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ItemMulti-factorial treatment paradigm detection could be the answer to complex diseases: a case study of ALS(Georgia Institute of Technology, 2017-12) Kittel, Tyler ElizabethAmyotrophic Lateral Sclerosis (ALS) is a debilitating neurodegenerative disease with no known cause or cure. Through a combination of an open market-space, scientific curiosity, and the humanitarian motivation to advance medicine, every treatment option imaginable has been attempted for this condition in the hopes of finding a cure. This analysis incorporates 5026 paired treatment-to-control data points of the G93A SOD1 mouse model, the most commonly tested ALS model, in an effort to organize the vast amount of published data in the field and evaluate which approaches are most promising for further experimentation. An ANOVA analysis was completed comparing nine different pathophysiological treatment approaches to ALS as a function of seven stages of disease progression throughout the entire lifespan of the mice. Treatment efficacy was evaluated based on how well the treatment improved three disease metrics compared to their own experimental control. Patterns emerged for overall disease benefit, as well as for the three modality assessments including onset delay, survival prolongment, and general health scores. Combination treatments that fit into more than one category also performed better than individual therapies later in life. Interestingly, most treatments were administered before disease onset, yet benefit was almost solely found post-onset. These results suggest that patients may benefit from a targeted pro-active combinatorial treatment approach to combat the multiple failed regulations and general homeostatic instability characteristic of ALS. Such a conclusion correlates with the trend towards complex personal medicine treatment plans in other multifactorial diseases.
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ItemCrowdsourcing Analysis of Off-label Intervention Usage in Amyotrophic Lateral Sclerosis(Georgia Institute of Technology, 2017-05) Mertens, Benjamin IsaacBackground Amyotrophic Lateral Sclerosis is a neurodegenerative disease resulting in death within 3-5 years. Only riluzole is widely prescribed by clinicians to target the ALS etiology. Most interventions prescribed are “off-label”, meaning they were not developed for ALS, but are used to treat ALS or co-morbid symptoms. We examine relationships between intervention usage, disease duration, and sub-population characteristics (onset age, onset type, gender). Methods A form of physician crowdsourcing was utilized to examine intervention usage in a retrospective cohort of 1,585 ALS patients. Data was compiled on a per-visit and per-patient basis. Interventions were aggregated by active ingredient or indication. Principal component analysis (PCA), Fisher exact test, Kaplan Meir, and conditional random forest were used to determine the significance of relationships between patient characteristics, intervention usage, and disease duration. Results A total of 4,168 individual interventions and 564 intervention categories were identified in the cohort. A total 54 intervention categories met the threshold for statistical assessment (e.g. >8.5% usage prevalence); 19 corresponded to statistically significant (p<0.05) increases in disease duration ranging from +4.5-6.5 months. Interventions identified by random forest as the strongest predictors of disease duration (all p<0.01), are: vitamin A (+8.9 months), multivitamin (+8.2 months), feeding tube (+15.5 months), alternative herbal supplements (+9.7 months), antihistamines (+8.4 months), muscle relaxants (+13.4 months), stimulant laxatives (+7.1 months), anti-spasticity (+16.4 months). Usage of anti-cholinergic, anti-depressant, and non-opioid pain medication also resulted in a statistically significant (p<0.05) increase in survival duration (+6.2, +16.4 months, and +15.2 months, respectively). Riluzole, used by 60% of the cohort, increased disease duration by 1.3 months, albeit insignificantly (p>0.05). No interventions resulted in a significant decrease in survival duration. Female patients used more interventions than males, but gender was not an independent predictor of survival. Conclusions We found many “off-label” interventions perform better than the ALS-specific drug, riluzole. Our findings illustrate the complexity of variables contributing to ALS disease duration. Multiple interventions that increase overall health and quality of life, irrespective of whether they specifically target ALS etiology, profoundly increase survival duration likely by boosting “will to live”.
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ItemA Meta-Analysis Assessing the Role of Phosphorylated Tau and Amyloid-Beta on Cognitive Decline in a Preclinical Model Of Alzheimer's Disease(Georgia Institute of Technology, 2017-05) Huber, Colin MichaelAlzheimer’s Disease (AD) pathology is characterized by the accumulation of extracellular amyloid-β (Aβ) plaques in the brain followed by growth of phosphorylated tau (pTau) proteins into neurofibrillary tangles (NFTs). Both Aβ plaques and NFTs interfere with normal neuronal cell function by disrupting proper synaptic signaling and inflicting damage to neurons, eliciting cognitive decline. The presence of Aβ coincides with a decrease in cognitive performance; however, quantified Aβ accumulation does not correlate with cognitive decline. There have been no FDA-approved drugs capable of curing AD or delaying disease progression with research efforts heavily focused on amyloid-β as the primary causative agent in AD pathology. We performed a meta-analysis examining research studies matching inclusion criteria extracted from a database of more than 3,000 Alzheimer’s mouse model peer-reviewed articles. Phosphorylated tau, total tau, and amyloid-β levels were compared to measure the largest impact on cognitive performance by correlative assessment with Morris water maze escape latency and Novel Object Recognition. Phosphorylated tau accumulation into NFTs more strongly correlates with cognitive decline than Aβ despite a smaller total concentration, and therefore, pTau may contribute more to Alzheimer’s Disease progression. The two proteins interact through GSK3β and other phosphorylation pathways causing more rapid cognitive decline, and the onset of Aβ leads to the development of NFTs. Aβ and tau pathologies are interwoven in a complex manner that prevents separation. Alzheimer’s disease treatment will require the removal of both protein accumulation, and research should focus on combination drugs and defining the connection between Aβ and pTau.
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ItemExpression of Heat-Shock Proteins in the Presence of Oxidative Stress in the Sod1-G93a Amyotrophic Lateral Sclerosis Mouse Model(Georgia Institute of Technology, 2017-05) Bernhardt, Kamren DAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes death of motoneurons, resulting in paralysis, dysphagia, respiratory distress and ultimately death. The precise causes of this fatal disease are unknown, but the mechanisms contributing to motoneuron death have been researched extensively. Oxidative stress has been established as one mechanism of motoneuron death associated with ALS. Protein misfolding is a cellular dysfunction that occurs more commonly in increased levels of oxidative stress. Large concentrations of misfolded proteins interfere with neuron signaling and trigger apoptotic pathways leading to degeneration. Heat Shock Proteins (HSPs) are chaperones that assist in proper protein folding. The purpose of this research is to determine where and to what extent HSP levels are not being properly upregulated to counter the negative effects of oxidative stress associated with ALS, to determine their corresponding impact on cellular degeneration, and to assess the susceptibility of spinal motoneurons and muscle to oxidative stress. We perform a meta-analysis of HSPs from 11 peer-reviewed experimental journal articles assessing HSP levels in the SOD1-G93A transgenic ALS mouse model. Aggregated analysis of HSP levels in SOD1-G93A ALS transgenic mice revealed that HSPs are downregulated in the limbs at most stages of the disease, and are significantly lower than HSP levels in the spine. In contrast, HSP levels in the spine are significantly upregulated in comparison to wild type or non-ALS mice. Since HSPs combat protein misfolding, the compensatory upregulation of HSPs in the ALS pathology is insufficient to counteract oxidative stress. Our results suggest that the muscle cells are more vulnerable to oxidative-related degradation than spinal motoneurons. In summary, HSPs as a clinical therapeutic strategy delivered to the muscle and/or spine could be particularly helpful in early stages of ALS, where their effect in delaying oxidative stress induced cellular death is maximal.
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ItemMulti-scale Quantitative Assessment of Apoptosis, Bioenergetics, and Oxidative Stress Molecular Mechanisms in the SOD1 G93A Transgenic ALS Mouse Model(Georgia Institute of Technology, 2017-05) Zhang, Kenneth Y.Apoptosis, bioenergetics, and oxidative stress have been implicated in Amyotrophic Lateral Sclerosis (ALS) disease progression; it is unclear as to how the interactions within this highly inter-related triad of categories influences the time course of the disease or, how effective therapeutic modulation could be accomplished. In this multi-scale study, we aim to simulate the molecular responses in ALS and map the timing of the interactions between the response mechanisms in high-copy SOD1 G93A (superoxide dismutase-1, glycine 93 to alanine) transgenic mice in order to determine which parameters and relationships have the most significant impact on ALS in each stage of the pathology. In addition, the possibility of homeostatic instabilities within the triad prior to, during, and after ALS symptom onset is examined. We observed several apoptosis- and oxidative stress-related metrics which are elevated throughout ALS disease course, with evidence of early disturbances. We identify regulatory differences within the apoptosis-bioenergetics-oxidative stress triad between G93A and wild type mice that could contribute to homeostatic instability leading to ALS symptom onset and disease progression.
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ItemStudy of Recaptured Primary Data in Journal Articles Concerning the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis(Georgia Institute of Technology, 2016-05) Kim, Renaid B.Amyotrophic lateral sclerosis (ALS) is a debilitating disease that is characterized by late-onset, progressive neuronal degeneration of the motor neurons, which results in dysphagia, dyspnea, dysarthria and eventually death. There is currently no cure for ALS, with riluzole being the only FDA-approved drug that only extends survival by 3 to 6 months without repairing the damaged motor neurons. Transgenic mice, especially the one with superoxide dismutase 1 glycine 93 to alanine mutation (SOD1-G93A), have been a mainstay in the study of ALS and its underlying pathophysiology, with more than 3,000 articles upon a Pubmed search of (Amyotrophic Lateral Sclerosis OR ALS) AND (G93A OR Mouse). Such a wealth of data allows for informatics approaches to understanding the pathophysiology of ALS. To form a framework for conducting an informatics study with primary journal articles about ALS, a nine-category ontology was created via a comprehensive, keyword-based agnostic survey of more than 1,300 journal articles, which is presented in Chapter 2. A meta-analysis of 45 journal articles was conducted to examine temporal relationships between calcium homeostasis, mitochondrial dysfunction and oxidative stress and to elucidate the timing of the disturbances, which is presented in Chapter 3. Chapter 4 thoroughly describes the biocuration process used for the projects in the laboratory and presents interesting findings about the associates in the laboratory.
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ItemImplementing Effective Biocuration Process, Training, and Quality Management Protocols on Undergraduate Biocuration of Amyotrophic Lateral Sclerosis(Georgia Institute of Technology, 2015-08-18) True, Rachel WilcoxBiocuration is manual scientific collection, annotation and validation of literary information of biological and model organisms into a single database. Successful biocuration processes involve those with an extensive collection of literature, a user-friendly database interfaces for entering and analyzing data from published papers, and highly regulated training and quality assurance protocols. Due to the rapid expansion of biomedical literature, an efficient and accurate biocuration process has become more valuable due to the magnitude of data available in published literature. As the biocuration process incorporates undergraduates, it is critical that the medium for data collection is simple, ergonomic, and infallible. A reconstructed FileMaker Pro database was introduced to previously trained undergraduate students for process evaluation. Streamlining the biocuration process and grouping data structure to be more intuitive were two goals the new database interface hoped to achieve. The creation of a rigorous training program and strict quality management protocol is needed to prepare the lab for the introduction of efficient biocuration processes. Through the database designing process, training protocols were drafted to effectively call the biocurator’s attention to important changes in the interface design. Upon prototyping the database, entry errors were reviewed, training protocols were adjusted, and the quality protocols were drafted. When the combination of undergraduate biocurators and the reconstructed database under these new protocols was compared to statistics in the biocuration field, results proved to show increase in both productivity rates as well as accuracy rates. By having such efficiency at the undergraduate level, subject matter experts will no longer be required to perform this type of research and can focus on analysis. This will increase research productivity and reduce costs in the overall biocuration process. With over 12,000 published papers regarding Amyotrophic Lateral Sclerosis on Pubmed in 2014 alone, this revolutionary combination could lead to quickly finding a suitable cure for these patients.