MEDICA@MUSC (Medical University of South Carolina)
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Real-World Use of Bevacizumab for Treatment of Advanced Ovarian Cancer Among Elderly Women in the U.S.
Get PDFBevacizumab, a targeted VEGF inhibitor, is recommended for treatment of advanced ovarian cancer based on clinical trials demonstrating improved progression-free survival when added to standard chemotherapy. This study describes demographic, clinical and social factors, and outcomes associated with bevacizumab use among ovarian cancer patients in the US Medicare 5% sample. Kaplan-Meier curves and propensity score-weighted Cox proportional hazards models were used to estimate overall survival (OS) comparing bevacizumab to non-bevacizumab regimens. Of 3,760 patients with a principal diagnosis of ovarian cancer from 2016 to 2019, 1,508 had at least one observed line of chemotherapy; 457 had a second line following a treatment-free interval (TFI) ≥60 days, of whom 52% (N=237) received bevacizumab. Receipt of bevacizumab did not vary by dual eligibility for Medicaid (an indicator of poverty) or residing in a vulnerable community (measured by the social vulnerability index). Patients receiving bevacizumab were more likely to have metastatic disease and a TFI ≤180 days (an indication of platinum-resistant disease) at second-line treatment initiation. Bevacizumab was associated with a modest survival advantage and lower relative risk of death (hazard ratio=0.80, 95% confidence interval=0.66, 0.97) among patients who received bevacizumab within 30 days after second-line initiation, particularly those younger than age 75
Gut Check: Exploring the Role of Acinetobacter in Intestinal Inflammation
Get PDFInflammatory Bowel Disease (IBD) is a chronic disorder characterized by excessive intestinal inflammation. Alterations in the gut microbiota have been consistently observed in individuals with IBD, but it is unclear which bacteria participate in driving inflammation. A comprehensive survey of publicly available RNA-sequencing datasets revealed that Acinetobacter species are elevated in the gastrointestinal tract of IBD patients. We found that A. calcoaceticus was particularly elevated in Crohn’s Disease patients; a subset of IBD. It is well documented that Acinetobacter species are resistant to several antibiotics, but there is very little information on the effects of Acinetobacter in the gut and hardly any data on A. calcoaceticus. Computational analysis of Acinetobacter genomes revealed that A. calcoaceticus harbored a wide repertoire of multi-drug efflux pump and beta-lactam resistance genes. We found that A. calcoaceticus strains were moderately to highly resistant to certain antibiotics within fluoroquinolones, aminoglycosides, tetracyclines, and other antibiotic classes. Modeling the conditions of the gut, we found that A. calcoaceticus strains tolerated varying levels of pH, osmolarity, ethanol and hydrogen peroxide. Biolog phenotypic microarrays further revealed that A. calcoaceticuscould use a range of nutrient sources found in the gut, including monosaccharides, disaccharides, glycosides, and amino acids. Moreover, A. calcoaceticus could grow anaerobically in stool-based bioreactors. Using inside-out intestinal organoids, we found that A. calcoaceticus stimulated pro-inflammatory cytokines; suggesting that A. calcoaceticus could initiate inflammation. In vivo, we found that A. calcoaceticus did not stimulate inflammation in the setting of a complex gut microbiota. However, disruption of the gut microbiota with antibiotics resulted in enhanced inflammation in A. calcoaceticus treated mice. To model IBD, we administered 2,4,6- trinitrobenzene sulfonic acid (TNBS) and we observed that TNBS treated mice receiving A. calcoaceticus lost more weight and had worse histological scores than mice treated with vehicle control and TNBS; indicating Acinetobacter worsens intestinal inflammation. Addition of antibiotics to the TNBS model further heightened the inflammation induced by A. calcoaceticus. Collectively, these data demonstrate that A. calcoaceticus is antibiotic resistant, well adapted to survive the gastrointestinal tract, and is capable of initiating inflammation in the setting of an altered gut microbiota
Engineering Mesenchymal Stromal Cells to Suppress Inflammation and Increase Beta-Cell Mass for Treating Type 1 Diabetes
No full textType 1 diabetes (T1D) is a life-threatening autoimmune disease where the immune system destroys the insulin producing beta-cells in the pancreas. There is no cure for the disease, and the current treatment involves life-long, daily injection of insulin. An ideal therapy for T1D will be the suppression of autoimmunity and increased functional beta-cell mass. The immune regulatory cytokine IL10 can suppress inflammation in various autoimmune diseases. On the other hand, several growth factors and peptide hormones are known to promote an increase in beta-cell mass, through neogenesis and beta-cell proliferation. However, efficient induction of increased beta-cell mass requires preferential and persistent delivery of these factors to the pancreatic microenvironment. Recently, our lab showed that Mesenchymal Stromal Cell (MSC) mediated delivery of the peptide hormone Gastrin, in the absence of immunomodulation therapy, protects the non-obese diabetic (NOD) mice from T1D for a significant duration. Considering these aspects, we hypothesized that co-delivery of Gastrin and IL-10, preferentially to the pancreatic microenvironment, will suppress inflammation and increase beta-cell mass, thus reversing hyperglycemia in T1D. To test this hypothesis, we used MSCs engineered to express Gastrin and IL-10 individually and in combination. We engineered MSCs to express these factors using a lentiviral expression system. The cells were characterized post-engineering to express relevant surface markers (CD44, Sca-1, and CD29). Intracellular expression and section of gastrin and IL10 was successfully detected. The therapeutic effects of engineered MSCs on T1D and insulitis were measured using various methods. In our first cohort of treated NOD mice with varying levels of blood glucose we found difference in blood glucose values between control and each of the treatment, however there was no significant difference within the three types of treatments. With our second cohort of mice tissue sections were collected to determine the impact of treatment. Pancreatic sections were stained with anti-insulin antibody to detect islet areas for functional beta-cells and EdU staining was done to assess the proliferative nature of different cells. We found considerable differences the frequencies of insulin positive islets in some of the treated groups compared to controls. Similarly, using H&E staining found higher number of islets with less severe insulin in some of the treatment groups compared to controls. Furthermore, spleen cells were analyzed for the frequencies of T cells with pro- and anti-inflammatory cytokine expression such as IL10, IL17a, IL9, TNF-α, and IFN-γ. We found that expression and secretion of some of the proinflammatory cytokines was lower in treatment groups compared to controls. Finally, in a preliminary experiment, we modified the MSCs expanded from luciferase-transgenic mice to express the inflamed tissue homing molecules PSGL and SLeX or CXCR3 and CXCR4. In-vivo imaging showed that engineered MSCs were able to traffic to the general pancreatic area, however further studies are needed to validate this effect and the therapeutic value of similarly engineered MSCs. In conclusion, our studies show that co-delivery of Gastrin and IL-10 using MSCs can lead to better suppression of inflammation and increase in beta-cell number compared to control MSCs. However, further long-term studies are needed to measure the impact of this treatment in pancreatic microenvironment and beta-cell mass and function
Supporting Preschool Educators Through Developmental Resources to Promote Proper Development for Children Ages 0-5
Get PDFEducating teachers on development can help build a strong foundation to begin a child’s formal education. The project aim was to provide education on development upon hire to help teachers create a healthy and age-appropriate environment for kids to learn. Onboarding modules and customized educational materials were created for the teachers and families. Teachers reported the material was relevant and appropriate for their classroom
Juntos Podemos (Together We Can): A Resource Platform for Special Education Teachers in Latin America
No full textIntroduction: The purpose of this occupational therapy doctoral project is to address the problem of limited access to resources that special education teachers in Nicaragua and other LMICs face by providing access to educational materials on unfamiliar topics. Millions of people all over the world face barriers associated with disabilities. In Nicaragua, there is a lack of child development programs and educational resources. Method: A quality improvement study consisting of quantitative and qualitative data collection determined the effectiveness of the app resource platform Juntos Podemos. Brief REDCap surveys and a focus group gathered teacher feedback about the resource platform. Results: Results were analyzed using descriptive statistics and thematic analysis. The results revealed high satisfaction scores and that teachers agree the app improves their access to resources. All the participants reported they would use the app at least once every month. Conclusion: The results from this study revealed that the app accomplished its purpose of improving teacher access to educational resources in LMICs. The sustainability of the app facilitates future growth and impact for caregivers of children with disabilities and special needs in LMICs
Supporting the Caregiver’s Transition Home After SCI: Resource Development for Roper Rehabilitation’s Family Training Program
Get PDFNatural Language Processing for Precise Identification of Primary Tumor Histology and Radiation Necrosis in Stereotactic Radiosurgery Patients
Get PDFThe management of brain metastases and their associated complications, such as radiation necrosis, has long posed significant challenges in radiation oncology. Stereotactic radiosurgery (SRS) is a key treatment modality for patients with brain metastases, yet the complexity of metastatic disease and limitations in diagnostic coding systems, such as the International Classification of Diseases (ICD), often obstruct the accurate extraction of critical information from electronic health records (EHRs). This difficulty especially impacts the identification of primary tumor histology and the detection of post-treatment complications like radiation necrosis (RN), both of which are crucial for improving clinical outcomes and conducting robust observational research. Traditional methods, which rely on ICD-10 codes and manual chart reviews, tend to be inefficient and imprecise, limiting both the scale and timeliness of research.
This research aims to address these challenges by (1) developing advanced machine learning (ML) and natural language processing (NLP) algorithms to enhance the automated identification of primary tumor histologies in patients undergoing SRS, (2) creating an electronic phenotype for accurately detecting radiation necrosis in clinician notes, and (3) implementing and evaluating the RN electronic phenotype in a real world dataset showing the practical utility of the algorithm. Together these methods focus on improving data extraction and diagnostic precision of that extraction of clinical EHR data. Together, these aims contribute to a more streamlined, accurate framework for researching SRS for brain metastases and understanding treatment-related complications.
Aim 1 involved the creation of an ML and NLP algorithm to extract primary tumor histology from clinical records, overcoming the limitations of ICD-10-based classification systems. By accurately identifying the primary tumor type, this algorithm improved the precision and accuracy of identification of patient diagnosis in the EHR, enabling better patient stratification for observational research. We demonstrated that the NLP model greatly improved classification F1-score over ICD. In addition we demonstrated the ability to classify patients by subtypes further demonstrating improvement over ICD classification.
Aim 2 focused on developing an NLP model to detect instances of radiation necrosis in clinical notes. The algorithm analyzed unstructured clinical data, identifying key terms and patterns indicative of RN, facilitating RN detection from the EHR notes. After several failed attempts and making a more elaborate NLP model, we restricted the data to a more uniform corpus and used a simple model that successfully had an F1-score of 0.92 for classifying RN.
Aim 3 focused on a real world practical trial of the RN NLP model. Detailed are 3 separate attempts to improve the precision of the RN classifier while keeping the recall high. After the limit of the algorithm was reached, we investigated the remaining errors highlighting the difficult and often overlapping signs and symptoms. We demonstrated that the NLP algorithm reduced the volume of clinical notes requiring manual review by 90%. Although the notes identified by the algorithm were sometimes false positives, they frequently represented edge cases where the clinician was uncertain about the diagnosis. The NLP algorithm significantly outperformed traditional rule-based text searches, reducing the false positive rate and improving the efficiency of identifying potential RN cases for further review.
Through these specific aims, the study significantly improved the efficiency and accuracy of data extraction for large-scale research and clinical applications. It provided valuable insights into extracting electronic phenotypes radiation necrosis in SRS patients, which potentially may facilitate more informed patient care
Development of Transportation Training Modules for Adults with Disabilities to Support Community Mobility
Get PDFBackground: A person with Autism spectrum disorder (ASD) or Intellectual disability (ID) may encounter internal barriers to public transportation modes including executive functioning. These may include challenges in initiation, planning, topographical orientation, waiting, and selecting correct embarkment transfers trains and buses. Additionally, the whole person journey is negatively impacted by sensory overload from light, sounds, crowded spaces, and impaired regulation strategies.
Purpose: The purpose of this quality improvement project is to mitigate these challenges of internal barriers inhibiting transit needs within this population by developing and dispersing a transportation education video tool. These efforts aim to promote optimal transportation engagement that will in turn increase community-based participation and self-efficacy.
Methods: Feedback from surveys was used in development of the final video tool. Initially, a two pilot video module was dispersed and feedback was collected to gain knowledge and understanding to increase IADL engagement within this population. The findings were analyzed and subsequent videos were enhanced accordingly. In the videos an emphasis was placed on methods to decrease any anxiety before embarkment. Additionally, another supplementary series of video modules were developed using a collaborative approach with participants. These modules focused on communicating a systematic method that introduces sensory regulation strategies to increase independent transportational engagement
Results: Four surveys were distributed with qualitative questions (n= 14). Participants include: 4 neurodivergent adults, 5 supporting staff, and 5 Occupational therapists. Results demonstrated positive outcomes using the video module tool with responses generally stating the desire to utilize the video for future community outings, continue audio and visual cues for each tasks, and to continue to use as a primary tool before trips.
Conclusion: Practical action implemented via a priming video tool with audio and visual cues was used effectively to break down components of task analysis in public transportation navigation. The proper management of sensory overload in the transit environment will increase success in origin to destination
The Regulation of BRD4 in Transcription and DNA Repair
No full textThe DNA damage response (DDR) is crucial for maintaining genomic stability and integrity. The epigenetic reader BRD4 acts as a molecular scaffold and is a key regulator of both transcription and DNA repair. In response to DNA double-strand break (DSB), BRD4’s interaction with chromatin undergoes dynamic changes. However, the detailed mechanisms that govern BRD4 binding to chromatin remain elusive. This study aims to investigate the regulatory mechanism of BRD4 binding to chromatin, focusing on its displacement from regions of damaged chromatin. I show the significance of ATM in mediating the displacement of BRD4 from chromatin utilizing Xenopus egg extracts and multiple in vitro assays. I show that BRD4 is a direct ATM substrate that is phosphorylated at Ser345. Surprisingly, ATM does not displace BRD4 from chromatin by phosphorylation, but instead through direct protein-protein binding. ATM-mediated phosphorylation reduces BRD4’s affinity for ATM, allowing it to be released. In addition, I reveal the role of PRMT4 in DSB repair through BRD4 methylation at the 3R region, which is required for retention of BRD4 on chromatin. This methylation is also stimulated by DSB induction and acts downstream of ATM-mediated displacement of BRD4. In this study, I further explore TIP60 revealing a role in BRD4 regulation that is distinct from its established role in activating ATM upstream of BRD4 displacement from chromatin. Overall, this research highlights multiple ways that post-translational modifications can modulate BRD4 activity, leading to new mechanistic insights that can be exploited in cancer therapeutics
Therapeutic Inhibition of Complement Component 3 in Spontaneous Osteoarthritis
Get PDFOsteoarthritis (OA) is a debilitating disease that affects 32.5 million US adults. It is characterized by loss of joint space and cartilage erosion, which eventually causes bone to rub on bone and causes pain and decreased mobility. Not only is it physically detrimental, but it is a financial burden as well. Current treatments of OA are used to control symptoms and leave intense side effects. Despite efforts in the past, there still is no disease-modifying OA drugs (DMOAD) approved on the market yet. The lack of disease-modifying drugs stems from poor understanding of the mechanisms initiating and driving the disease. As a result, there is a critical, medical need for improved agents for the treatment of OA. In response to this, our lab is identifying novel targets that could potentially be inhibited by small molecules to prevent the progression of OA. The results from our preliminary studies as well as prior research show that several complement factors are secreted in higher amounts in OA, especially complement C3. The complement cascade is important for innate immune responses against pathogens and can be activated through the classical, alternative, and mannose lectin pathway. All these pathways converge on the cleavage of complement component C3 and this is the central point of the cascade. This system is highly regulated and when this regulation breaks down, it could cause various diseases. In the case of OA, this overactive complement system could contribute to the degradation of the cartilage in the joint and the pathogenesis of OA. We also found that transcription factor signal transducer and activator of transcription 1 (STAT1) is involved in increasing C3 expression levels. STAT1 is involved in different inflammatory pathways specifically increasing IFN-γ expression and cancer. It has not been explored in the context of OA. This dissertation aims to identify the relationship between STAT1 and C3 in the context of OA, as well as using small molecule agents to target over expressed C3 expression to prevent progression of OA. First, we identified where STAT1 is associating with C3. Then, we discovered that STAT1 is involved in complement overexpression by using a specific STAT1 inhibitor, fludarabine. Lastly, we tested these inhibitors in vivo in Dunkin-Hartley guinea pigs to assess the inhibitor’s ability to attenuate cartilage damage in OA