Undergraduate Medical Education Works

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Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets
(Frontiers, 2019-08-14) Mitchell, Dana; Chintala, Sreenivasulu; Fetcko, Kaleigh; Henriquez, Mario; Tewari, Brij N.; Ahmed, Atique; Bentley, R. Timothy; Dey, Mahua; Neurological Surgery, School of Medicine
Spontaneous canine (Canis lupus) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated (n = 1858) and ~50% were downregulated (n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.
Unique Molecular Features in High-Risk Histology Endometrial Cancers
(MDPI, 2019-10-27) Pandita, Pooja; Wang, Xiyin; Jones, Devin E.; Collins, Kaitlyn; Hawkins, Shannon M.; Obstetrics and Gynecology, School of Medicine
Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with endometrial cancer will develop high-risk histologic tumors including uterine carcinosarcoma or high-grade endometrioid, clear cell, or serous carcinomas. These high-risk histologic tumors account for more than 50% of deaths from this disease. In this review, we will highlight the biologic differences between low- and high-risk carcinomas with a focus on the cell of origin, early precursor lesions including atrophic and proliferative endometrium, and the potential role of stem cells. We will discuss treatment, including standard of care therapy, hormonal therapy, and precision medicine-based or targeted molecular therapies. We will also discuss the impact and need for model systems. The molecular underpinnings behind this high death to incidence ratio are important to understand and improve outcomes.
Seeing With Sound: Educational Insights of the 200th Anniversary of Laennec's Magnum Opus
(Elsevier, 2019) Mohiuddin, Amer M.; Gunderman, Richard B.; Radiology and Imaging Sciences, School of Medicine
Cell Cycle–Mediated Cardiac Regeneration in the Mouse Heart
(Springer, 2019) Eghbali, Arash; Dukes, Austin; Toischer, Karl; Hasenfuss, Gerd; Field, Loren J.; Medicine, School of Medicine
Purpose of Review Many forms of heart disease result in the essentially irreversible loss of cardiomyocytes. The ability to promote cardiomyocyte renewal may be a promising approach to reverse injury in diseased hearts. The purpose of this review is to describe the impact of cardiomyocyte cell cycle activation on cardiac function and structure in several different models of myocardial disease. Recent Findings Transgenic mice expressing cyclin D2 (D2 mice) exhibit sustained cardiomyocyte renewal in the adult heart. Earlier studies demonstrated that D2 mice exhibited progressive myocardial regeneration in experimental models of myocardial infarction, and that cardiac function was normalized to values seen in sham-operated litter mates by 180 days post-injury. D2 mice also exhibited markedly improved atrial structure in a genetic model of atrial fibrosis. More recent studies revealed that D2 mice were remarkably resistant to heart failure induced by chronic elevated afterload as compared with their wild type (WT siblings), with a 6-fold increase in median survival as well as retention of relatively normal cardiac function. Finally, D2 mice exhibited a progressive recovery in cardiac function to normal levels and a concomitant reduction in adverse myocardial remodeling in an anthracycline cardiotoxicity model. Summary The studies reviewed here make a strong case for the potential utility of inducing cardiomyocyte renewal as a means to treat injured hearts. Several challenges which must be met to develop a viable therapeutic intervention based on these observations are discussed.
A Case of Aceruloplasminemia Which Was Not Wilson Disease
(2021-03-26) Williams, Cody; Clemens, Joseph; Wu, Joey; Zimmerman, Michelle
Case: A 58 year old woman presented with 5+ years of fatigue and joint pain as well as recent short term memory concerns. She was evaluated for Lyme disease and was found to have mild anemia with elevated iron and persistently elevated ferritin as high as 2100 ng/ml. An unrelated cardiac scan had the incidental finding of hepatic iron accumulation. No fibrosis was noted on MRI. Liver biopsy was significant for 3-4+ hemochromatosis with sinusoidal dilation and congestion. Labs showed aceruloplasminemia with low urine and serum copper. Eye exam was negative for Kayser Fleischer rings but did show retinal iron deposits and early macular degeneration not supporting Wilson disease. Later genetic testing for CP (ceruloplasmin) gene showed heterozygosity for sequence variant c.2342A>C, predicted to cause amino acid substitution p.Lys781Thr. Conclusion: She is currently awaiting MRI to evaluate possible CNS disease in the setting of aceruloplasminemia but was delayed due to significant COVID-19 risk. Otherwise, she is tolerating deferasirox well. Significance: Our patient had a complex path to diagnosis given that low ceruloplasmin is commonly associated with Wilson disease. However, ceruloplasmin is also a key component in regulating ferric iron binding to transferrin and maintaining copper and iron homeostasis. This case was an exemplar of interdisciplinary diagnosis. Clinical evidence of anemia, ophthalmologic findings, and subjective cognitive dysfunction combined with histology and genetic results contributed to accurate characterization of aceruloplasminemia related hemochromatosis rather than Wilson’s disease. Genetic analysis revealed CP gene c.2342A>C (p.Lys781Thr), a novel mutation not reported elsewhere to our knowledge. Given her heterozygous status for the mutation, further investigation is needed. More importantly for our patient, recognition and treatment at this stage could reduce morbidity from neurodegeneration, pancreatic, and hepatic disease.
Is Operative Diagnosis for Aseptic Revision Total Hip Arthroplasty Related to Patient Reported Outcomes?
(2018-07) Holder, Erik; Ciesielski, Alex; Ziemba-Davis, Mary; Meneghini, R. Michael
Background and Hypothesis: Component loosening and instability are the leading causes of revision total hip arthroplasty (THA). The purpose of this study was to compare patient-reported outcomes after revision THA based on failure etiology. We hypothesized that outcomes would differ based on reason for revision. Project Methods: 187 consecutive revision THAs performed between 2010 and 2017 were retrospectively reviewed. Prospectively collected preoperative and minimum one-year Hip Disability and Osteoarthritis Outcome Score/HOOS Jr., UCLA Activity Level, WOMAC Index, and patient satisfaction were assessed based on failure etiology. Demographic variables and covariates were accounted for including sex, age, BMI, ASA classification, heart disease, lumbar spine pathology, narcotic use, fibromyalgia, depression, and autoimmune arthritis. Results: Latest UCLA activity level did not differ based on failure etiology (p=0.381). However, the degree of improvement in activity level was higher (p= 0.04) in patients revised for loosening, instability, and infection compared to ALTR and polyethylene wear. HOOS Jr (p=0.949) and WOMAC total (p=0.147) scores did not differ based on failure etiology at latest follow-up, although patients revised for loosening had greater WOMAC improvement compared to all other groups except polyethylene wear (p=0.016). Satisfaction did not vary based on failure etiology (p=0.365), and demographic and covariates were unrelated to outcomes (p³0.165). Conclusion and Potential Impact: We observed that patient-reported outcomes following revision THA vary based on revision reason and activity level improvement is mitigated patients revised for ALTR and poly wear. These findings may help surgeons and patients alike set expectations for recovery following revision THA.
Avascular Necrosis of the Hip with Truvada
(2021-01-23) Wu, Joey; Henry, Arnold
Background and Introduction Tenofovir disoproxil fumarate (Truvada) is a common HIV Pre-exposure prophylaxis regimen. Rare side effects such as renal toxicity, bone mineral loss have been reported but well documented relationship between Truvada use and AVN has not been well reported. The patient reported in this case study has no additional risk factor or underlying conditions that predisposes him to AVN of the hip aside from Truvada use. Case presentation 37-year-old gay male who is HIV negative in a monogamous relationship with a male of undetectable HIV viral load on Truvada prophylaxis with goal of decreasing HIV transmission risk. He began taking Truvada in Jan of 2015 and was without complications until Apr 2018 when he presented with left hip/quadricep pain initially diagnosed with IT band syndrome. He failed to improve with multiple courses of physical therapy and pain has been recurrent. He received X-ray of pelvis, bilateral hips, and lumbar spine with 4 views in Jun 2019. Result was significant for avascular necrosis of the left hip. He has no other comorbidities and began taking NSAIDs for pain control. His Truvada was discontinued Jun 2019 and pt began Descovy (Tenofovir alafenamide fumarate) but his ROC visit/imaging in Aug 2020 shows worsening AVN and symptomatic pain. Physical exam also shows significant atrophy of left lower extremity muscle groups and antalgic gait. Conclusion Truvada has been associated with AVN in patients without previous health risks for decreased bone health/density. Previous research have identified improved bone mineral density with discontinuing Truvada and beginning Descovy. However, this patient fails to improve with Descovy and continues to have worsening AVN, perhaps suggesting AVN is not associated with bone mineral loss but possibly other occult reasons.
Predictors of Quality of Life after Liver Transplant
(2020-11-14) Wu, Joey; Desai, Archita
Background and Hypothesis: The impact of chronic liver diseases on patients and their family member is often understated and understudied. Chronic liver diseases can sometimes progress to a need for Liver transplant (LT). While recent studies have described quality of life (QOL) at different stages of liver disease, the impact of the patient’s QOL in LT survivors has not been examined. The importance of studying QOL in patients is due to its effect on the survivorship of LT recipients. We hypothesize that QOL in LT patients is lower than the general population. Our aim was to describe predictors of QOL in a well-described cohort of LT patients. Methods:Patients were enrolled at the Digestive and Liver Disease Liver clinic at Indiana University Hospital. All patients over the age of 18 were approached, if patients consented to the study, they were then enrolled during their liver follow up visit. The PROMIS survey was administered on an iPad and completed during the clinic visit. Survey were then scored and analyzed.Results: The T-scores for post liver transplant patients are lower in physical function, anxiety and depression, but higher in general life satisfaction compared to the general population. LT recipients have similar T-scores in Fatigue, Sleep disturbance, ability to participate in social activities, and pain interference compared to the general population. Conclusion and Potential Impact: Previous diagnosis of PBC, HCC, diagnosis of depression, household income, insurance status, Charlson Comorbid Index and number of non-transplant related medications have the highest association with quality of life. Further enrollment is needed to increase the power of the study. However, this can inform physicians the importance to taking these factors in to consideration in order to improve the QOL in LT recipients.
Is Manipulation Under Anesthesia Effective in Improving Patient Reported Outcomes After Total Knee Arthroplasty? A Matched Cohort Analysis.
(2019-12) Ciesielski, Alex; Holder, Erik; Deckard, Evan; Ziemba-Davis, Mary; Meneghini, R Michael
Introduction: Manipulation under anesthesia (MUA) after total knee arthroplasty (TKA) is considered effective for postoperative stiffness, but strong scientific justification is lacking. This study compared outcomes in two matched cohorts: patients who met criteria and underwent MUA and patients who met criteria but did not undergo MUA. Methods: MUA (experimental) cases had ≤ 90° flexion 4-weeks postoperatively and underwent MUA surgery within 12 weeks of the index TKA. Control cases had ≤ 90° flexion 4-weeks postoperatively and did not undergo MUA. The latter group was alternatively treated with aggressive flexion exercises, frequent follow-up, and pain control modalities per surgeon discretion. 42 MUAs performed by three surgeons between 2011 and 2017 at the same center using the same standardized clinical and rehabilitation protocols were retrospectively reviewed. Six MUAs were excluded for potential confounds. The remaining 36 MUA cases were matched one-to one on sex (p= 1.00), age (p=0.893), race (p=0.938), BMI (p=0.069), and implant manufacturer (p= 1.00) to 36 control cases. Outcome variables included amount of improvement in flexion from preoperative baseline to latest follow-up and standardized PROMS. Covariates potentially affecting outcomes were taken into account. Results: Overall MUA incidence during the time period was 1.9%. Experimental and control groups did not differ on preoperative fibromyalgia, depression, and narcotic use; or intraoperative analgesia (p≥0.084). Four control patients and no experimental patients had inflammatory disease (p=0.054), and six of the former compared to none of the latter had lumbar spine pain or disease (p=0.025). Flexion data are provided in Table 1. Mean pre-primary TKA flexion was significantly greater in experimental patients (112.4 vs. 98.6°, p=0.002). On average, between pre-primary surgery and latest follow-up, experimental patients lost 10.7° of flexion compared to a gain of 12.7° by control patients (p<0.001). Pre-primary to latest follow-up improvement in pain walking on level ground (-3.3 and -4.7 points, p=0.190) and climbing stairs (-3.7 vs. -5.1, p=0.192) did not significantly differ between experimental and control patients respectively. As shown in Figure 1, prior to primary surgery experimental and control patients had similar activity levels (p=0.624). At latest follow-up, however, control patients were significantly more active than experimental patients (Figure 1, p=0.009). Figure 2 shows the proportions of patients in each group who reported their knee never feels normal prior to primary surgery (p=0.580) and at latest follow-up (p=0.0004). Surgery significantly improved this metric for control but not experimental patients. At latest follow-up 88.6% of control patients and 50% of experimental patients were satisfied or very satisfied with their knee surgery (p=0.001). Conclusion: Patients with ≤ 90° flexion 4-weeks after TKA who underwent MUA had significantly worse flexion and PROM scores than matched control patients who did not undergo MUA. These findings question the effectiveness of MUA as a legitimate treatment for postoperative TKA stiffness.
Activation of the oncogene ERG by the Ras/ERK and PI3K/AKT pathways
(2019-08) Willhite, Sydney; Strittmatter, Brady; Hollenhorst, Peter
Background and Hypothesis: The TMPRSS2-ERG re-arrangement occurs in ~50% of prostate cancers and results in aberrant expression of the transcription factor ERG in the prostate. ERG is known to be activated by the Ras/ERK and PI3K/AKT pathways, however, the exact mechanism of this activation is not fully understood. The aim of this project is to identify how activation of these signaling pathways differentially effect transcription of ERG target genes. Experimental Design or Project Methods: In order to test how the Ras/ERK and PI3K/AKT pathways effect ERG target gene transcription, normal prostate epithelial cells (RWPE1) were transfected with constitutively active AKT in combination with phospho-mutants of ERG. These cell lines were then used to conduct Quantitative Reverse Transcription PCR and Western blotting of known downstream ERG target genes to identify how the activation status of these signaling pathways affected transcription and protein production. Results: Overall, our results demonstrate that ERG mediated transcription of the VIM gene, a marker of EMT, was activated by the Ras/ERK pathway and was repressed by the PI3K/AKT pathway. In addition, we found that ERG expression decreased FOXO1 protein expression in our cell lines regardless of Ras/ERK and PI3K/AKT status. Transcription and protein quantification was also measured for ERG target gene VEGFA, a critical regulator of angiogenesis. Conclusion and Potential Impact: This project helps identify the molecular mechanisms by which a common oncogene in prostate cancer is activated. Our results demonstrate how upstream signaling pathways differentially regulate oncogenic transcription and cell transformation. Overall, this project will provide insight to the molecular mechanisms of possible therapeutic targets in prostate cancer, the most common cancer amongst men.

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