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Full-Text Articles in Medicine and Health Sciences
Beyond Apoptosis: Insight Into The Complex Intracellular Networks That Govern Cell Fate, Hayley Neal Widden
Beyond Apoptosis: Insight Into The Complex Intracellular Networks That Govern Cell Fate, Hayley Neal Widden
All ETDs from UAB
The determination of cell fate is a dynamic process regulated by hundreds of proteins that converge into complex cell signaling pathways. Upon irreparable intracellular stress, a cell undergoes programmed cell death, a process known as intrinsic apoptosis. Apoptosis is regulated by the Bcl-2 family, a class of proteins that act either as pro-survival or pro-death signaling molecules. Due to the oncogenic upregulation of pro- survival Bcl-2 family proteins across human cancer cell types, a novel class of small molecule inhibitors called ‘BH3-mimetics’ have emerged as promising anti-cancer therapeutics currently under clinical investigation. Here, we highlight the crosstalk between anti-apoptotic Bcl-2 …
Structural Changes To Desmosomal Architecture During Assembly And Maturation, Reena R. Beggs
Structural Changes To Desmosomal Architecture During Assembly And Maturation, Reena R. Beggs
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Desmosomes are macromolecular junctions important in adhesion and resisting mechanical stress in epithelial and cardiac tissue. Desmosomes have a complex architecture with transmembrane cadherins, desmogleins and desmocollins, constituting the adhesive interface and plaque proteins, including plakoglobin and desmoplakin, binding the cadherin tails and integrating with intermediate filaments. Dysregulation of desmosomes occurs in many disease states, such as cardiomyopathies, skin diseases, and various cancers. While mature desmosomes' structure is generally understood, less is known about desmosome architecture during assembly and recycling. Desmosomes are dynamic, biochemically intractable, and diffraction-limited, making them challenging to study. To overcome these obstacles, I applied the super-resolution …
Local Priming Of Long-Lived Tcf1+ Memory Cd8+ T Cell Responses In The Spleen During Influenza Virus Infection By Lung Derived Migratory Dendritic Cells, Meagan Jenkins
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Initiation of CD8+ T cell responses to influenza virus infection requires the trafficking of activated lung-migratory dendritic cells (mDCs) from the lung into the lung-draining mediastinal LN (med-LN). As such, when mDCs are absent from the lungs or are unable to migrate into the med-LN, T cell responses are severely compromised, and the mortality rate increases in mouse models of influenza infection. Importantly, it is generally considered that mDCs die shortly after reaching the med-LN. Thus, the current paradigm suggests that priming of all subsets of influenza-specific CD8+ T cell responses by mDCs takes place solely in the med-LN. Recent …
Heads Or Tails? Structural Studies Of Host Interaction And Molecular Piracy In Bacteriophages, James Lewis Kizziah
Heads Or Tails? Structural Studies Of Host Interaction And Molecular Piracy In Bacteriophages, James Lewis Kizziah
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Staphylococcus aureus is an opportunistic human pathogen dependent mainly on bacteriophages (phages) for dissemination of the virulence factors that contribute to its pathogenicity. Most phages have double-stranded DNA (dsDNA) genomes which are packaged into protein capsids attached to tails of varying morphology to form their complete virion structures. S. aureus pathogenicity islands (SaPIs) are highly specialized mobile genetic elements that encode various virulence factors and have been named molecular pirates for their ability to parasitize certain helper phages. SaPI1 is capable of hijacking virions constructed by the helper phage 80α, partly by altering the size of the capsid to only …
The Impact Of Blimp1 On Etreg Stability And The Tumor Microenvironment, Michael Dixon
The Impact Of Blimp1 On Etreg Stability And The Tumor Microenvironment, Michael Dixon
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CD4+ Foxp3+ regulatory T (Treg) cells are responsible for maintaining immunological homeostasis and self-tolerance through the regulation of immune responses against foreign and self-antigens, and they comprise both central Treg and effector Treg (eTreg) subsets. Because of their ability to suppress potent immune responses, eTreg cells expressing the transcription factor Blimp1 are frequently recruited to the tumor microenvironment (TME) to suppress anti-tumor responses by tumor infiltrating effector cells. Here, we demonstrate in murine transplantable tumor models that Blimp1 is required for intratumoral eTreg stability and that loss of Blimp1 by intratumoral eTreg cells results in their reduced suppressive activity and …
Analysing The Contribution Of Snare-Dependent Exocytosis From Astrocytes To Huntinton's Disease Pathogenesis Using The Bachd Mouse Model, Annesha C. King
Analysing The Contribution Of Snare-Dependent Exocytosis From Astrocytes To Huntinton's Disease Pathogenesis Using The Bachd Mouse Model, Annesha C. King
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Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein. Multiple studies have indicated the importance of mutant huntingtin (mHTT) in astrocytes to HD pathogenesis. Increased extracellular glutamate levels were observed after evoking SNARE-dependent exocytosis from cultured mHTT expressing astrocytes. To determine whether astrocytic SNARE-dependent exocytosis contributed to behavioral and neuropathological changes in vivo, we crossed BACHD mice to dominant negative SNARE (dnSNARE) mice and analyzed behavioral and neuropathological phenotypes. First, we found that reduc-ing astrocytic SNARE-dependent exocytosis had differential effects on the psychiatric-like and motor phenotypes observed in BACHD mice where …
Experience-Dependent Plasticitiy Of Functional Connectivity In Human Visual Cortex Following Central Vision Loss, Leland Lanelle Fleming
Experience-Dependent Plasticitiy Of Functional Connectivity In Human Visual Cortex Following Central Vision Loss, Leland Lanelle Fleming
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The human brain is shaped by a dynamic interplay between innate factors and life experiences. Neuroscience has long grappled with understanding this relationship, particularly with regard to how changes in experience impact the brain during adulthood. This question is especially important in the context of macular degeneration, a disease that causes significant visual impairment and drastically alters day-to-day visual experiences for individuals afflicted by the disease. Specifically, people with macular degeneration lose the ability to use vision in the center of the visual field, the region of the retina with the highest spatial resolution. Subsequently, these individuals must rely on …
Regulation Of Nitric Oxide Syntahse 3 By Histone Deacetylase, Luke S. Dunaway
Regulation Of Nitric Oxide Syntahse 3 By Histone Deacetylase, Luke S. Dunaway
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In the vasculature, nitric oxide is produced by nitric oxide synthase 3 (NOS3) and protects against the development of cardiovascular disease (CVD). The histone deacetylases (HDACs) are a family of enzymes responsible for lysine deacetylation of both histone and non-histone proteins. Understanding how NO signaling is regulated by HDACs will allow us to better understand how HDAC inhibitors may be of use in treating CVD. This dissertation seeks to provide novel insight into the regulation of NOS3 by this family of enzymes. Endothelial NO production is impaired in human subjects and rodents fed a high salt diet (HS). We have …
Neonatal Murine Cytomegalovirus Infection Disrupts Synapse Remodeling During Development, Jerome Moulden
Neonatal Murine Cytomegalovirus Infection Disrupts Synapse Remodeling During Development, Jerome Moulden
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Human cytomegalovirus (HCMV) is a complex double stranded DNA betaherpesvirus. Its linear DNA in enclosed in an icosahedral capsid, and has a genome size of about 230kb and encodes about 170 genes. Primary infection with HCMV lead to a lifelong persistent infection. HCMV can also be transmitted across the placenta and infect the developing fetus leading to infection of the newborn infant, an infection which is commonly described as congenital HCMV infection. In the United States, the prevalence of congenital HCMV infection is between 0.2-1.2%. Approximately 5-15% of these newborn infants will develop long-term neurological damage resulting, motor disorder, cognition …
Suppressing Islet Graft Rejection With Antioxidant-Based Encapsulation Materials, Jessie Marie Barra
Suppressing Islet Graft Rejection With Antioxidant-Based Encapsulation Materials, Jessie Marie Barra
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A hallmark of Type 1 diabetes (T1D) is the autoimmune destruction of insulin-producing pancreatic β-cells. Once the β-cells are lost, patients are reliant on less efficient exogenous insulin therapies to maintain glycemic control, leaving them at risk for secondary complications. Islet transplantation can restore the ability to regulate glucose levels without the need for exogenous insulin, however long-term islet graft survival has proven challenging in part due to ongoing immune-mediated destruction. Systemic immunosuppression strategies have proven somewhat effective at preventing rejection, but chronic use leaves the patient susceptible to opportunistic infections and organ toxicity. Reactive oxygen species (ROS), such as …
Diurnal Variation In Hippocampal Neurophysiology And Pathophysiology, Allison R. Fusilier
Diurnal Variation In Hippocampal Neurophysiology And Pathophysiology, Allison R. Fusilier
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Circadian rhythms are ~24-hour cycles in biological processes that are endogenously generated, entrained to light, and synchronized by the suprachiasmatic nucleus of the hypothalamus. One process that is influenced by circadian rhythms is cognitive function, which varies over the course of the day and is likely influenced by changes in neuronal physiology over the course of the day. Dysfunction in circadian rhythms has been documented in many diseases, including Alzheimer’s disease (AD). AD is a neurodegenerative disease most notably characterized by dementia, amyloid beta plaques, and tau tangles. There is currently no cure for AD, and treatments only slow disease …
Tau-Sh3 Interactions And Alzheimer's Disease, Jonathan Roth
Tau-Sh3 Interactions And Alzheimer's Disease, Jonathan Roth
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Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, and its impact will increase with an aging population. It is characterized by dementia associated with accumulation of extracellular amyloid-β (Aβ) plaques, intracellular hyperphosphorylated Tau tangles, and neurodegeneration. Additionally, network hyperexcitability occurs early in AD and likely contributes to disease pathogenesis. Current therapies provide minor delay of disease progression at best, so it is imperative to develop novel therapeutic approaches to prevent and treat AD. As Tau pathology correlates better with cognitive function than Aβ pathology and Tau reduction prevents Aβ-induced dysfunction in preclinical models, targeting Tau is a growing …
Novel Roles For Classic And Predicted Cilia Genes, Melissa Bentley
Novel Roles For Classic And Predicted Cilia Genes, Melissa Bentley
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Primary cilia are highly conserved microtubule-based appendages that are present on the surface of nearly every mammalian cell type, and function as signaling hubs for the cell. Their function depends on their ability to assemble, traffic signaling components into and out of the cilium, and disassemble. These events require precise coordination of ciliary machinery and regulation of ciliary infrastructure including, but not limited to, the ciliary basal bodies, transition zone (TZ), and BBSome. The basal bodies reside at the base of the cilium and serve as the foundation for ciliary axoneme construction. Distal to the basal bodies is the TZ, …
Biological Pathways And Processes Underlying The Cardiac Regenerative Response Post-Injury In Small And Large Mammals, Eric Yang Zhang
Biological Pathways And Processes Underlying The Cardiac Regenerative Response Post-Injury In Small And Large Mammals, Eric Yang Zhang
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Mammalian cardiomyocytes exit the cell-cycle shortly after birth. Consequently, the adult heart is unable to properly compensate for cardiac muscle lost to injury. As such, heart failure has remained the leading cause of death in the developed world for more than three decades. In this work, we illustrate our findings in using novel in-vivo animal models to examine two regenerative phenomena observed following myocardial injury:i.) neonate cardiomyocyte proliferation in large mammals ii.) the ‘paracrine effect’ as mediated by mesenchymal stromal cells In i.) we use a large animal model of myocardial injury during the early postnatal develop-mental stage to establish …
Hyperphosphatemia Contributes To Functional Iron Deficiency And Skeletal Muscle Wasting, Brian Anthony Czaya
Hyperphosphatemia Contributes To Functional Iron Deficiency And Skeletal Muscle Wasting, Brian Anthony Czaya
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Chronic kidney disease (CKD) is a global health threat that increases risk of death, which is credible to both impaired renal function and a multitude of CKD- associated comorbidities such as systemic inflammation, anemia and skeletal muscle dys- function. A distinctive feature of CKD is the dysregulation of mineral metabolism, where excess serum levels of phosphate (hyperphosphatemia) and of fibroblast growth factor 23 (FGF23) are not only viewed as biomarkers for disease severity but also exert deleterious effects towards various CKD-associated pathologies. Elevated levels of FGF23 can lead to the activation of FGF receptor 4 (FGFR4) in cell types that …
Targeting Oncogenic Microrna In Lung Cancer, Mackenzie Lauren Davenport
Targeting Oncogenic Microrna In Lung Cancer, Mackenzie Lauren Davenport
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Lung cancer is the leading cause of cancer-related death both in the United Statesand the world. While several genetic drivers of lung cancer have been identified, major improvements in patient outcome are lacking, highlighting the need to further understand the genetic and molecular mechanisms of this disease. The microRNA miR-31 has been implicated in oncogenesis in a variety of cancer types, and prior data from our laboratory has shown it to be overexpressed in human lung adenocarcinoma tumors compared to normal lung, high miR-31 levels correlate with decreased patient survival, and overexpression of miR-31 alone in the mouse lung epithelium …
Use-Dependent, Post-Critical Period Structural Plasticity In Primary Visual Cortex Following Central Vision Loss, Matthew Defenderfer
Use-Dependent, Post-Critical Period Structural Plasticity In Primary Visual Cortex Following Central Vision Loss, Matthew Defenderfer
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To facilitate learning throughout life, the adult brain must be capable of change, known as neuroplasticity. While evidence for adult structural plasticity in primary visual cortex (V1) exists, the relationship between plasticity and amount of use of a cortical region is not fully understood. Here, I use macular degeneration (MD) to model adult cortical plasticity. Macular degeneration causes loss of central vision, and patients learn to use a portion of peripheral vision called the preferred retinal locus (PRL) as a replacement for the fovea. The PRL is used more often than other usable areas of peripheral vision for daily tasks. …
The Hocl Response Of Escherichia Coli., Rhea Marie Derke
The Hocl Response Of Escherichia Coli., Rhea Marie Derke
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Inflammatory bowel diseases (IBDs), like Chron’s disease and ulcerative colitis, affect millions of people worldwide. There are limited treatment options available for these diseases because their direct causes are unknown. IBDs are characterized by chronic inflammation of the gastrointestinal tract and changes in the composition of the gut microbiome. Enterobacteria, including Escherichia coli, bloom to high levels in the gut during inflammation and contribute to the pathology of IBDs. E. coli must tolerate high levels of antimicrobial compounds produced by the immune system to survive during persistent inflammation. A large proportion of such compounds are reactive oxygen and reactive chlorine …
Upregulation Of Somatostatin Receptor 2 In Neuroendocrine Tumors Using Histone Deacetylase Inhibitors, Rachael Elizabeth Guenter
Upregulation Of Somatostatin Receptor 2 In Neuroendocrine Tumors Using Histone Deacetylase Inhibitors, Rachael Elizabeth Guenter
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Neuroendocrine cancer is complex disease of the diffuse neuroendocrine system. Neuroendocrine tumors (NETs) can arise throughout the body, including the lungs and pancreas. These tumors are phenotypically and genetically heterogeneous, making accurate diagnoses difficult with current imaging standards. New diagnostic options, coupled with a better understanding of neuroendocrine cancer etiology, is urgent and necessary to provide patients with better futures. Many NETs overexpress somatostatin receptor 2 (SSTR2) on their cellular surfaces, making patients eligible for [68Ga]-DOTATATE PET/CT imaging and SSTR2-based therapies. However, patients that lack sufficient SSTR2 overexpression cannot benefit from SSTR2-targeted imaging or therapeutic options. We found that histone …
Identifying Novel Therapeutics And Therapeutic Entry Points For The Treatment Of Duchenne Muscular Dystrophy Through Regulation Of Gene Expression, Rylie Maria Hightower
Identifying Novel Therapeutics And Therapeutic Entry Points For The Treatment Of Duchenne Muscular Dystrophy Through Regulation Of Gene Expression, Rylie Maria Hightower
All ETDs from UAB
My graduate research has primarily focused on genetic and epigenetic modifiers of Duchenne muscular dystrophy and understanding how those modifiers can be used as novel therapeutic entry points for treatment. A vast array of promising therapeutic strategies is being explored outside the realm of directly targeting dystrophin deficiency. This is primarily due to the lack of successful clinical trials that have demonstrated the ability to benefit a significant number of DMD patients. Here, I have expanded the field’s understanding of using the regulation of gene expression as a way to target dystrophin-deficiency associated pathology through, 1) therapeutic treatment of a …
Inducible T Cell Costimulator Stabilizes Regulatory T Cell Phenotype And Controls Host-Microbiota Interactions To Reduce Susceptibility To Intestinal Inflammation, Ashley Elizabeth Landuyt
Inducible T Cell Costimulator Stabilizes Regulatory T Cell Phenotype And Controls Host-Microbiota Interactions To Reduce Susceptibility To Intestinal Inflammation, Ashley Elizabeth Landuyt
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Genome wide association studies (GWAS) have identified a loss-of-function mutation in the gene encoding inducible T cell costimulator ligand (ICOSL) as correlating with inflammatory bowel disease (IBD). The reason for this association was largely unknown. ICOS signals have been implicated in controlling the dynamics of regulatory T (Treg) cells, which are essential to intestinal homeostasis. Compared to WT mice, ICOS-deficient mice possessed fewer Treg cells in the colonic lamina propria (cLP). The deficit in ICOS-deficient Treg cell numbers was attributable to preferential loss of Foxp3 expression. Bisulfite sequencing revealed that ICOS-deficient Treg cells did not demethylate conserved noncoding sequence 2 …
Mucus Matters: Mucociliary Physiology In Chronic Lung Diseases, Jacelyn Emily Peabody Lever
Mucus Matters: Mucociliary Physiology In Chronic Lung Diseases, Jacelyn Emily Peabody Lever
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The mucociliary escalator is an innate defense mechanism in the lung comprised of the ciliated, pseudostratified epithelium that lines the conducting airways and the mucus that sits atop the cilia. Mucus traps inhaled particulate matter/pathogens, and the cilia brush works in concert to propel the mucin gel proximally. Therefore, proper mucociliary physiology is critical to maintaining lung health. A metachronal wave propagated across the epithelium can occur when the phase of the ciliary stroke is shifted in time relative to its neighbors. Metachrony has been hypothesized to help overcome the viscoelastic forces required for the propulsion of mucus. Still, its …
Investigating Pathological Features Of Tdp-43 In Neurodegeneration, Joshua Mathew Marcus
Investigating Pathological Features Of Tdp-43 In Neurodegeneration, Joshua Mathew Marcus
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Transactivation response element (TAR) DNA binding protein of 43 kDa (TDP-43) is an essential RNA-binding protein required for coordinating multiple aspects of RNA metabolism. TDP-43 is multifunctional in both nuclear and cytoplasmic cellular compartments and shuttling in and out of the nucleus is an integral part of TDP-43 function. Nuclear depletion and cytoplasmic accumulation of TDP-43, aggregation of TDP-43 within inclusion bodies in the cytoplasm, and aberrant post-translational modifications and truncation of TDP-43 are all common pathological features of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). Localization of TDP-43 is connected to essential …
Investigation Into The Structure And Function Of Streptococcal Antigen I/Ii Family Of Proteins, Joshua L. Mieher
Investigation Into The Structure And Function Of Streptococcal Antigen I/Ii Family Of Proteins, Joshua L. Mieher
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Streptococci are involved in the infections of the oral cavity as well as at various sites throughout the body. Their initial contact with tissues/surfaces is enabled by adhesins present on the microbial surface. Among these the Antigen I/II- family (AgI/II) of adhesins are known be important factors in these infections as they enable adherence to multiple host proteins thus allowing the bacteria to gain a foot hold. In this thesis, we have structurally and functionally characterized yet another adhesin on S. mutans, the glucan binding protein C, which resembles the V-region of AgI/II. In addition, we have also resolved the …
Delineation Of B Cell Follicle Associated Cd4+ T Cell Subsets, Ryan James Mcmonigle
Delineation Of B Cell Follicle Associated Cd4+ T Cell Subsets, Ryan James Mcmonigle
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High affinity antibody responses rely on the interaction between CD4+ T cells andB cells, but these cell populations are segregated into different regions of secondary lymphoid organs (SLO). Early-stage follicular helper CD4+ T cells (Tfh cells) upregulate the B cell follicle-homing chemokine receptor CXCR5 in order to move from the T cell zone to the B cell follicle and establish interactions with cognate B cells that are essential for T-dependent humoral immune responses. Cognate Tfh and B cell interactions progress to the formation of germinal center (GC) reactions, where B cell receptors undergo rapid evolution to substantially increase antigen recognition …
The Role Of The Β-Catenin Signaling Pathway In Modulating The Nucleolar Proteome Of Triple Negative Breast Cancer, Shannon E. Meier
The Role Of The Β-Catenin Signaling Pathway In Modulating The Nucleolar Proteome Of Triple Negative Breast Cancer, Shannon E. Meier
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Previously, abnormal nucleoli were noted as indicators of cancerous lesions andused as a pathologic readout of neoplasia. Nucleolar hypertrophy and increased nucleolar number have been correlated with increased breast cancer (BC) mortality rates. Although various functions of the nucleolus have been investigated, it remains widely understudied in the context of cancer. The nucleolus was initially thought to be solely the site of ribosome biogenesis. However, over half of the proteins found in the nucleolus are associated with other biological functions. It is evident that the nucleolus plays major roles in stress response, DNA repair, and critical cellular aspects that influence …
Omics Discovery For Cardiometabolic Traits In African Americans, Bre Ashanti Minniefield
Omics Discovery For Cardiometabolic Traits In African Americans, Bre Ashanti Minniefield
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Research shows African Americans are more likely to suffer from a chronic disease compared to other American populations. Due to the fact that African Americans are extremely underrepresented within human health research, the potential biological causes of the racial/ethnic differences are not well understood. Some of these health differences may be due to genomic variations within either the mitochondrial genome, nuclear genome, or both. To aid the revolution of inclusive human health research, we examined genomic factors related to cardiometabolic diseases in African Americans.African Americans have the highest prevalence of hypertension compared to all other American populations. With the majority …
Alternative Splicing Of Anxa7 Dictates Receptor Tyrosine Kinase Fates In Glioblastoma, Sindhu Nair
Alternative Splicing Of Anxa7 Dictates Receptor Tyrosine Kinase Fates In Glioblastoma, Sindhu Nair
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Alternative splicing (AS) is a tightly regulated process essential for lineage specification in complex tissues like the brain. Dysregulated splicing in glioblastoma (GBM) is a mechanism exploited by tumor cells to retain or splice out exons consequently rewiring isoform-specific protein interactions to sustain tumor phenotypes. Receptor tyrosine kinases (RTK) amplifications are frequent events in GBM driving tumor growth and progression and are key targets for chemotherapy. However, RTK targeting in GBM has achieved limited success predominantly due to adaptive mechanisms of resistance in a constantly evolving tumor microenvironment. Clonal populations and crosstalk between RTKs sustain heterogeneity within a tumor leading …
Biomarker And Target Discovery In Cancer, Alyncia Dominique Robinson
Biomarker And Target Discovery In Cancer, Alyncia Dominique Robinson
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Cancer is a complex disease characterized by uncontrolled growth of transformed cells that can arise in many tissue types throughout the body (e.g., breast, lung, prostate, pancreas, lymph nodes) and is a major cause of death worldwide. Cancer progression resulting in aggressive or metastatic disease accounts for one of the leading causes of death worldwide, second only to heart disease in the US. Incidentally, cancer-related mortality has been on a steady decline, dropping 25% over the last 25 years [1]. This could be attributed to improved and earlier diagnoses and better treatment options being developed over the past few decades. …
Mechanism Of Stat3 Mediated Drug Persistence In Chronic Myeloid Leukemia Stem Cells, Sweta B. Patel
Mechanism Of Stat3 Mediated Drug Persistence In Chronic Myeloid Leukemia Stem Cells, Sweta B. Patel
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Drug persistence is one of the major impediments for cancer therapeutics. There are two known evolutionary models for tumor drug persistence. First, a pre-existing sub-population is inherently resistant to treatment; and second, a sub-population acquires resistance by drug-induced molecular reprograming. One ideal model to study the mechanism of drug persistence is chronic myeloid leukemia (CML), a hematopoietic stem cell (HSC) disorder. HSCs acquire a single translocation between chromosome 9 and 22, forming BCR-ABL, a constitutively active tyrosine kinase. Tyrosine kinase inhibitors (TKI), the standard regimen, have been able to efficaciously control CML and yet many patients relapse upon treatment discontinuation …