. Metastasis is more complex than tumor growth, so we need different conceptual models to guide that research. This dissertation begins with a pair of conceptual models, that I argue engage with important causal factors not contained in the molecular and mechanistic frameworks used to study tumorigenesis. I then use a simple model (budding yeast, Saccharomyces cerevisiae) and experimental evolution to empirically validate one of the models that suggests changes in interactions between levels of organization are causally informative in understanding the evolution of a trait (e.g., the evolution of cancer). This work explores how mitochondrial defection is involved in the evolution of tolerance to heat shock, which I use as proof of concept that one needs to consider multiple levels of organization together to understand cancer. In other words, this interdisciplinary dissertation demonstrates how context matters both in interpreting data and setting up research questions. The models I present here may help interpret existing data but also encourage novel research programs such as the empirical work presented here.Item Regulation of APOBEC3B catalyzed mutation in ovarian cancer(2015-08) Leonard, BrandonCancer is the second highest cause of death in the United States. A greater understanding of the underlying causes of this disease is critical to improve patient outcomes. For years, researchers have known that cancer is primarily a genetic disease, caused by mutations that can activate oncogenes and inactivate tumor suppressors. Several studies have also shown that UV radiation, smoking and certain defects in DNA repair cause some of the mutations that lead to cancer, but the sources of mutations found in many tumor types are yet to be explained. Here, we build upon our initial finding that APOBEC3B is a source of mutation in breast cancer by defining its role in ovarian cancer. Parallel analyses looking globally at mutation in cancer have shown that APOBEC3B also contributes to mutation in several other tumor types. Additional studies have elucidated a major signaling mechanism that regulates APOBEC3B expression in cancer. While many efforts have been made to directly inhibit APOBEC3B enzymatic activity, the advances described here have the potential to inform alternative therapeutic strategies aimed at transcriptionally downregulating APOBEC3B to slow tumor evolution and improve the durability of conventional anti-cancer drugs. Ultimately, a more comprehensive understanding of the basic biology of APOBEC3B catalyzed mutagenesis in cancer will translate to larger impacts in the clinical arena.Item The role of DNA repair & regulatory proteins in the maintenance of human telomeres and their control of cellular immortalization(2017-04) Harvey, AdamTelomeres are the nucleoprotein structures that protect the ends of linear chromosomes from recognition as a double-stranded DNA break (DSB). In the absence of proper telomere function, the ends of a chromosome fuse together, creating di-centromeric chromosomes, which can no longer properly segregate at mitosis. Thus, proper telomere maintenance is absolutely essential for all eukaryotic life. Unfortunately, maintaining telomeres at a size that is protective is problematic. For example, as a consequence of “the end-replication problem,” telomeres shorten incrementally during every cell cycle. These short telomeres can, in turn, function to regulate the lifespan of any given cell. Perhaps not surprisingly, therefore, humans have evolved a vast array of genes to enable telomere stability, in order to counteract any premature ageing or cell death. In order to ensure that offspring may begin their life with a default telomere length that is sufficient for stability during the organism’s lifespan, stem cells must not be subjected to overall telomere shortening. Thus, all telomere shortening that a stem cell occurs during its eternal proliferation must be correspondingly compensated for by a lengthening event. This telomere elongation mechanism in essence confers cellular immortality. The most well-characterized of these cellular immortality pathways is controlled by the enzyme telomerase, which precisely elongates telomeres in a stochastic way to maintain a telomere length equilibrium. Unfortunately, this functional, essential pathway can also be conscripted to perform pathological reactions. In human cancer, all malignant growths must enable cellular immortalization to allow for their characteristic uncontrolled proliferation. In most cases this is achieved simply by the reactivation of telomerase. Interestingly, 5 to 15% of all human cancers are telomerase negative. These cancers can be described as ALT cancers, as the Alternative Lengthening of Telomeres pathway enables their immortality. ALT, which is specific to cancer, achieves telomere elongation by aberrant recombination between telomeres. My research has found that DNA repair proteins, such as PARP1, (poly ADP ribose polymerase 1) are critical for both the maintenance of the genome and specifically for proper telomere maintenance. Furthermore, my research has demonstrated that the mutation of a single gene, ATRX, (alpha thalassemia mental retardation on the X chromosome) is an active repressor of ALT immortalization. In summary, I have contributed to the understanding of human telomere length maintenance and these studies have implications for human aging and the genesis of cancer.