Luke Jackson, John Muller, Elise O’Herron, Scott Cooper, Angela Richardson
Background and Hypothesis:Glioblastoma (GBM) is an aggressive primary malignancy of the CNS with a dismal prognosis (~15-20 months) despite standard of care therapies. The poor prognosis of GBM despite ongoing research may be due to inaccuracies in preclinical models of the disease. Cell lines typically used to study GBM are exposed to ambient air containing 21% oxygen (normoxia compared to physiologic oxygen tension, physoxia, ~5%). In extracranial tumors, exposure to the oxygen in ambient air triggers epigenetic changes that alter cell growth, metabolism, and treatment responsiveness. The aim of this study is to obtain preliminary data on the impact ofphysiologic oxygen tensions on primary glioma cell growth in vitro. Experimental Design:Growth of primary glioma cell lines (GB43, GB10, GB001) and one immortalized cell line (293T HEK) was assessed in normoxia and physoxia. All cell lines were plated at 10,000 cells per well. Cells were harvested and counted in triplicate on days 2, 4, 6, 8, 10, 12. On each day the cells were counted, the media in the remaining wells was changed. This experiment was repeated three times. Wound healing assays with all cell lines were also performed at normoxia and physoxia. Results:Cells line growth curves were plotted and showed consistent exponential growth after counting on day two. From these graphs, the cell doubling time was calculated over a period of four days during which the cells were undergoing exponential growth. Conclusions:Current results indicated that primary glioblastoma cell lines grow at different rates at differing oxygen tensions. In ongoing studies, we are exploring the effect of low oxygen tensions on functional assays such as wound-healing. Future work will assess rates of growth and functional consequence of physoxia in tumor samples never exposed to ambient air to most accurately recapitulate the in-situ environment.
{"title":"Effect of Oxygen Tension on Glioblastoma Cell Growth","authors":"Luke Jackson, John Muller, Elise O’Herron, Scott Cooper, Angela Richardson","doi":"10.18060/27862","DOIUrl":"https://doi.org/10.18060/27862","url":null,"abstract":"Background and Hypothesis:Glioblastoma (GBM) is an aggressive primary malignancy of the CNS with a dismal prognosis (~15-20 months) despite standard of care therapies. The poor prognosis of GBM despite ongoing research may be due to inaccuracies in preclinical models of the disease. Cell lines typically used to study GBM are exposed to ambient air containing 21% oxygen (normoxia compared to physiologic oxygen tension, physoxia, ~5%). In extracranial tumors, exposure to the oxygen in ambient air triggers epigenetic changes that alter cell growth, metabolism, and treatment responsiveness. The aim of this study is to obtain preliminary data on the impact ofphysiologic oxygen tensions on primary glioma cell growth in vitro. \u0000Experimental Design:Growth of primary glioma cell lines (GB43, GB10, GB001) and one immortalized cell line (293T HEK) was assessed in normoxia and physoxia. All cell lines were plated at 10,000 cells per well. Cells were harvested and counted in triplicate on days 2, 4, 6, 8, 10, 12. On each day the cells were counted, the media in the remaining wells was changed. This experiment was repeated three times. Wound healing assays with all cell lines were also performed at normoxia and physoxia. \u0000Results:Cells line growth curves were plotted and showed consistent exponential growth after counting on day two. From these graphs, the cell doubling time was calculated over a period of four days during which the cells were undergoing exponential growth. \u0000Conclusions:Current results indicated that primary glioblastoma cell lines grow at different rates at differing oxygen tensions. In ongoing studies, we are exploring the effect of low oxygen tensions on functional assays such as wound-healing. Future work will assess rates of growth and functional consequence of physoxia in tumor samples never exposed to ambient air to most accurately recapitulate the in-situ environment.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":" 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139625562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and Hypothesis: Glaucoma affects 3 million Americans and is the second most common cause of blindness globally, after cataracts. It involves the degeneration of the optic nerve, often associated with increased eye pressure, leading to vision loss. Trabeculectomy was traditionally the standard surgical approach for managing glaucoma progression once medication and laser had failed. Recently, minimally invasive glaucoma surgeries (MIGS) have gained FDA approval for mild and moderate cases and are being implemented in practice. We hypothesize that MIGS procedures are just as effective as trabeculectomy in mild, moderate, and severe cases of glaucoma. Experimental Design or Project Methods: Using data from IU Health, patients that underwent either a MIGS procedure or a trabeculectomy for open-angle glaucoma at least a year ago were identified. Visual field data was used to stage their glaucoma. Any future glaucoma surgery was noted. Using this information, three separate Kaplan-Meier curves at 95% confidence intervals were created corresponding to each stage of glaucoma with a second surgery defined as a failure and a survival analysis was done to visualize the difference between these surgical approaches. Results: The sample included 119 patients and 179 eyes with a mean age of 80 and 57% females. The study had 80% power at a two-sided 5% significance level. Based on the survival analysis, there were no significant differences between trabeculectomy and MIGS in mild and moderate glaucoma (p=0.69 and 0.97 respectively). In severe glaucoma, MIGS had a lower failure rate compared to trabeculectomy (p=0.026). Conclusion and Potential Impact: The research comparing trabeculectomy to MIGS is still relatively new and this study shows the safety and efficacy of MIGS procedures. If confirmed, this study could potentially change the standard of care to MIGS for all stages of open-angle glaucoma.
{"title":"A Comparison of the Effectiveness Between Trabeculectomy and Minimally Invasive Glaucoma Surgeries","authors":"Esa Syed, Louis Cantor","doi":"10.18060/27793","DOIUrl":"https://doi.org/10.18060/27793","url":null,"abstract":"Background and Hypothesis: Glaucoma affects 3 million Americans and is the second most common cause of blindness globally, after cataracts. It involves the degeneration of the optic nerve, often associated with increased eye pressure, leading to vision loss. Trabeculectomy was traditionally the standard surgical approach for managing glaucoma progression once medication and laser had failed. Recently, minimally invasive glaucoma surgeries (MIGS) have gained FDA approval for mild and moderate cases and are being implemented in practice. We hypothesize that MIGS procedures are just as effective as trabeculectomy in mild, moderate, and severe cases of glaucoma. \u0000Experimental Design or Project Methods: Using data from IU Health, patients that underwent either a MIGS procedure or a trabeculectomy for open-angle glaucoma at least a year ago were identified. Visual field data was used to stage their glaucoma. Any future glaucoma surgery was noted. Using this information, three separate Kaplan-Meier curves at 95% confidence intervals were created corresponding to each stage of glaucoma with a second surgery defined as a failure and a survival analysis was done to visualize the difference between these surgical approaches. \u0000Results: The sample included 119 patients and 179 eyes with a mean age of 80 and 57% females. The study had 80% power at a two-sided 5% significance level. Based on the survival analysis, there were no significant differences between trabeculectomy and MIGS in mild and moderate glaucoma (p=0.69 and 0.97 respectively). In severe glaucoma, MIGS had a lower failure rate compared to trabeculectomy (p=0.026). \u0000Conclusion and Potential Impact: The research comparing trabeculectomy to MIGS is still relatively new and this study shows the safety and efficacy of MIGS procedures. If confirmed, this study could potentially change the standard of care to MIGS for all stages of open-angle glaucoma.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":" 29","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139625763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Grant Hammons, Ally Aldrich, Rebecca Douglas, Catherine Guilfoy, Nina J. Jain, Ashleigh McMullan, Princess Murray, Caelen Rathke, Mark Wakulchik, Ellen Voskoboynik, James B. Zwierzynski, Matthew Durbin
Background and Hypothesis: Congenital heart defects (CHD) are the most common, and most frequently fatal birth defects, but most etiology remains unknown. We identified a patient with CHD and implicated a gene called SHROOM3. SHROOM3 binds Dishevelled2 which is the central cytoplasmic component of both canonical and noncanonical Wnt/planar cell polarity (PCP) signaling pathways. PCP drives cell movement and is important to embryogenesis and disruption causes CHD. We hypothesize CHD can result from SHROOM3-loss-of-function due to PCP disruption. Project Methods: To interrogate SHROOM3’s role in CHD and PCP we utilized an established in vivo SHROOM3-loss-of-function model, Shroom3 gene trap mice (Shroom3gt). We also utilized a loss-of-function model for PCP membrane component VANGL2, (Vangl2+/-). We assayed genetic interaction between Shroom3 and Vangl2 during cardiac development by crossing singly heterozygous null mice to produce compound heterozygous embryos, harvested embryos, and performed histologic analysis for cardiac defects. We also utilized a human in vitro SHROOM3-loss-of-function model, a CRISPR-Cas9 edited SHROOM3 knockout HELA cell line. We assayed cell movement using a scratch assay. Results: Compound heterozygous Shroom3+/gt;Vangl2+/- embryos had a three fold increase in heart defects compared to singly heterozygous Shroom3+/gt;Vangl2+/+ or Shroom3+/+;Vangl2+/- embryos (3 of 19 or 15.7%, versus 1 of 17 or 5.2%, and 1 of 19 or 4.8%, respectively), demonstrating a trend towards genetic interaction between SHROOM3 and VANGL2/PCP during cardiac development. The scratch assays demonstrated cell movement defects due to SHROOM3-loss-of-function consistent with increased cell movement. Conclusion and Potential Impact: We demonstrate SHROOM3 interacts with Wnt/PCP during cardiac development. Further interrogation of SHROOM3’s role in Wnt signaling will provide insight into the mechanisms by which a novel CHD candidate participates in cardiogenesis and will improve CHD diagnosis, management, and therapeutic development.
{"title":"The Role of SHROOM3 in Congenital Heart Disease","authors":"Grant Hammons, Ally Aldrich, Rebecca Douglas, Catherine Guilfoy, Nina J. Jain, Ashleigh McMullan, Princess Murray, Caelen Rathke, Mark Wakulchik, Ellen Voskoboynik, James B. Zwierzynski, Matthew Durbin","doi":"10.18060/27902","DOIUrl":"https://doi.org/10.18060/27902","url":null,"abstract":"Background and Hypothesis: Congenital heart defects (CHD) are the most common, and most frequently fatal birth defects, but most etiology remains unknown. We identified a patient with CHD and implicated a gene called SHROOM3. SHROOM3 binds Dishevelled2 which is the central cytoplasmic component of both canonical and noncanonical Wnt/planar cell polarity (PCP) signaling pathways. PCP drives cell movement and is important to embryogenesis and disruption causes CHD. We hypothesize CHD can result from SHROOM3-loss-of-function due to PCP disruption. \u0000Project Methods: To interrogate SHROOM3’s role in CHD and PCP we utilized an established in vivo SHROOM3-loss-of-function model, Shroom3 gene trap mice (Shroom3gt). We also utilized a loss-of-function model for PCP membrane component VANGL2, (Vangl2+/-). We assayed genetic interaction between Shroom3 and Vangl2 during cardiac development by crossing singly heterozygous null mice to produce compound heterozygous embryos, harvested embryos, and performed histologic analysis for cardiac defects. We also utilized a human in vitro SHROOM3-loss-of-function model, a CRISPR-Cas9 edited SHROOM3 knockout HELA cell line. We assayed cell movement using a scratch assay. \u0000Results: Compound heterozygous Shroom3+/gt;Vangl2+/- embryos had a three fold increase in heart defects compared to singly heterozygous Shroom3+/gt;Vangl2+/+ or Shroom3+/+;Vangl2+/- embryos (3 of 19 or 15.7%, versus 1 of 17 or 5.2%, and 1 of 19 or 4.8%, respectively), demonstrating a trend towards genetic interaction between SHROOM3 and VANGL2/PCP during cardiac development. The scratch assays demonstrated cell movement defects due to SHROOM3-loss-of-function consistent with increased cell movement. \u0000Conclusion and Potential Impact: We demonstrate SHROOM3 interacts with Wnt/PCP during cardiac development. Further interrogation of SHROOM3’s role in Wnt signaling will provide insight into the mechanisms by which a novel CHD candidate participates in cardiogenesis and will improve CHD diagnosis, management, and therapeutic development.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":" 41","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139625997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and Hypothesis:Cataracts are among the leading causes of blindness in the world. Smoking tobacco has been linked to cataract formation in old age. However, its linkage in causing an earlier onset is much more questionable. Assessing this linkage can help identify risk factors and help understand the causes and pathogenesis in development of cataracts over time. This can help direct modifiable risk factors in patients to prevent early deterioration in health, finance, physical capabilities, and overall comfort. It is hypothesized that history and intensity of smoking tobacco correlates with earlier onset cataracts. Experimental Design or Project Methods:Patient data of patients aged 40-65 were gathered from the last two years of cataract surgeries from Deen-Gross Eye Centers EMR (n=718). Age at date of surgery was used as observed value for determining earlier onset, and pre-operation charts were used to collect patient data on smoking status (light, someday, every day, heavy, former, never), age, gender, hypertension, diabetes, number of eyes operated on, family history (cataracts/glaucoma), and glaucoma. Statistical analysis was performed among the gathered data. Results:Statistical analysis revealed no significant difference in the ages of cataract surgeries between smokers and non-smokers. Controlling for non-hypertensive and non-diabetic patients revealed a similar result. There was no significant difference in smoking status between ages 40-55 and ages 56-65 who underwent surgery. There was no significant difference in age of surgery among each of the individual types of smokers. Conclusion:No significant associations were found. This calls for further research to better understand the linkage between tobacco smoking and cataracts, as well as the pathogenesis of earlier onset cataracts. No modifications in directing patient care can be made yet.
{"title":"Tobacco smoking and early onset cataracts","authors":"Albab Uddin, David Gross","doi":"10.18060/27871","DOIUrl":"https://doi.org/10.18060/27871","url":null,"abstract":"Background and Hypothesis:Cataracts are among the leading causes of blindness in the world. Smoking tobacco has been linked to cataract formation in old age. However, its linkage in causing an earlier onset is much more questionable. Assessing this linkage can help identify risk factors and help understand the causes and pathogenesis in development of cataracts over time. This can help direct modifiable risk factors in patients to prevent early deterioration in health, finance, physical capabilities, and overall comfort. It is hypothesized that history and intensity of smoking tobacco correlates with earlier onset cataracts. \u0000Experimental Design or Project Methods:Patient data of patients aged 40-65 were gathered from the last two years of cataract surgeries from Deen-Gross Eye Centers EMR (n=718). Age at date of surgery was used as observed value for determining earlier onset, and pre-operation charts were used to collect patient data on smoking status (light, someday, every day, heavy, former, never), age, gender, hypertension, diabetes, number of eyes operated on, family history (cataracts/glaucoma), and glaucoma. Statistical analysis was performed among the gathered data. \u0000Results:Statistical analysis revealed no significant difference in the ages of cataract surgeries between smokers and non-smokers. Controlling for non-hypertensive and non-diabetic patients revealed a similar result. There was no significant difference in smoking status between ages 40-55 and ages 56-65 who underwent surgery. There was no significant difference in age of surgery among each of the individual types of smokers. \u0000Conclusion:No significant associations were found. This calls for further research to better understand the linkage between tobacco smoking and cataracts, as well as the pathogenesis of earlier onset cataracts. No modifications in directing patient care can be made yet.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139626462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and Objective: Consecutive exotropia after unilateral or bilateral medial rectus recession is a common clinical problem. One surgical intervention to address the misalignment involves isolating and reattaching healthy muscle to the globe. The purpose of this study was determining factors indicative of surgical success in medial rectus resection and advancement with non-adjustable sutures for consecutive exotropia. Methods: Through retrospective chart review, 118 patients were identified to have consecutive exotropia using billing codes from June 2016 to October 2020 at Indiana University Health. 60 of these patients who maintained adequate follow-up either underwent the above intervention (n = 49) or underwent resection only (n = 11). Exclusion criteria included lack of medial rectus procedure or poor postoperative documentation. Patient demographics and data were gathered, including preoperative and intraoperative measurements, final postoperative deviation, and whether additional surgeries were necessary. Chi-squared and two-sample t-tests were performed to analyze the effect of each parameter on surgical success, defined as distance deviation ≤ 10 prism diopters of esotropia or exotropia at final postoperative visit. Results: Smaller total intraoperative adjustment–resection plus advancement–was significantly associated with surgical success (p = 0.044). Additionally, smaller preoperative deviations were significantly associated with patients who underwent unilateral surgery (p = 0.0093 near and 0.0021 distance). Conclusion: Patients with smaller preoperative deviations tended to have better outcomes, and those patients tended to have unilateral surgery. It is unclear whether a smaller deviation might have led surgeons to select unilateral medial rectus surgery or if the smaller deviation itself is a predictor of success. Relatively limited time of follow-up is a limitation in this study, as there is well-documented postoperative drift of increasing exotropia over time. A larger cohort or randomized controlled trial may provide additional insight that could increase the percentage of successful outcomes with a single surgery.
{"title":"Factors Predictive of Surgical Success in Medial Rectus Resection/Advancement for Consecutive Exotropia","authors":"Tate Lockwood, Tyler Knight","doi":"10.18060/27722","DOIUrl":"https://doi.org/10.18060/27722","url":null,"abstract":"Background and Objective: Consecutive exotropia after unilateral or bilateral medial rectus recession is a common clinical problem. One surgical intervention to address the misalignment involves isolating and reattaching healthy muscle to the globe. The purpose of this study was determining factors indicative of surgical success in medial rectus resection and advancement with non-adjustable sutures for consecutive exotropia. \u0000Methods: Through retrospective chart review, 118 patients were identified to have consecutive exotropia using billing codes from June 2016 to October 2020 at Indiana University Health. 60 of these patients who maintained adequate follow-up either underwent the above intervention (n = 49) or underwent resection only (n = 11). Exclusion criteria included lack of medial rectus procedure or poor postoperative documentation. Patient demographics and data were gathered, including preoperative and intraoperative measurements, final postoperative deviation, and whether additional surgeries were necessary. Chi-squared and two-sample t-tests were performed to analyze the effect of each parameter on surgical success, defined as distance deviation ≤ 10 prism diopters of esotropia or exotropia at final postoperative visit. \u0000Results: Smaller total intraoperative adjustment–resection plus advancement–was significantly associated with surgical success (p = 0.044). Additionally, smaller preoperative deviations were significantly associated with patients who underwent unilateral surgery (p = 0.0093 near and 0.0021 distance). \u0000Conclusion: Patients with smaller preoperative deviations tended to have better outcomes, and those patients tended to have unilateral surgery. It is unclear whether a smaller deviation might have led surgeons to select unilateral medial rectus surgery or if the smaller deviation itself is a predictor of success. Relatively limited time of follow-up is a limitation in this study, as there is well-documented postoperative drift of increasing exotropia over time. A larger cohort or randomized controlled trial may provide additional insight that could increase the percentage of successful outcomes with a single surgery.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":" 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139626533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Allison Gatz, Chenxi Xiong, Xiaochun Li, Michael Eadon, Jing Su
Background: Health disparities in acidosis risk are entangled with a range of factors including clinical conditions, genomic traits, and demographic features. Current clinical guidelines and policies on the safety of metformin have not yet taken holistic considerations of health disparities and other risk factors. The All of Us (AoU) research dataset provides comprehensive information including longitudinal real-world data for diseases and treatments, genetic data, and surveys for social determinants of health, with a focus on minority groups and the underserved population. This study leverages the AoU data to understand the health disparities in acidosis risk and provides real-world evidence to support clinical decisions. Methods: A case-control design was used to identify risk factors associated with emergent acidosis events, with a 1:4 matching using propensity scores specified by enrollment date, number of diagnoses, and length of medical history. Risk factors were sex, age, race, ethnicity, metformin use, Charlson comorbidities, and insurance status. Adjusted odds ratios (aOR) were estimated using conditional logistic regression. Results: The study includes the case group (n=2,666) and the control group (n=10,664). Health disparities were observed among participants. Compared with those who did not have health insurance, those with employer provided insurance (aOR: 0.49, 95%CI: 0.40 – 0.61), Medicare (aOR: 0.62, 95%CI: 0.52 – 0.74), or Medicaid (aOR: 0.80, 95%CI: 0.66 – 0.97) were less likely to develop acidosis. African Americans (aOR: 1.35, 95%CI: 1.15 – 1.58) showed higher acidosis risk. Other major risk factors include liver disease, renal disease, diabetes, and metformin use. Conclusion: Health insurance coverage is a major determinant of acidosis risk. Patients with kidney and liver diseases or diabetes should be monitored carefully for signs of acidosis, especially if they have been prescribed metformin. In future work, for diabetes patients with both kidney and liver diseases, pharmacogenomics analysis will be performed for precision management of metformin-related acidosis risks.
{"title":"Health Disparities in Acidosis Risks","authors":"Allison Gatz, Chenxi Xiong, Xiaochun Li, Michael Eadon, Jing Su","doi":"10.18060/27852","DOIUrl":"https://doi.org/10.18060/27852","url":null,"abstract":"Background: Health disparities in acidosis risk are entangled with a range of factors including clinical conditions, genomic traits, and demographic features. Current clinical guidelines and policies on the safety of metformin have not yet taken holistic considerations of health disparities and other risk factors. The All of Us (AoU) research dataset provides comprehensive information including longitudinal real-world data for diseases and treatments, genetic data, and surveys for social determinants of health, with a focus on minority groups and the underserved population. This study leverages the AoU data to understand the health disparities in acidosis risk and provides real-world evidence to support clinical decisions. \u0000Methods: A case-control design was used to identify risk factors associated with emergent acidosis events, with a 1:4 matching using propensity scores specified by enrollment date, number of diagnoses, and length of medical history. Risk factors were sex, age, race, ethnicity, metformin use, Charlson comorbidities, and insurance status. Adjusted odds ratios (aOR) were estimated using conditional logistic regression. \u0000Results: The study includes the case group (n=2,666) and the control group (n=10,664). Health disparities were observed among participants. Compared with those who did not have health insurance, those with employer provided insurance (aOR: 0.49, 95%CI: 0.40 – 0.61), Medicare (aOR: 0.62, 95%CI: 0.52 – 0.74), or Medicaid (aOR: 0.80, 95%CI: 0.66 – 0.97) were less likely to develop acidosis. African Americans (aOR: 1.35, 95%CI: 1.15 – 1.58) showed higher acidosis risk. Other major risk factors include liver disease, renal disease, diabetes, and metformin use. \u0000Conclusion: Health insurance coverage is a major determinant of acidosis risk. Patients with kidney and liver diseases or diabetes should be monitored carefully for signs of acidosis, especially if they have been prescribed metformin. In future work, for diabetes patients with both kidney and liver diseases, pharmacogenomics analysis will be performed for precision management of metformin-related acidosis risks.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139626542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jesse Mast, Md Sazzad Hassan, Annie Ritter, Akashdeep Singh, U. von Holzen
Background: Esophageal adenocarcinoma (EAC) is a major cancer in the United States with increasing incidence. It is an aggressive cancer involving columnar-type cells different from the normal esophageal (NE) squamous cells. This metaplasia often involves an intermediary morphology called Barrett’s esophagus (BE), which occurs from repeated acid exposure of the esophagus from gastroesophageal reflux disease (GERD). GERD leading to BE is a common pre-occurrence in EAC patients, but the mechanism remains obscure. To explore the mechanism and its components, we compared gene expression in BE and EAC cells with normal cells and discovered the overexpression of TRIM31 in the pathogenic cells. Although previous studies have shown oncogenic potential of TRIM31 in some cancers, its role in EAC is yet to be understood. Methods: RNA sequencing and transcriptomic profiling were performed on human NE, BE, and EAC epithelial tissue samples. TRIM31 expression in NE cell line (Het-1A) and EAC cell lines (OE19, Flo-1, OE33, SK-GT-2, and OACM5.1C) were identified by Western blot. The Het-1A cell line, after exposure to acidic pH and bile acid, was assessed for variable TRIM31 expression. Cell viability analysis of NE and EAC cell lines after exposure to acidic pH and bile acids was observed by WST-1 assay. Results: RNA sequencing, transcriptomic profiling, and western blot revealed overexpression of TRIM31 in BE and EAC epithelium. Exposure of Het-1A cells to bile acids in acidic pH changed the cell morphology with enhanced expression of TRIM31. WST-1 revealed that EAC cells were more resistant to acidic pH and bile acid exposure. Conclusions and potential impact: Our data suggests that increased TRIM31 expression correlates with esophageal epithelium resistance when exposed to bile acids and acidic pH. Consequently, TRIM31 may be a key player in the metaplasia of GERD-induced EAC development and may be an innovative therapeutic target and marker for EAC.
{"title":"TRIM31: A Protein With an Oncogenic Role in Esophageal Adenocarcinoma","authors":"Jesse Mast, Md Sazzad Hassan, Annie Ritter, Akashdeep Singh, U. von Holzen","doi":"10.18060/27729","DOIUrl":"https://doi.org/10.18060/27729","url":null,"abstract":"Background: Esophageal adenocarcinoma (EAC) is a major cancer in the United States with increasing incidence. It is an aggressive cancer involving columnar-type cells different from the normal esophageal (NE) squamous cells. This metaplasia often involves an intermediary morphology called Barrett’s esophagus (BE), which occurs from repeated acid exposure of the esophagus from gastroesophageal reflux disease (GERD). GERD leading to BE is a common pre-occurrence in EAC patients, but the mechanism remains obscure. To explore the mechanism and its components, we compared gene expression in BE and EAC cells with normal cells and discovered the overexpression of TRIM31 in the pathogenic cells. Although previous studies have shown oncogenic potential of TRIM31 in some cancers, its role in EAC is yet to be understood. \u0000Methods: RNA sequencing and transcriptomic profiling were performed on human NE, BE, and EAC epithelial tissue samples. TRIM31 expression in NE cell line (Het-1A) and EAC cell lines (OE19, Flo-1, OE33, SK-GT-2, and OACM5.1C) were identified by Western blot. The Het-1A cell line, after exposure to acidic pH and bile acid, was assessed for variable TRIM31 expression. Cell viability analysis of NE and EAC cell lines after exposure to acidic pH and bile acids was observed by WST-1 assay. \u0000Results: RNA sequencing, transcriptomic profiling, and western blot revealed overexpression of TRIM31 in BE and EAC epithelium. Exposure of Het-1A cells to bile acids in acidic pH changed the cell morphology with enhanced expression of TRIM31. WST-1 revealed that EAC cells were more resistant to acidic pH and bile acid exposure. \u0000Conclusions and potential impact: Our data suggests that increased TRIM31 expression correlates with esophageal epithelium resistance when exposed to bile acids and acidic pH. Consequently, TRIM31 may be a key player in the metaplasia of GERD-induced EAC development and may be an innovative therapeutic target and marker for EAC.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":"40 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139533309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background/Objective:Chest pain in children is rarely caused by a life-threatening pathology. Despite the rarity of potentially life-threatening disease, most children presenting to EDs are evaluated with chest radiographs and laboratory tests without yielding helpful information that significantly changes immediate management. While the utilization of cardiac Point-of-Care Ultrasound (POCUS) by adult emergency physicians has become standard of practice, the data in pediatric emergency departments (PED) is not as robust. This study aims to describe practice patterns in the evaluation of pediatric chest pain presenting in a PED and determine clinical outcomes. Methods:We reviewed charts of previously healthy children aged <18 years old who presented to Riley Children’s Hospital from January 2019 to July 2020 with a chief complaint of chest pain. Patients with known medical history, prior evaluations by a pediatric cardiologist, transfers from other hospital with existing workup were excluded. Patient demographics, laboratory tests and imaging ordered while in the ED, electrocardiography (EKG), consults with subspecialties, disposition and follow up plans were analyzed. We categorized clinical significance of PED interventions as minor, moderate, or major. Results:Out of three hundred and nineteen patients included in the study, 79.6% (254) received chest radiographs, 93.4% (298) underwent EKG, and 4.1% (13) received cardiac POCUS. The findings of these orders prompted minor interventions in 92.8% (296) of patients, moderateintervention in 4.7% (15) of patients, and major intervention in 2.5% (8) of patients. Conclusion and Implications:These results show a lack of use for POCUS in pediatric patients presenting with chest pain while chest radiography is preferred in the ED. Additionally, POCUS did not result in any moderate or major significant clinical outcomes.
{"title":"Utility of Cardiac POCUS in the Evaluation of Pediatric Chest Pain in the Emergency Department","authors":"Connor Emsley, Benjamin Nti, Pamela C. Soriano","doi":"10.18060/27896","DOIUrl":"https://doi.org/10.18060/27896","url":null,"abstract":"Background/Objective:Chest pain in children is rarely caused by a life-threatening pathology. Despite the rarity of potentially life-threatening disease, most children presenting to EDs are evaluated with chest radiographs and laboratory tests without yielding helpful information that significantly changes immediate management. While the utilization of cardiac Point-of-Care Ultrasound (POCUS) by adult emergency physicians has become standard of practice, the data in pediatric emergency departments (PED) is not as robust. This study aims to describe practice patterns in the evaluation of pediatric chest pain presenting in a PED and determine clinical outcomes. \u0000Methods:We reviewed charts of previously healthy children aged <18 years old who presented to Riley Children’s Hospital from January 2019 to July 2020 with a chief complaint of chest pain. Patients with known medical history, prior evaluations by a pediatric cardiologist, transfers from other hospital with existing workup were excluded. Patient demographics, laboratory tests and imaging ordered while in the ED, electrocardiography (EKG), consults with subspecialties, disposition and follow up plans were analyzed. We categorized clinical significance of PED interventions as minor, moderate, or major. \u0000Results:Out of three hundred and nineteen patients included in the study, 79.6% (254) received chest radiographs, 93.4% (298) underwent EKG, and 4.1% (13) received cardiac POCUS. The findings of these orders prompted minor interventions in 92.8% (296) of patients, moderateintervention in 4.7% (15) of patients, and major intervention in 2.5% (8) of patients. \u0000Conclusion and Implications:These results show a lack of use for POCUS in pediatric patients presenting with chest pain while chest radiography is preferred in the ED. Additionally, POCUS did not result in any moderate or major significant clinical outcomes.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":"43 13","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139533829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background/Objective:While G-POEM remains an effective and exciting treatment for GP patients, predictors of clinical success remain poorly characterized. Botox injection of the pylorus prior to committing to GPOEM can help differentiate those who might have a favorable clinical response to this procedure in patients with GP. Methods:To evaluate the utility of Botox injection prior to G-POEM, 124 patients with clinically diagnosed GP who underwent a GPOEM were assessed in this retrospective cohort study. All G-POEM procedures were conducted at a single center and were completed between February 2018 and May 2023. Patients who had received intrapyloric Botox injection (n=79) had QoL and clinical success rates compared to patients who received other treatment options (n=45). Results were assessed at 1-, 3-, 6-, 12-, 24-, 36-, 48-months post G-POEM. Results:When assessing symptom severity, the difference between the change in GCSI values for Botox patients and patients receiving other prior therapy was statistically significant at 6 months post-GPOEM; +1.27 for Botox patients vs +0.55 for other treatments (p-value of 0.03). At this 6-month checkpoint, 64% of the Botox group achieved clinical success compared to 37.5% for the other treatment group. When comparing QoL, intrapyloric Botox injection has statistically significant improvements in SF-36 total score at 1, 3-, 6-, 12-, and 36-months post G-POEM, while patients receiving other treatments had no statistically significant improvements in their SF-36 total scores. Conclusion:We hypothesize that clinical improvement on pre GPOEM Botox selects patients with a higher component of pyloric spasm who end up responding more favorably to G-POEM. Scientific/Clinical/Policy Impact and Implications:Intrapyloric Botox injection is technically feasible in almost all patients with GP and does not require special expertise, training, or equipment; therefore, this should be strongly considered prior to referring a patient for G-POEM.
{"title":"Using Botulinum Toxin for the Treatment of Gastroparesis (GP) for the selection of Patients with Higher Clinical Success, Improved Quality of Life (QOL), and Improved Social Functioning Post Gastric Peroral Endoscopic Myotomy (GPOEM)","authors":"Amr Kais, Mohammad A. Al-Haddad","doi":"10.18060/27904","DOIUrl":"https://doi.org/10.18060/27904","url":null,"abstract":"Background/Objective:While G-POEM remains an effective and exciting treatment for GP patients, predictors of clinical success remain poorly characterized. Botox injection of the pylorus prior to committing to GPOEM can help differentiate those who might have a favorable clinical response to this procedure in patients with GP. \u0000Methods:To evaluate the utility of Botox injection prior to G-POEM, 124 patients with clinically diagnosed GP who underwent a GPOEM were assessed in this retrospective cohort study. All G-POEM procedures were conducted at a single center and were completed between February 2018 and May 2023. Patients who had received intrapyloric Botox injection (n=79) had QoL and clinical success rates compared to patients who received other treatment options (n=45). Results were assessed at 1-, 3-, 6-, 12-, 24-, 36-, 48-months post G-POEM. \u0000Results:When assessing symptom severity, the difference between the change in GCSI values for Botox patients and patients receiving other prior therapy was statistically significant at 6 months post-GPOEM; +1.27 for Botox patients vs +0.55 for other treatments (p-value of 0.03). At this 6-month checkpoint, 64% of the Botox group achieved clinical success compared to 37.5% for the other treatment group. When comparing QoL, intrapyloric Botox injection has statistically significant improvements in SF-36 total score at 1, 3-, 6-, 12-, and 36-months post G-POEM, while patients receiving other treatments had no statistically significant improvements in their SF-36 total scores. \u0000Conclusion:We hypothesize that clinical improvement on pre GPOEM Botox selects patients with a higher component of pyloric spasm who end up responding more favorably to G-POEM. \u0000Scientific/Clinical/Policy Impact and Implications:Intrapyloric Botox injection is technically feasible in almost all patients with GP and does not require special expertise, training, or equipment; therefore, this should be strongly considered prior to referring a patient for G-POEM.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":"17 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139534190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zachary Chastain, Imade Williams, Vrushabh Ulhaskumar, John Wang, Haddie DeHart, Haimanti Ray, Richard L. Carpenter
Hsp90 inhibitors have been attempted as a targeted therapy with poor results. Despite numerous clinical trials, there are currently no FDA approved Hsp90 inhibitors available. It is known that Hsp90 sequesters HSF1 in the cytoplasm to suppress HSF1 activity, an oncogenic transcription factor. We hypothesize that HSF1 activation in response to Hsp90 inhibition is a significant reason that previous Hsp90 inhibitors have failed. Once released, HSF1 enters the nucleus and drives expression of many processes that promote the initiation and progression of tumors. This hypothesis was tested by evaluating the response of cancer cells to Hsp90 inhibition with or without combined inhibition of HSF1, thereby removing HSF1 activity as a consequence of Hsp90 inhibition. We observed synergy between Hsp90 inhibition (17-DMAG) and HSF1 inhibition (KRIBB11) from calculation of combination index in ovarian cancer cells (OVCAR8) and breast cancer cells (BT474). This synergy observed in cell viability assays were further reinforced in spheroid formation and clonogenic growth assays where the combination of these inhibitors had a greater effect than either treatment alone. These results further support the hypothesis that Hsp90 inhibition efficacy is mitigated by increased HSF1 activity and that HSF1 inhibitors synergize with Hsp90 inhibitors to improve their efficacy.
{"title":"Inhibition of HSF1 as a Mechanism for Overcoming Hsp90 Treatment Resistance","authors":"Zachary Chastain, Imade Williams, Vrushabh Ulhaskumar, John Wang, Haddie DeHart, Haimanti Ray, Richard L. Carpenter","doi":"10.18060/27850","DOIUrl":"https://doi.org/10.18060/27850","url":null,"abstract":"Hsp90 inhibitors have been attempted as a targeted therapy with poor results. Despite numerous clinical trials, there are currently no FDA approved Hsp90 inhibitors available. It is known that Hsp90 sequesters HSF1 in the cytoplasm to suppress HSF1 activity, an oncogenic transcription factor. We hypothesize that HSF1 activation in response to Hsp90 inhibition is a significant reason that previous Hsp90 inhibitors have failed. Once released, HSF1 enters the nucleus and drives expression of many processes that promote the initiation and progression of tumors. This hypothesis was tested by evaluating the response of cancer cells to Hsp90 inhibition with or without combined inhibition of HSF1, thereby removing HSF1 activity as a consequence of Hsp90 inhibition. We observed synergy between Hsp90 inhibition (17-DMAG) and HSF1 inhibition (KRIBB11) from calculation of combination index in ovarian cancer cells (OVCAR8) and breast cancer cells (BT474). This synergy observed in cell viability assays were further reinforced in spheroid formation and clonogenic growth assays where the combination of these inhibitors had a greater effect than either treatment alone. These results further support the hypothesis that Hsp90 inhibition efficacy is mitigated by increased HSF1 activity and that HSF1 inhibitors synergize with Hsp90 inhibitors to improve their efficacy.","PeriodicalId":20522,"journal":{"name":"Proceedings of IMPRS","volume":"23 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139534250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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