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    The Use of a Modified Total Knee Arthroplasty to Treat End-Stage Osteoarthritis and Concurrent Osseous Metastasis to the Distal Femoral Metaphysis
    (2021) Rechter, Griffin; Brotherton, Stephen
    Background: In recent years, improved survivorship in cancer patients is paralleled by increasing demand for total knee arthroplasty (TKA) procedures. Thus, there is a need to explore different approaches to patients requiring a TKA with comorbid metastatic disease of the distal femur. We herein present a patient who underwent a modified primary TKA for end-stage osteoarthritis and concurrent skeletal metastasis to the distal femur. Case Information: An 84-year-old woman presented to our clinic for severe osteoarthritis. Imaging revealed an osteoblastic lesion in the distal femoral metaphysis, and MRI identified it to be a metastasis of an undisclosed diagnosis of renal cell carcinoma. She underwent a modified TKA with a 175-mm femoral stem with resection of the bony metastasis. The postoperative course was unremarkable. Conclusions: We believe patients with distal femoral metastases and end-stage osteoarthritis should be considered candidates for a modified TKA. It offers immediate weight-bearing, tumor resection, pathologic fracture prevention, and is fiscally favorable to the alternative, a limb salvage procedure with endoprosthesis. The femoral stem component allowed for immediate stability, decreased risk for aseptic loosening, and protection of the canal from further development of metastases. This is the first report discussing the utilization of a modified TKA in treating end-stage osteoarthritis with simultaneous resection of bony metastases from renal cell carcinoma and prophylactic pathologic fracture management. Improvements in cancer survivorship requires orthopedic surgeons to consider modified interventions for patients with osteoarthritis and comorbid metastatic disease of the distal femur.
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    Correlating DCE-MRI Vascular Changes and T2-MRI Contour Changes of the Muscles of Swallowing in Patients with Osteoradionecrosis of the Mandible following Intensity-Modulated Radiation Therapy for Head and Neck Cancers.
    (2021) Cooksey, Luke; Fuller, Clifton; Lai, Stephen; Mohamed, Abdallah
    PURPOSE: Radiotherapy is a highly-effective mainstay of the standard treatment regimen for head and neck cancers. Though beneficial in most cases, radiotherapy in the head and neck area carries several toxicity risks associated with treatment: dysphagia, chronic aspiration pneumonia, and osteoradionecrosis are considered amongst those with considerable negative impact. Osteoradionecrosis (ORN), or death of bone tissue due to radiation, affects only a small percentage of those receiving radiotherapy. However, ORN carries significant risks and detriments to quality-of-life when it does occur. Our work in this area seeks to identify and correlate changes in Dynamic Contrast-Enhanced (DCE) MRI vascular parameters with changes in T2-MRI swallowing muscle contours in patients who have received a diagnosis of ORN following Intensity-Modulated Radiation Therapy (IMRT). METHODS: For 95 patients who received a diagnosis of ORN, swallowing muscles were precisely contoured on pre-treatment and during-treatment T2 MRI images. The images were then compiled and registered with pre-treatment CT-based radiation plans and DCE-MRI images using a software called "Dicompyler." RESULTS/CONCLUSIONS: While the work is still on-going, preliminary observations have indicated it is likely the overall aim to create a database registry and timeline for assessing patient risk of ORN development is very possible. Future directions, based on preliminary observations, should be to continue compiling and registering ORN patient correlation data and to begin preliminary work of establishing parameters and algorithms that can be safely utilized in patients for analysis of clinical efficacy and effectiveness.
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    Characterization of rHDL Nanoparticles as a Delivery Vehicle for Glioblastoma Multiforme Chemotherapy
    (2021) Mathew, Ezek; Sabnis, Nirupama; Dossou, Akpedje; Dickerman, Rob; Lacko, Andras G.; Fudala, Rafal
    Purpose: Glioblastoma Multiforme (GBM), is a brain tumor that presents with a very poor prognosis; new approaches are needed to improve patient outcomes. Design of an effective therapeutic approach must include a suitable delivery vehicle, which can cross the blood-brain barrier, and can selectively target GBM tumors. Our project uses reconstituted high-density lipoprotein (rHDL) nanoparticles (NPs), which possess the above characteristics, amplifying efficacy of chemotherapy. To target the PI3K/mTOR pathway involved in the pathophysiology of GBM, we chose to encapsulate PI-103 in preliminary studies. Methods: After encapsulation and purification, the drug-containing rHDL NPs will be characterized with regard to their physical/chemical properties. We will assess drug loading, entrapment efficiency, stability, particle diameter, homogeneity and molecular weight. Afterwards, cytotoxicity against human GBM cells will be compared to normal human astrocytes. Because the scavenger receptor B type 1 (SR-B1) is known to interact with circulating HDL and the rHDL NPs, we will compare the cytotoxic efficiency of the drug transporting rHDL NPs against a high SR-B1 expressing GBM line (LN229) versus a low SR-B1 expressing GBM line (U87MG). SR-B1 levels will be assessed for all cell lines. Results: In this work we will demonstrate that after encapsulation of PI-103 into rHDL and characterization, we will observe cytotoxic effect against GBM cell lines, not normal astrocytes. Conclusion: If successful, future spheroid and mice studies, in addition to combination therapy studies, will advance the proof of concept of this therapy, allowing translation toward clinical applications.
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    The Genetic Link between Phocomelia, Endometrial Stromal Sarcoma and Dysplastic Marrow: A Case Study
    (2021) Garcia, Laura; Hamby, Tyler; Howrey, Richard
    Background: Phocomelia is a malformation of the upper limbs, which can occur from various causes such as genetics, spontaneous mutation, and in utero teratogenic exposure (e.g., thalidomide). It is often associated with other congenital malformations. Myelodysplastic syndrome (MDS) signifies ineffective hematopoiesis. Patients are often asymptomatic and diagnosed through an incidental finding. However, there is risk of progression to myeloid leukemia for which a bone marrow transplant is needed for cure. Endometrial stromal sarcoma (ESS) is a rare, malignant uterine tumor most often seen in women 40 to 55 years of age. It is characterized by myometrial invasion with polymenorrhagia at presentation. Case Information: We report a case of phocomelia, MDS, and ESS in a pediatric patient, which demonstrates the impact a genetic link can have in clinical management. Patient is a 20-year-old female with phocomelia of the upper extremities. She presented with dysfunctional bleeding, which was thought to be secondary to uterine fibroids. An MRI was performed for evaluation and revealed a uterine sarcoma. Pre-operative screening revealed pancytopenia with intermittently persistent thrombocytopenia and dysplastic marrow with suspected MDS. Conclusions: With the presentation of three seemingly unrelated disorders, it is important to consider an underlying genetic link. There was suspicion that a chromosome 7 abnormality could link phocomelia, ESS and MDS, leading to a high risk of progression to leukemia. However, microarray analysis revealed a genetic mutation associated with thrombocytopenia absent-radius syndrome, which has a much lower likelihood of progression to bone marrow malignancy in the future.
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    Association of baculoviral inhibitor of apoptosis repeat-containing 5 in the survival of clear cell renal cell carcinoma patients: In silico analysis
    (2021) Spore, Paul; Basha, Riyaz; Tran, Nora; Ibarra-Aleman, Victoria
    Purpose Inhibitor of apoptosis proteins (IAPs) regulate several cellular processes and impacts tumor development, progression and resistance to therapy in several cancers. Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is a member of the IAP family, which block the release of caspases from the mitochondria, a step in the cell death signaling pathway, allowing uncontrolled growth. Clear cell renal cell carcinoma (ccRCC) is the 4th most common variant of renal cell carcinoma. The objective of this study is to determine the association of BIRC 5 in the survival of ccRCC patients and evaluate the expression of BIRC 5 with the survival of patients of differing race/ethnicity. Methods Data was obtained from the online data sets (The Cancer Genome Atlas utilizing the UALCAN platform). Data of all patients (both genders and all races) revealed that BIRC5 is over-expressed in ccRCC tumors when compared to normal tissue. Results Data analysis showed significant relationship between low BIRC5 expression and higher survival probability than those with tumors that expressed high levels of BIRC5 expression, especially in Caucasians. The African American group did not have a statistical difference in survival probability between the low expression and high expression groups. There was no statistical difference in survival probability when comparing males to females or Caucasians to African Americans with the same level of BIRC5 expression. Conclusion Considering the strong association of BIRC5 with ccRCC, BIRC5 potentially serve as a predictor of prognosis and a target of treatment for improving the outcomes in ccRCC patients.
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    Determining the cytotoxicity of Clotam and Copper-Clotam against Cardiomyocytes
    (2021) Siraj, Sohail; Patel, Krishna; Mukka, Lasya; Sankpal, Umesh; Basha, Riyaz
    Background: Chemotherapy (ChT) is required in the treatment of many cancers. Most ChT agents exhibit unwanted side-effects by causing damage to healthy cells. Side effects from many common ChT agents are leaving pediatric cancer survivors with lasting organ system damage, specifically damage to the heart. Past studies conducted by our group demonstrated the anti-cancer activity of clotam (tolfenamic acid-TA) and copper-clotam (CuTA). Our laboratory demonstrated the anti-cancer activity of CuTA against several cancer cell lines. CuTa is showing higher cytotoxicity against cancer cells even at much lower dose than TA. Our long term objective is to test CuTA to sensitize cancer cells to ChT. Methods: Cardiomyocytes H9c2 (cell line derived from rat heart tissue) originally obtained from the American Type Culture Collection (Manassas, VA) were cultured as per the supplier's instructions. H9c2 cells were treated with TA or Cu-TA or Doxorubicin and combinations (for example, TA and Doxorubicin) and cell viability assay was measured using CellTiterGlo (Promega) kit at 48 hours post-treatment following manufacturer's instructions. Results & Conclusion: We found that TA or CuTA were not cytotoxic in H9c2 cells at tested doses. TA kept more cells alive in conjunction with Doxorubicin than did the control. Our results also demonstrate that the IC50 values of TA and CuTA, determined with cancer cell lines, are not toxic to H9c2 cells. These results provide evidence that CuTA does not induce toxicity in cardiomyocytes and supports further testing for translational application in combination therapy with ChT.
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    Design and Characterization of Inhibitory Peptides (iPeps) derived from MIEN 1 Protein sequence
    (2021) Kumar Tripathi, Amit; Desai, Priyanka; Vishwanatha, Jamboor
    Purpose: MIEN1 is a tumor-specific protein that regulates migration and invasion of cancers. It is overexpressed in human breast, prostate, colorectal, ovarian cancers, making this protein a potential therapeutic target for these cancers. Our goal is to identify small inhibitory peptides (iPeps) derived from the native MIEN1 protein. Methods: CASTp server was used to identify the pockets or empty concavities on the MIEN1 protein surface into which potential inhibitory molecules can gain access. Peptide desiging tools like AntiCp , Cancer PPD and Chimera program were utilized. The peptides were the synthesized locally and the ability of the peptides to inhibit proliferation, migration and invasion were assayed. Results: All the peptides designed were cationic and hydrophobic. AntiCP, a support vector machine (SVM)-based web server, showed that the peptides had an SVM threshold of more than 0.5. The peptides were able to form hydrogen bonding with MIEN1 in chimera which is an indication of their MIEN1 binding. AntiCp server also indicated their anticancer activity. Of the 5 peptides tested, three peptides designed based on MIEN 1 protein sequence showed inhibition of MDA-MB-231 cell proliferation in the MTT assay at a concentration of 100 μg/mL. Ongoing experiments will examine the effect of inhibitory peptides on migration and invasion mediated by MIEN 1. Conclusions: Preliminary data demonstrated that peptide sequences potentially blocked MIEN1 functional activities. We will establish these peptides as the first inhibitory molecules of MIEN1 protein and determine their mechanism of action to further develop potent MIEN1 inhibitors
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    Identifying the role of Annexin A2 in acquired chemoresistance in triple negative breast cancer (TNBC)
    (2021) Trivedi, Rucha; Vishwanatha, Jamboor
    Purpose Triple negative breast cancer accounts for 20% of all breast cancers. Chemotherapy remains the standard of care due to lack of targeted therapy, but patients frequently develop resistance which renders the tumors untreatable. AnnexinA2, a Ca2+-dependent phospholipid binding protein is abundant in TNBC cells. In chemoresistant breast cancer cells, AnnexinA2 is highly overexpressed and shown to reduce sensitivity to chemotherapy drugs by inhibiting apoptosis. Here, we demonstrate the role AnnexinA2 in imparting chemoresistance in TNBC cells. Methods MDA-MB-231 and MCF-7 breast cancer cells were treated with frontline chemotherapy agents to determine the half-maximal inhibitory (IC50) concentration using cell cytotoxicity assay. The cells will be treated with predetermined concentration of drugs and AnnexinA2 protein levels will be analyzed using western blot. AnnexinA2 will be knocked-down or overexpressed to detect the change in sensitivity to the drugs. Results MDA-MB-231 cells were treated with Doxorubicin at concentration of 50 to 10,000 nM for 48 hours and inhibited cell viability in a dose-dependent manner yielding an IC50 of 2,351 nM. AnnexinA2 expression analysis upon Doxorubicin treatment is currently ongoing. AnnexinA2 expression as a function of Doxorubicin, Paclitaxel and Carboplatin exposure to MDA-MB-231 and MCF-7 cells will be presented. Conclusion Preliminary data indicate that Doxorubicin has significant anti-cancer activity on MDA-MB-231 cells with concentrations above 2,000 nM. Future experiments will determine the effect of other chemotherapeutic drugs on TNBC cells and the role of AnnexinA2 in chemoresistance in TNBC.
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    Optimization and characterization of mannose-decorated lipoprotein nanoparticles for the targeting of tumor-associated macrophages
    (2021) Dossou, Akpedje; Kapic, Ammar; Sabnis, Nirupama; Fudala, Rafal; Lacko, Andras G.
    Purpose: Reconstituted high-density lipoprotein nanoparticles (rHDL NPs) have been shown to accumulate into tumors. This effect is achievable because of their small size and their affinity toward the scavenger receptor SR-B1 which is overexpressed in most tumors. Thus, rHDL NPs appear suitable to target tumor-associated macrophages (TAMs) which express SR-B1 as well as the mannose receptor CD206. While cancer cells promote an immunosuppressive (M2) phenotype in TAMs, it has been shown that a re-orientation of TAMs toward an immunostimulating (M1) phenotype results in rapid tumor regression. Because a generalized immunostimulating effect is not desirable, the targeted approach via rHDL NPs offers a safer alternative via selective delivery of an M2-to-M1 reversal agent to TAMs. Vadimezan (also called DMXAA) is such an agent. Consequently, the goal of this study is to develop and characterize a formulation of DMXAA encapsulated in mannose-decorated rHDL NPs. Methods: Six formulations of DMXAA with mannose-decorated rHDL NPs with increasing concentration of the mannose moiety were prepared via microfluidics and characterized via dynamic light scattering, fast protein liquid chromatography, and colorimetric assays for their contents. Results: The formulations decorated with the mannose moiety, displayed larger particle diameters compared to the control rHDL NPs and achieved a drug incorporation efficiency of about 60%. Conclusion: The characteristics of these particles show that the mannose moiety was stably incorporated into the rHDL NPs. Consequently, this formulation is anticipated to selectively target TAMs and, thus, achieve an enhanced therapeutic effect.
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    Fluorescence Characterization and Cellular Localization of the Mesoionic Compound MIH 2.4Bl
    (2021) Mathis, James; Debnath, Dipti; Lacko, Andras G.; Souza, Helivaldo; Filho, Petrônio; Fudala, Rafal; Zhang, Jinmin
    Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide, making this disease a critical public health problem. Mesoionic compounds, which possess a 5-membered heterocyclic aromatic ring associated with a sextet of electrons, have shown remarkable promise as anti-cancer agents due to their unique structure and reaction properties. We previously reported the synthesis of a new 1,3-thiazolium-5-thiolate derivative of the mesoionic class (MIH 2.4Bl) and characterization of its selective cytotoxicity in a panel of breast cancer cell lines. Our studies suggest that treatment with MIH 2.4Bl mediates apoptotic death in breast cancer cells through mitochondrial dysfunction. To advance potential translational studies toward therapeutic applications, we have begun studies of the fluorescence properties of MIH 2.4Bl, using steady-state and time-resolved fluorescence techniques. Our preliminary steady-state measurements showed that the absorption spectrum of the drug is similar in different tested solvents. All samples, dissolved in various solvents, exhibited maximum absorbance between 440 and 480 nm; excitation at 480 nm elicited the highest emission at approximately 615 nm. These results may allow for future detection and localization of MIH 2.4Bl in vitro and in vivo. Follow-up studies utilizing fluorescence confocal microscopy are anticipated to reveal the site(s) of drug accumulation in situ and how cytotoxicity is induced in cancer cells. In addition, fluorescence lifetime measurements will be conducted to provide assessments of changes in the macromolecular conformational and experimental dynamic range of the drug.
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    Engineering a Nanotherapeutic for Metastatic Prostate Cancer with Bone-targeting Specificity
    (2021) Lampe, Jana B.; Desai, Priyanka; Ranjan, Amalendu; Vishwanatha, Jamboor
    Prostate cancer (PCA) derived bone metastases account for 90% of metastatic tumors with a five-year overall survival rate of 29.5%. Our objective is to develop a clinically feasible nano-delivery system targeting bone-metastatic sites to prolong overall survival and improve quality of life. The purpose of this project is to engineer a cabazitaxel-loaded, poly-lactic(co-glycolic) acid (PLGA) nanoparticle (NP) with alendronate (ALN) coating to target and treat metastatic bone lesions. We hypothesize that a bone targeted nano-delivery system will ameliorate bone lesions and trigger tumor cell apoptosis. Methods: NPs were formulated using a water-in-oil-in solvent evaporation method. NPs were prepared by sonicating 50 mg/ml PLGA in dichloromethane (DCM), 5% polyvinyl alcohol (PVA), and Bis(sulfosuccinimydyl)suberate (BS3) linker. Later, ALN was conjugated to the NP. Results: Our average NP size was around 200 nm in diameter with a Zeta Potential (ZP) of – 28 mV. Our drug loading capacity (DL) was 12.4% and encapsulation efficiency was 25.3%. The IC50 value is 10 μM. NPs have also shown to be easily taken up by cancer cells. Conclusion: We have shown that our PLGA NPs have an optimal size, PDI, ZP, DL%, and EE%, which indicates that we have developed a NP that will function as a nanotherapeutic for bone metastatic PCa. The next steps will include spheroid cultures and in vivo studies.
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    (2021) Donkor, Michael; Jones, Harlan
    Combination therapies involving chemotherapy and radiation, aimed at reducing metastasis and mortality have faced challenges, including limiting the effectiveness of immunotherapy. Ocimum tenuiflorum (O. tenuiflorum) has been used traditionally in Indian culture for the treatment of disease and proven scientifically to have immunomodulatory effects. The purpose of this study was to determine the anti-tumor effect of the natural plant O. tenuiflorum on 4T1 murine mammary carcinoma cells (4T1). Hypothesis: O. tenuiflorum decreases the rate of growth and metastatic potential of 4T1 tumor cells. 4T1 cells were grown in culture medium and exposed to increasing concentrations of O. tenuiflorum. The metastatic potential was determined using the scratch assay technique. We were also interested in the mechanism by which O. tenuiflorum decreased the rate of growth and metastatic potential of 4T1 cells. We determined the changes in the mRNA expression of IL-4R, previously reported to drive breast cancer metastasis following exposure of 4T1 tumor cells O. tenuiflorum. Results: Exposing 4T1 cells to various concentrations of O. tenuiflorum decreased the rate of growth and metastatic potential of 4T1 tumor cells. Also, O. tenuiflorum downregulated the expression of IL-4R by 4T1 tumor cells with increasing concentration. We conclude that O. tenuiflorum has the potential to be used as adjunct treatment in management of breast cancer. Further studies will investigate in-depth the mechanism of O. tenuiflorum's on 4T1 including apoptosis, migration and other molecular mechanism on tumor evasiveness.
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    Evaluating new treatment strategy for medulloblastoma
    (2021) Mohammad, Shanzay; Basha, Raasil; Sankpal, Umesh
    Purpose: Medulloblastoma is the most common malignant pediatric brain tumor. Although chemotherapy, radiation, and surgical resection are often successful, patients in remission often suffer from long-term side effects and face the potential for re-growth of their cancer. This raises a need for effective, less toxic therapeutic strategies. An anti-apoptotic protein, Survivin, and its transcription factor, Sp1, are over-expressed in most cancers including medulloblastoma and are associated with a poor prognosis. Metformin, an anti-diabetic drug with relatively low toxicity profile, was found to have anti-cancer properties in many cancers. This study was conducted to evaluate the effects that Metformin has on the inhibition of medulloblastoma cells. We hypothesize that Metformin treatment will decrease the growth of medulloblastoma cells, possibly by inhibiting Survivin expression through Sp1 transcription factor downregulation. Methods: Human medulloblastoma cells were treated with increasing Metformin doses, then cell viability was assessed at 24 and 48 hours post-treatment using a CellTiter-Glo cell viability assay. Survivin and Sp1 expression in Metformin-treated cells was assessed by Western blot analysis. Results: As the concentration of Metformin increased, the number of metabolically active cells decreased. Sp1 and Survivin protein levels were reduced by Metformin in a dose/time dependent manner. Conclusion: The results validated that Metformin treatment resulted in reduced cell proliferation and decreased Survivin expression. Given that high Survivin levels are associated with resistance to chemotherapy and radiation, future studies will evaluate whether inhibiting Survivin using Metformin will sensitize cancer cells to chemotherapy.
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    (2021) Mylabathula, Preteesh; Desai, Priyanka; Chaudary, Pankaj; Vishwanatha, Jamboor
    Purpose: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer associated with poor clinical outcomes and lack of targetable molecular signatures. It was previously reported that serum exosomal-annexin A2 (Exo-ANXA2) is higher in TNBC patients. Additionally, higher levels were reported in African-Americans compared to Caucasian-Americans. Therefore, we propose to examine novel exosome isolation and characterization techniques to measure exo-AnxA2 levels in serum samples of TNBC patients that would be easily adaptable in a clinical setting to improve treatment strategies in African-American TNBC patients. Methods: A novel magnet-activated cell sorting (MACS) technology which employs microbeads (diameter=50nm) to isolate exosomes will be used to determine the exo-AnxA2 levels in serum samples. Exosomes isolated will be subsequently characterized through bead-associated exosomal flow cytometry, exo-ELISA, western blot, RNA isolation, and proteomics to analyze exo-AnxA2 levels and other cargo proteins. Results: Protein estimation of MACS-isolated exosomes revealed an average of 1.75 µg/µl of intact exosomes from 1.0 ml serum sample. These results suggest that approximately 200µl of patient serum sample would yield approximately 2.0 µg of exosomes for exosomal flow cytometry. Technical challenges include creating a clump-free exosome isolate for cytometry analysis without and adapting a non-specialized flow cytometer for exosomal analysis. Conclusion: We expect the results to identify significant co-expressive molecules with exo-ANXA2 that could improve detection, prognosis, and treatment choice of aggressive forms of TNBC. Funding: Award Number R01CA220273 (JKV).
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    The effect of MIEN1 in promoting invasion and migration in cancer stem cells.
    (2021) Ranade, Payal; Vishwanatha, Jamboor
    Purpose MIEN1 (Migration and Invasion Enhancer 1 – MIEN1), located on chromosome 17q12, encodes a membrane-anchored protein that functions as an oncoprotein in several types of cancers (breast, prostate, oral and colorectal cancer), enhancing the biological processes of migration and invasion. The aim of this project is to evaluate the effect of MIEN1 on migration and invasion in Breast Cancer Stem Cells (BCSCs). Methods BCSCs were isolated from breast cancer cell line MDA MB 231, MDA MB 231 derivatives with varying levels of MIEN1 (A2, A10 and B7), MCF7 and a breast epithelial cell line MCF10A as control. Breast cancer cells were used for spheroid cultures for 21 days, which were used to isolate stem cells. ALDH (Aldehyde dehydrogenase) kit was used to isolate stem cells from spheroid cultures using FACS. Levels of MIEN1 protein will be evaluated by western blot. Results Spheroids with a dense core and loosely attached cells at the periphery were observed in ultra-low attachment 96 well plate after 21 days of seeding. BCSCs were isolated from spheroid cultures of MDA MB 231 and its derivatives A2, A10 and B7 using FACS and the data was analyzed using FlowJo software. MIEN1 protein levels will be checked in the isolated stem cell population using western blot. Conclusions Isolation of BCSCs from spheroid cultures yielded ~1% ALDH positive cells when 4.7x105 cells were used for sorting. Cells from 2-D cultures with more than 106 cells, grown in enhanced media, will be used for BCSC isolation.
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    Evaluating the anti-leukemic effect of clotam and copper-clotam using CCRF-CEM cell lines
    (2021) Patel, Krishna; Siraj, Sohail; Basha, Riyaz; Sankpal, Umesh
    Purpose: Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children younger than 5 years. Patients with ALL have bone marrow that produces immature white blood cells, which are unable to effectively fight infections. NSAIDs are common pain reliving agents that act through COX inhibition, which stops the production of prostaglandins. Clotam (Tolfenamic Acid/TA) is an NSAID that has anti-tumor proliferative effects. It works through targeting specificity protein (Sp) transcription factors that assist cancer cells in inhibiting apoptosis. Our objective is to test TA and copper-TA (Cu-TA), a derivative of TA, to induce an anti-leukemic response. Methods: The T-cell ALL cell line CCRF-CEM was obtained from the American Type Culture Collection (Manassas, VA) and cells were cultured as per the supplier's instructions. A cell viability assay was performed in which cells were plated in a 96-well plate and treated with increasing concentrations of TA and Cu-TA. After 48-hours, the cells were lysed, and the amount of ATP in the cells was measured using luminescence. Using this data, IC50 values were calculated. Results: The IC50 values showed both TA and Cu-TA had anti-cancer proliferative effects. Cu-TA was 15 times more potent than TA in its ability to kill CCRF-CEM cells. Conclusion: Our results demonstrate that Cu-TA is more effective than TA for killing CCRF-CEM cells. This study suggests better implications of Cu-TA in ALL therapy, if further tested using pre-clinical models.
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    Brain Low Grade Gliomas: Association of Specificity Protein Transcription Factor Sp1 and MAOB with Patient Survival
    (2021) Ibarra-Aleman, Victoria; Basha, Riyaz; Tran, Nora; Spore, Paul
    Purpose MAOB and SP1 are transcription factors expressed in low-grade gliomas (LGGs). MAOB and SP1 are both involved in the regulation of MAOB and have a positive feedback that leads to increased expression of MAOB in cells. We investigated the relationship between survival times in patients with LGGs and the transcription factors SP1 and MAOB. The levels of these markers in relation to gender and race were also evaluated. Methods Data was obtained through The Cancer Genome Atlas (TCGA) utilizing "UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses". Using Kaplan Meier plots, information was obtained on expression of SP1 and MAOB alone, levels of expression and race, and levels of expression and gender in patients with LGG. Results SP1 and MAOB had lower survival times with high levels of expression. Asians and African Americans had lower survival times than Caucasians with both high and low expressions of SP1 and MAOB. There was a stark difference in survival times between high and low expression of SP1 in females as compared to males. Conclusions It appears that chemotherapeutics that target MAOB could be helpful in extending the survival times for patients with low grade gliomas. Further studies should be done to determine whether the results of gender and race are due to genetic differences or a source of health disparities.
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    A Biological Approach in Exploring Breast Cancer Disparities
    (2021) Ali, Arkoon; Sankpal, Umesh
    Purpose: In the United States, healthcare disparities lie across a multitude of diseases including breast cancer. These disparities are caused by multiple different factors such as socioeconomic status, education, environment, biology, and others. To overcome the disparities, each factor needs to be addressed with research and development. In the US, breast cancer death rates have significantly declined since the start of 21st century. However, looking closer at breast cancer outcomes between races, a significant racial disparity is seen between white and black women. Research has found that black women are diagnosed with breast cancer at an earlier age and with the most aggressive triple negative tumors. These factors attribute to the differences in outcomes between the black and white populations. Studies have also identified various biological differences between the two populations that can potentially affect outcomes for breast cancer. Method: Genomic data from breast tumor was used to obtain differentially expressed genes between the two populations. These were evaluated as possible biological markers for racial disparity in breast cancer. Results: Genes were identified that were expressed at higher levels in tumor tissue from black women compared to white. This also correlated with the lower survival rates observed for black women. Conclusion: In addressing the disparities of healthcare and more specifically those seen in breast cancer, novel approaches are needed to reduce mortality and improve outcomes for the black population. These approaches need to include a combination of public health strategies along with biological methods and techniques to improve outcomes.
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    NEJM Case 13-2013: A 6-Year-Old Girl with Bone and Joint Pain and Abdominal Distension
    (2021) Chin, Christine; Mesmin, Melson
    Background: B-Cell Acute Lymphoblastic Leukemia/Lymphoma (B-ALL) is the most common childhood malignancy. B-ALL has good prognostic outcomes when diagnosed in its early stages, with a 5 year overall survival rate > 85%. Case: A 6-year-old female initially presented to her pediatrician's office with bone pain following a fall and was repeatedly evaluated by her orthopedist and rheumatologist for recurrent limb pain over a year. She eventually developed a high intermittent fever of 39.8C, abdominal distention/discoloration, and periorbital erythema/edema. On admission at Massachusetts General Hospital, her physical exam findings were consistent with the pre-admission evaluation and labs were notable for normal WBC and platelet counts. CT and PET studies showed lymphadenopathy, multiple lytic lesions, and a large abdominal mass with increased uptake. Examination of a biopsy specimen from the abdominal-pelvic mass showed a monotonous population of primitive cells. Immunohistochemical studies of these cells showed coexpression of terminal deoxynucleotidyl transferase (TdT) and CD10, as well as positivity for the B-cell marker PAX5, consistent with B lymphoblasts. The patient was diagnosed with B-ALL one year after her first bone pain episode. After treatment with a 3-drug induction and two bone marrow transplants, she died 20 months after her diagnosis. Conclusion: This case demonstrates the varied presentation of B-ALL that requires physicians to maintain a high index of suspicion. Despite its good prognosis, the presentation with intra- and extramedullary involvement and normal hematologic values can be a challenge to physicians evaluating young patients.
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    Fort Worth Adolescent and Young Adult Cancer Registry: First Look at Initial Data
    (2021) Rose, Sushreyta; Bowman, William; Basha, Riyaz; Albritton, Karen; Garcia, Joanna
    Purpose: The adolescent and young adult (AYA) cancer population, defined as patients diagnosed between the age of 15-39, may benefit from focused research in improving health outcomes as compared to younger and older patients. A retrospective data registry was created to collect protected health information (PHI) on AYA cancer cases from four Fort Worth healthcare systems to foster collaboration in research. Methods: Initially testing feasibility, the registry is currently collecting a limited dataset of demographic, diagnostic and treatment information on incident AYA malignant cases between January 2016 through December 2019 via a secure database. A descriptive analysis was performed on the current data. Results: 3 of 4 institutions have submitted data on 514 AYA cancer patients. Even though expected cancer incidence rates increase with age, 195 patients were between 15-19 years of age followed by 128 patients in the 35-39 years of age range. 59% of the total patients were females. The top five cancers with the highest incidence rates were Thyroid cancer, Breast Cancer, GI tract cancer, Germ Cell cancer and Hodgkin's Lymphoma. In terms of insurance, 47% of the total patients were covered by private insurance followed by 18% covered by Medicaid. Conclusions: Initial analysis highlighted the need for further improving the data collection process in terms of handling delays retrieving data and ensuring good data quality. In the future, the registry seeks to increase institutions submitting data with PHI. This repository should be a useful resource for community partners for AYA research.