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HMS Theses and Dissertations

Mostrando recursos 1 - 20 de 206

  1. Utilizing a Novel Giant Congenital Melanocytic Nevus Murine Model to Investigate Therapeutic Strategies and Model Tumorigenesis

    Dobry, Allison S.
    Giant congenital melanocytic nevi (gCMN) are oncogene-driven proliferations of melanocytes present since birth that are greater than 20 cm in projected adult size, and have a melanoma conversion frequency of ranging from 5-15%. Patients with gCMN typically develop melanoma in early childhood that is extremely aggressive and almost universally fatal. Therefore, targeted therapies to induce nevus regression would be enormously beneficial. NRAS activating mutations are postulated to be the driver mutation gCMN. Described here are two novel gCMN preclinical murine models that harbor an NrasQ61R mutation. Evaluation of both the constitutive nevus model (Dct promoter-driven constitutive Cre with NrasQ61R mutation)...

  2. Suppressed Activity of Tumor-Specific T Cells in Human Merkel Cell Carcinomas

    Dowlatshahi, Mitra
    Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. We studied T cells in MCC to determine how these virally mediated tumors evade immune responses. MCC tumors were infiltrated by T cells, including effector, central memory and increased numbers of CD4 and CD8 FOXP3+ regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T cell activation, proliferation, enhanced cytokine production and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes...

  3. Hippocampal Subfield Alterations Across the Psychotic Disease Spectrum

    Gardin, Tova
    Psychiatry stands at a pivotal point of development. With the advent of brain imaging modalities, descriptive diagnostic criteria have been called into question. Psychotic disorders, historically dichotomized into “schizophrenia” and “bipolar disorder,” and the intermediate “schizoaffective disorder,” have been shown to overlap in clinical symptomatology, familial inheritance, and genetic association studies. Scientific investigation of disease pathogenesis provides an opportunity to develop biological diagnostic criteria from the ground upwards – correlating anatomy, pathophysiology, genetics, and symptomatology. In this context, structural MRI studies have the capacity to shed light on structural abnormalities underlying psychotic disorders (schizophrenia, schizoaffective disorder, and psychotic bipolar disorder)...

  4. Low-Value Service Variation and Physician Characteristics

    Schwartz, Aaron
    Importance: Reducing spending on unnecessary medical procedures is a global priority. Understanding patterns of low-value service use across physicians can inform efforts to reduce wasteful care. Objective: To quantify the extent of physician-level variation within region and within provider organization in the rates of primary care related low-value health care services, and to assess for associations between low-value service rates and physician characteristics. Design, Setting, and Participants: Retrospective analysis of low-value service use in 2008‒2013 using Medicare fee-for-service claims and enrollment data for 4,797,293 beneficiaries served by 66,675 generalist physicians. We employed multilevel models to quantify the magnitude of service use across...

  5. Leveraging CRISPR/Cas Genome Editing Technology to Identify and Characterize Causal GWAS Variants for Blood Lipids

    Raghavan, Avanthi
    Genome-wide association studies (GWAS) have identified a number of novel genetic loci linked to serum cholesterol and triglyceride levels. The causal DNA variants at these loci and the mechanism by which they influence phenotype and disease risk remain largely unexplored. Expression quantitative trait locus (eQTL) analyses of patient liver and adipose biopsies indicate that many lipid-associated variants influence gene expression in a cis-regulatory manner. However, linkage disequilibrium (LD) among neighboring single nucleotide polymorphisms (SNPs) at a GWAS-implicated locus makes it challenging to pinpoint the actual variant underlying an association signal. Here we performed high-throughput identification of putative disease-causal loci through...

  6. Old and New Methods of Glaucoma Diagnosis Using Spectral-Domain Optical Coherence Tomography: Testing Limitations of Older Retinal Nerve Fiber Layer Thickness Measurements and Diagnostic Potential of Newer Retinal Volume Measurements

    Liu, Yingna
    Purpose: Optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness measurements are a reproducible and quantitative diagnostic modality widely used for glaucoma evaluations, but a high rate of testing artifacts limits its clinical utility. In Part I of this thesis, we aimed to characterize artifact types and assess artifact rates in two-dimensional (2D) RNFL thickness measurements obtained by the Spectralis OCT machine (Heidelberg Engineering, Heidelberg, Germany), as well as to determine patient factors and eye conditions associated with a higher artifact prevalence. In Part II of this thesis, we aimed to compare a new parameter, peripapillary retinal volume (RV),...

  7. Characterization of the Spatiotemporal Network in Prefrontal Cortex-Hippocampal Synchronization: The Role of the Thalamic Nucleus Reuniens and Delta Band 2-5 Hz Oscillations

    Roy, Alexis T.
    Background: Schizophrenia is a devastating mental health illness in which our pharmacologic options do not treat the cognitive deficits that largely contribute to long-term disability. Problems with cognition likely arise from dysfunctional neural networks in which spatially distinct brain regions are unable to temporally coordinate electrical activity accurately. More specifically, the hippocampus (HC) normally achieves long-range, temporal coordination through generation of theta (4-8 Hz) oscillations by which the prefrontal cortex (PFC) can synchronize its activity. This synchronization occurs through direct HC-to-PFC monosynaptic projections, and disruptions in this pathway can replicate key features of schizophrenia. Although prior research has concentrated heavily...

  8. Widespread Non-Additive and Interaction Effects Within Human Leukocyte Antigen Loci Modulate the Risk of Autoimmune Diseases

    Deutsch, Aaron J.
    Autoimmune diseases occur when the immune system mistakenly targets normal tissues. These diseases comprise a wide range of conditions, such as systemic lupus erythematosus, inflammatory bowel disease, and multiple sclerosis. For most autoimmune diseases, the strongest genetic risk is conferred by the human leukocyte antigen (HLA) genes, which are located within the major histocompatibility complex (MHC). The proteins encoded by HLA genes present peptide antigens to T cells, which then determine if a given antigen represents a self-peptide or a foreign peptide. In certain cases, this process can go awry, leading to T cell-mediated destruction of healthy tissues. Importantly, each...

  9. A Contemporary, Population-Based Analysis of the Incidence, Cost, Outcomes, and Preoperative Risk Prediction of Postoperative Delirium Following Major Urologic Cancer Surgeries

    Ha, Albert Sangji
    Introduction Postoperative delirium is associated with poor outcomes and increased healthcare costs across numerous surgical and medical disciplines. Although characterized in other surgical fields, the population-based incidence, outcomes, and cost of delirium have not been assessed in major urologic cancer surgeries. We sought to evaluate the incidence, outcomes, and cost of postoperative delirium after major urologic cancer surgeries, specifically after radical prostatectomy (RP), radical nephrectomy (RN), partial nephrectomy (PN), and radical cystectomy (RC) in the USA. We have also developed a preoperative risk prediction model specific to major urologic cancer surgeries to identify patients at high risk for postoperative delirium. Methods Using the...

  10. The State of Quality in the NHS in England: a Qualitative Analysis of Interviews With Forty-Three High-Ranking Representatives of the NHS

    Martin, Sara
    Recent years have seen dramatic changes in the quality infrastructure of the NHS in England. In addition to the large-scale restructuring that occurred under the 2012 Health and Social Care Act, there have been copious changes intended to address well-publicized and scandalous lapses in the quality of care. Meanwhile, the NHS in England is coping with ever-restrictive budgetary demands. The resultant picture is of dynamic and complex development with multiple players. Given this, a key question is how best to move forward? How to develop a balanced strategy for quality that develops short, medium and long term goals, and can...

  11. Predictors of Potentially Burdensome Transitions of Care for Hospitalized Patients With Advanced Cancer

    Lage, Daniel E.
    Background: Patients with advanced cancer experience frequent hospitalizations and potentially burdensome transitions of care post-discharge that could negatively impact the quality of their end-of-life care. We examined predictors of discharge location for patients with advanced cancer, including patient-reported physical and psychological symptoms, and assessed the relationship between discharge location and survival. Methods: We prospectively enrolled patients with advanced cancer who experienced an unplanned hospitalization at the Massachusetts General Hospital from September 2014 to March 2016. Upon admission, we assessed patients’ physical symptoms (Edmonton Symptom Assessment System [ESAS]; 0-10) and psychological distress (Patient Health Questionnaire 4 [PHQ-4]; 0-12). The PHQ-4 includes depression...

  12. Leveraging Genomic Signatures to Understand Human Disease: Applications in Infectious Disease and Cancer

    Tabrizi, Shervin
    Genomics has been transformative to the study of human evolution and disease. With the dropping cost and increased availability of genome sequencing, it is now possible to probe the genetic mediators of human disease at an unprecedented level. My own research grew out of earlier work on the genomic signatures of natural selection in humans. As an undergraduate, I investigated the evidence for recent positive selection in large-scale genomic data, identifying pathways that appear to be targeted by evolution and prioritizing promising candidate variants for functional follow-up. In medical school, I turned my attention to applying tools in genomics and...

  13. Development and Implementation of a Clinical Pathway for Radiation of Bone Metastases in a Complex Academic Radiation Oncology Organization

    Rotenstein, Lisa
    Background: Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Evidence around treatment of complicated bone metastases is increasingly nuanced and although the American Society of Radiation Oncology and the American Association of Hospice and Palliative Medicine recommend single fraction radiation therapy (SFRT) for uncomplicated bone metastases, implementation is variable. We sought to determine the effects of a bone metastases-focused clinical pathway on Brigham and Women’s/Dana Farber Cancer Center’s (BW/DFCC) palliative radiation treatment patterns, which are determined by a dedicated palliative radiation consult service (SPRO) at the main BW/DFCC campus, and network physicians who treat more than...

  14. The Forest for the Trees: Using Big Data to Improve Preoperative Assessment and Risk Stratification in Pediatric Orthopedic Surgery

    Bartolozzi IV, Arthur R
    This thesis uses the Kid’s Inpatient Database to analyze surgical epidemiology, clinical outcomes, LOS, and total costs for two major pediatric surgeries. The goal is to establish clinically meaningful identifiers of risk, complexity, and variation in management both for improving preoperative assessment and understanding demographic determinants of health. Chapter 1 focused on open hip reduction for the treatment of DDH. This has become more expensive despite shorter hospital stay over time. It is also a longer, more costly experience for children who have reached walking age particularly those over 3 years old. Other patient factors including: developmental delay, ethnicity and...

  15. Progenitor Diversity, Lineage Commitment, and Acquisition of Cell-Type Identity in the Cerebral Cortex

    Custo Greig, Luciano
    An extraordinary variety of neuronal subtypes, each with distinct morphologies, patterns of connectivity, and electrophysiological properties, is generated during neocortical development. Elucidating programs of molecular controls that govern progressive specification of neuronal subtype identity in the cerebral cortex contributes toward our understanding its development, organization, evolution, and function. Establishing a basic framework for how and when cell fate specification decisions are made will enable more efficient manipulation of these transitions in vitro, and therefore has important practical implications for biomedical research, as it will help improve protocols for generation of specific cortical neuron subtypes for use in disease modeling, drug...

  16. Cellularized Collagen-Membrane Lung Assist Devices for Efficient Gas Transfer

    Lo, Justin H.
    Chronic lower respiratory disease afflicts over 5% of the United States population, leading to over 145,000 deaths annually. There remains a need for safer and more durable alternatives to lung transplant for patients who progress to end-stage lung disease. Portable or implantable gas oxygenators based on microfluidic technologies can address this need, though harnessing their potential depends on efficient and biocompatible design. Incorporating biomimetic materials into such devices can help replicate efficient native gas exchange function and additionally support cellular components. In this work, we developed microfluidic devices that enable blood gas exchange across ultra-thin collagen membranes (as thin as...

  17. The Roles of Aldosterone and Protein Kinase a Signaling in Vascular Smooth Muscle Cell Calcification

    Wang, David Wen Rui
    Vascular calcification is a disease prevalent in the elderly population. Intimal calcification, the dominant form, is calcification of the inner layer of the blood vessel wall and arises primarily after atherosclerotic plaque accumulation, thereby following the vascular distribution patterns of atherosclerosis. Medial calcification, calcium phosphate deposition in the middle layer of blood vessels, is much less common and is correlated with different disease states, such as type II diabetes and chronic kidney disease. It is widely recognized that vascular smooth muscle cells of the medial layer play a major role in the pathogenesis of vascular calcification. This study focuses on how...

  18. The ‘Natural’ History of Cancer in Africa: Tracking Malignancy, Oncology, and Its Ideologies (1957-1984), With a Comparative View to the 21st Century in Rwanda

    Djordjevic, Darja
    While it is widely accepted that cancer incidence is on the rise in Africa, and global oncology has burgeoned, the history of cancer and cancer research on the continent is generally not discussed. This thesis reviews data original research and policy statements on cancer in Africa from the 1950s til the early 1980s. The analysis herein seeks to unpack the movations for the etiological and epidemiological cancer surveys that seem to have risen to prominence beginning in the 1950s. It also charts the significance of racial difference as it was factored into the categorization, incidence, and outcomes of various cancers,...

  19. Small Molecule Modulators of Apoptosis

    Luccarelli, James
    Control of cell survival relies on a delicate balance between pro-apoptotic and anti-apoptotic signalling. In humans, the key regulatory proteins are those of the BCL-2 family, which include effector proteins such as BAX and BAK, anti-apoptotic proteins including BCL-2 and MCL-1, and pro-apoptotic proteins including BID and BIM. Dysregulation of apoptosis is among the Hallmarks of Cancer, and modulation of apoptosis holds promise as an effective therapeutic strategy for a range of malignancies. This thesis advances new strategies for modulating apoptosis using small molecules. The first section explores the properties of stapled peptides. These molecules incorporate two non-natural amino acids with...

  20. Rapid and Comprehensive Bacterial Identification and Antimicrobial Resistance Determination Using Microfluidic Enrichment and Whole-Genome Sequencing

    Anahtar, Melis N.
    Sepsis and other severe bacterial infections affect over 750,000 Americans annually, resulting in a 28% mortality rate and $16 billion in health care costs due to delays in proper diagnosis. The current gold-standard method for determining the species identification (ID) and antimicrobial resistance (AMR) profile of a clinical pathogen relies on the century-old method of growing bacteria in culture media, which takes 2-5 days, and frequently fails to cultivate the causative pathogen. In the absence of microbiologic data, physicians are forced to treat suspected infections with broad-spectrum empiric antibiotics that can have significant toxicity to the patient, are not always...

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