Medical Specialties Commons^™

Extra Medullar Granulocytic Sarcoma: A Case Report Of An Exceptional Localization, Bouhani Malek, Sakhri Saida, Jaidane Olfa, Adouni Olfa, Chargui Riadh, Rahal Khaled

Journal of Mind and Medical Sciences

Granulocytic sarcoma is a rare type of tumor composed of extramedullary immature cells. The breast location is very rare; it accounts for less than 8% of cases. The present study reports the case of a 36-year-old female with a medical history of myelodysplastic syndrome. She was referred because of a lump in the left breast. We have diagnosed a case of granulocytic sarcoma of the breast by core biopsy. Histology and immunohistochemistry showed hypercellular smears with immature myeloid cells. The blast cells were myeloperoxidase positive.

The patient underwent a lumpectomy. Five months later, she developed a contralateral recurrence, treated by …

Warty Carcinoma Of Uterine Cervix - Review Of The Literature And Case Report, Octavian Gabriel Olaru, Catalina Monica Pena, Oana Denisa Balalau, Anca Daniela Stanescu

Journal of Mind and Medical Sciences

Introduction. The Histological Classification of Epithelial Tumors of the Uterine Cervix of the World Health Organization includes inter alia warty carcinoma as a variant of squamous cell carcinoma. Until now several case reports and studies have shown that this particular cancer is associated with human papillomavirus/ HPV infection.

Case presentation. A 58-year-old woman presented with a vegetant cervical tumour. Biopsy samples were collected from the tumour, and the histological exam successively confirmed the warty cell carcinoma. Additional tests revealed the presence of single human papillomavirus/ type-45. An immunohistochemistry exam was performed in order to confirm the diagnosis, and …

Innovative Device For Indocianyne Green Navigational Surgery, Cătălin Aliuș, Nicolae Bacalbașa, Cristian Bălălău

Journal of Mind and Medical Sciences

Dynamic reality has been integrated into developing surgical techniques, with the goals of providing increased intraoperative accuracy, easier detection of critical anatomical landmarks, and better general results for the patient. Enhancement of the reality in surgical theaters using single or multi sensorial augmenters (haptic, thermic and visual) has been reported with various degrees of success. This paper presents a novel device for navigational surgery and ancillary clinical applications based on the fluorescent properties of Indocyanine Green (ICG), a safe, FDA-approved dye that emits fluorescence at higher wavelengths than endogenous proteins. The latest technological developments and the aforementioned convenient quantum behavior …

The Serine/Threonine Protein Kinase (Akt)/ Protein Kinase B (Pkb) Signaling Pathway In Breast Cancer, Daniela Miricescu, Camelia Cristina Diaconu, Constantin Stefani, Ana Maria Alexandra Stanescu, Alexandra Totan, Ioana Ruxandra Rusu, Ovidiu Gabriel Bratu, Dan Spinu, Maria Greabu

Journal of Mind and Medical Sciences

According to statistical data published in 2019, breast cancer is among the leading causes of death in women worldwide. The serine/threonine kinase (AKT) or protein kinase B (PkB) signaling pathway is activated by phosphorylation processes, which further is associated with cell growth, proliferation, and survival, but also with activation of glucose metabolism. Mutations of the AKT signaling pathway components (especially PI3KCA and PTEN) have been observed in breast cancer patients, which are associated with resistance to hormonal treatment. Many clinical trials are testing the effect of AKT inhibition in order to block the growth and proliferation of breast cancer cells. …

Treatment Of Lipomas And Diffuse Lipomatosis With Ndyag 1064 Nm Laser And Their Impact On The Quality Of Life, Valeriu Ardeleanu, Liliana Florina Andronache, Florentina Gherghiceanu, Stana Paunica, Cristian Balalau, Anca Pantea Stoian

Journal of Mind and Medical Sciences

Lipomas, the most common type of benign tumours, are generally developed from adipose tissue and present an incidence of 2.1 per 1000 inhabitants. In addition to lipomas, at least three other maladies of the adipose tissue lead patients to consult a doctor, especially for aesthetic purposes: multiple familial lipomatosis, diffuse congenital lipomatosis, and adiposa doloris. Unlike lipomas, these maladies are characterized by numerous lipomas, encapsulated or not, of different sizes, symmetrical or not, which may appear in the neck, limbs, or the trunk, sometimes being painful. The life quality of these patients is affected, not only from an aesthetic point …

Implementation Of A Chemotherapy Guideline: A Quality Improvement Project To Standardize The Chemotherapy Delivery Process, Sara Maciej

Nursing Posters

Adjusting chemotherapy rates is one gap in chemotherapy practice that evokes inconsistency. The purpose of this project was to implement a standardized guideline for staff to utilize in adjusting rates of chemotherapy medications.

Case Report: Effects Of Therapeutic Exercise On A Patient With Metastatic Osteosarcoma And Pathological Fracture, Jessica Phung, Sarah Mathew

San Marcos, Spring 2020

Purpose: The purpose of this case report is to demonstrate how conditioning exercise for patients with active metastatic neoplasms can improve quality of life (QoL) after a pathological fracture of lumbar vertebrae. Spinal metastasis, in this case from breast cancer, is primarily asymptomatic, and therefore, difficult to detect during early stages. Detection and diagnosis usually occur after initial manifestation of a pathological fracture leading to debilitating effects. Complications with metastatic bone cancer and surgical contraindications may bring patients into outpatient physical therapy to address the pathological fractures and QoL for patients.

Case Description & Methods: The patient is a 44-year …

Anticancer Activity Of Thmpp: Downregulation Of Pi3k/ S6k1 In Breast Cancer Cell Line., Suresh Palanivel, Akshaya Murugesan, Olli Yli-Harja, Meenakshisundaram Kandhavelu

Articles, Abstracts, and Reports

Breast cancer is the most common cancer that majorly affects female. The present study is focused on exploring the potential anticancer activity of 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP), against human breast cancer. The mechanism of action, activation of specific signaling pathways, structural activity relationship and drug-likeness properties of THMPP remains elusive. Cell proliferation and viability assay, caspase enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR, QSAR and ADME analysis were executed to understand the mode of action of the drug. The effect of THMPP on multiple breast cancer cell lines (MCF-7 and SkBr3), and …

The Write Stuff - Spring 2020 (Vol. 17, No. 2), Research Medical Library

Write Stuff 2020

• How to discuss your study's limitations effectively
• Reference letters vs. letters of support for NIH grant applications: What's the difference?
• NCI Bottom Line blog offers insight into grant funding and budgets
• Dissertations, Text Recycling, and Self-Plagiarism
• NIH Increases the use of Notices of Special Interest
• Tips for using Track Changes in Microsoft Word

Blood Cancers And Oral Health, Silvia Spivakovsky Dds, Gwen Nichols Md, Laura Romundstad Crnp, Msn, Elizabeth Kitlas Lmsw

The Journal of the Michigan Dental Association

Managing Blood Cancer Patients' Oral Complications: Preventive Strategies during and after Treatment

Blood cancers, encompassing leukemia, lymphoma, myeloma, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN), bring complex challenges to patient management due to their impact on hematopoiesis, immunity, and overall health. This review focuses on equipping dental practitioners with essential insights into preventing and managing intricate oral manifestations during and after treatment. Patient care strategies are outlined for leukemia subtypes such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML), emphasizing the need for tailored dental approaches. In lymphomas encompassing Hodgkin …

Oral Complications In Cancer Patients: A Review Of Practical Interventions In The Dental Setting, Caroline Bissonnette Dds, Kristin Mcnamara Dds, John Kalmar Dmd, Phd

The Journal of the Michigan Dental Association

Cancer prevalence in the United States is significant, with an estimated 40% of the population experiencing this diagnosis at some point in their lives. In 2020 alone, 1,806,590 new cancer cases were projected, encompassing 53,260 cases involving oral and oropharyngeal malignancies. Amidst barriers like financial constraints and irregular dental visits (highlighted by a 2014 American Dental Association survey indicating that 32.3% of the general population avoids yearly dentist appointments), patients battling cancer often encounter not just routine dental needs, but the intricate challenges arising from their malignancy and treatments. Dental professionals, pivotal in orchestrating optimal treatment strategies for cancer patients, …

Cervical Cancer Vaccination Awareness And Acceptance Among The Females Of Punjab, Pakistan, Sadia Minhas, Aneequa Sajjad, Muhammad Kashif, Zobaria Rehman, Muhammad Idrees, Farheen Ansari

Makara Journal of Health Research

Background: In developing countries like Pakistan, it is essential for health care professionals to have comprehensive knowledge regarding cervical cancer.

Methods: A cross-sectional self-administered paper-based questionnaire was administered to patients from 2016 to 2018. This study included 200 females who attended the gynecological OPD of Lady Willingdon Hospital Lahore, Punjab. We evaluated cervical cancer knowledge, screening, prevention, and acceptance towards the vaccination. Data entry and analysis were performed using SPSS version 20.

Results: The perception and knowledge related to cervical cancer (28%), screening (3%), prevention (3%), and vaccination (1%) among the females were poor, but a positive …

Disseminated Carcinomatosis Of Bone Marrow In An African Man With Metastatic Descending Colon Carcinoma, Harrison Chuwa, Nadeem Kassam, Casmir Wambura, Omar Sherman, Salim Surani

Internal Medicine, East Africa

Colorectal cancer (CRC) is ranked third worldwide and seventh in Tanzania. The liver and lungs are the most commonly involved sites. Disseminated carcinomatosis of the bone marrow (DCBM) from colorectal carcinoma is rare and typically indicates widespread disease and poor prognosis. We report a case of a 40-year-old African male, who presented to us with abdominal distension, weight loss, fever and change in bowel habit over the past month. He underwent colonoscopy which revealed a necrotic mass in the descending colon. Biopsies were taken, and histopathology confirmed the presence of poorly differentiated mucin-producing adenocarcinoma. The patient suffered a colonic perforation …

Dentistry’S Supporting Role For Cancer Patients, Christopher J. Smiley

The Journal of the Michigan Dental Association

Cancer diagnosis overwhelms patients and caregivers. As the spouse of a patient with leukemia who received bone marrow transplant therapy, I share insights into the challenges these patients face. Oral healthcare professionals play a vital role during these trials. Dental teams, often at the oncology's behest, conduct comprehensive exams and treatments before cancer therapy starts. Providing timely and efficient dental care is essential to achieve clearance to proceed with cancer therapy. Dental infections can be catastrophic for these patients who may be immune compromised. Untreated oral issues could lead to hospitalization, jeopardizing treatment schedules. Advocating for patients' financial needs, often …

J Mich Dent Assoc April 2020

The Journal of the Michigan Dental Association

This April 2020 issue of the Journal of the Michigan Dental Association presents original feature content on:

• Oral Health Considerations for Cancer Therapy Patients, with articles on Blood Cancer and Oral Health authored by an expert team from the Leukemia and Lymphoma Society (LLS) and a Review of practical interventions for dental providers to address oral complications in cancer patients, authored by experts from the Ohio State University College of Dentistry.
• We continue our feature series on implementing an evidence-based process into clinical care with an article on developing critical appraisal skills to assess literature authored by Dr. Julie Frantsve-Hawley, …

Extracorporeal Membrane Oxygenation As A Bridge To Chimeric Antigen Receptor T-Cell Therapy For Severe Refractory Sepsis In The Setting Of Relapsed Refractory Pediatric Acute Lymphoblastic Leukemia: A Case Report., Alyssa Stoner, Jenna Miller, Terrie Flatt, Jessica S. Wallisch

Manuscripts, Articles, Book Chapters and Other Papers

Pediatric oncology patients with sepsis are at higher risk of morbidity and mortality compared with pediatric patients without malignancy. Historically, patients with relapsed and/or refractory disease were not considered candidates for aggressive life support strategies including extracorporeal membrane oxygenation support.

Case Summary: We report a 4-year-old female with relapsed refractory pre-B cell acute lymphoblastic leukemia preparing for chimeric antigen receptor T cell therapy with tisagenlecleucel who was admitted with fever and neutropenia. She progressed to refractory septic shock secondary to

Conclusion: The ability to provide chimeric antigen receptor T-cell therapy at designated institutions can augment extracorporeal membrane oxygenation candidacy discussions …

An In Vivo Genome-Wide Crispr Screen Identifies The Rna-Binding Protein Staufen2 As A Key Regulator Of Myeloid Leukemia, Jeevisha Bajaj, Michael Hamilton, Yutaka Shima, Kendall Chambers, Kyle Spinler, Eric L Van Nostrand, Brian A Yee, Steven M Blue, Michael Chen, David Rizzeri, Charles Chuah, Vivian G Oehler, H Elizabeth Broome, Roman Sasik, James Scott-Browne, Anjana Rao, Gene W Yeo, Tannishtha Reya

Faculty, Staff and Students Publications

Aggressive myeloid leukemias such as blast crisis chronic myeloid leukemia and acute myeloid leukemia remain highly lethal. Here we report a genome-wide in vivo CRISPR screen to identify new dependencies in this disease. Among these, RNA-binding proteins (RBPs) in general, and the double-stranded RBP Staufen2 (Stau2) in particular, emerged as critical regulators of myeloid leukemia. In a newly developed knockout mouse, loss of Stau2 led to a profound decrease in leukemia growth and improved survival in mouse models of the disease. Further, Stau2 was required for growth of primary human blast crisis chronic myeloid leukemia and acute myeloid leukemia. Finally, …

Impedance Analysis Of Tissues In Nspef Treatment For Cancer Therapy, Edwin Ayobami Oshin

Biomedical Engineering Theses & Dissertations

Nanosecond pulsed electric field (nsPEF) for cancer therapy is characterized by applications of high voltage pulses with low pulsed energy to induce non-thermal effects on tissues such as tumor ablation. It nonthermally treats tissues via electroporation. Electroporation is the increase in permeabilization of a cell membrane due to the application of high pulsed electric field. The objective of this study was to investigate the effect of nsPEF on tissue by monitoring the tissue’s impedance in real-time. Potato slices (both untreated and electroporated), and tumors extracted from female BALBc mice were studied. 100ns, 1-10kV pulses were applied to the tissues using …

Association Of Immunophenotype With Expression Of Topoisomerase Ii Α And Β In Adult Acute Myeloid Leukemia., Andrew P Michelson, Shannon Mcdonough, Cheryl L Willman, Eric R Koegle, John E Godwin, Stephen H Petersdorf, Alan F List, Megan Othus, Frederick R Appelbaum, Jerald P Radich, Mahrukh K Ganapathi, Anjali S Advani, Ram N Ganapathi

Articles, Abstracts, and Reports

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P < 0.0001). In contrast to topo IIα, topo IIβ was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P < 0.0001) and CD54 (P < 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIβ and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIβ expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy.

Utilizing Digital Health To Collect Electronic Patient-Reported Outcomes In Prostate Cancer: Single-Arm Pilot Trial, Christine Tran, Ms, Adam Dicker, Md, Phd, Benjamin Leiby, Phd, Eric Gressen, Md, Noelle Williams, Md, Heather Jim, Phd

Kimmel Cancer Center Faculty Papers

Background: Measuring patient-reported outcomes (PROs) requires an individual’s perspective on their symptoms, functional status, and quality of life. Digital health enables remote electronic PRO (ePRO) assessments as a clinical decision support tool to facilitate meaningful provider interactions and personalized treatment.

Objective: This study explored the feasibility and acceptability of collecting ePROs using validated health-related quality of life (HRQoL) questionnaires for prostate cancer.

Methods: Using Apple ResearchKit software, the Strength Through Insight app was created with content from validated HRQoL tools 26-item Expanded Prostate Cancer Index Composite (EPIC) or EPIC for Clinical Practice and 8-item Functional Assessment of Cancer Therapy Advanced …

Associations Between Aquaglyceroporin Gene Polymorphisms And Risk Of Stroke Among Patients With Hypertension, Qingyun Tu, Li Yan, Chun Wang, Aohan Han, Yu Qin, Lan Cui, Quanyong Xiang

Department of Medical Oncology Faculty Papers

Background: Dysregulations ofAQP7andAQP9were found to be related to lipid metabolism abnormality, which had been provento be one of the mechanisms of stroke. However, limited epidemiological studies explore the associations betweenAQP7andAQP9and the risk of stroke among patients with hypertension in China.

Aims: We aimed to investigate the associations between genetic variants in AQP7andAQP9and the risk of stroke among patients with hypertension, as well as to explore gene-gene andgene-environment interactions.

Methods: Baseline blood samples were drawn from 211 cases with stroke and 633 matched controls. Genomic DNA was extracted by a commercially available kit. Genotyping of 5 single nucleotide polymorphisms (SNPs) in …

Allogeneic Autophagosome-Enriched Composition For The Treatment Of Disease, Traci Hilton, Sandra Aung, Rieneke Van De Ven, Christopher Paustian, Tarsem Moudgil, Christopher Dubay, Christopher Twitty, Hong-Ming Hu, Bernard A Fox

Technology Transfer - Patents

A method is presented for screening cells that produce allogeneic autophagosome enriched compositions able to induce expression of a selective marker on a subpopulation of peripheral blood mononuclear cells, the method comprising contacting a cell with a proteasome inhibitor, contacting the cell with a lysosome inhibitor, harvesting the resulting autophagosomes, determining a molecular signature of the harvested autophagosomes, and selecting cells that divert one or more Toll-like receptor agonist and/or one or more molecular chaperones to the harvested autophagosomes. By screening for cells that divert one or more Toll-like receptor agonist and/or one or more molecular chaperones to the harvested …

Allogeneic Autophagosome-Enriched Composition For The Treatment Of Disease, Traci Hilton, Sandra Aung, Rieneke Van De Ven, Christopher Paustian, Tarsem Moudgil, Christopher Dubay, Christopher Twitty, Hong-Ming Hu, Bernard A Fox

Technology Transfer - Patents

A method is presented for screening cells that produce allogeneic autophagosome enriched compositions able to induce expression of a selective marker on a subpopulation of peripheral blood mononuclear cells, the method comprising contacting a cell with a proteasome inhibitor, contacting the cell with a lysosome inhibitor, harvesting the resulting autophagosomes, determining a molecular signature of the harvested autophagosomes, and selecting cells that divert one or more Toll-like receptor agonist and/or one or more molecular chaperones to the harvested autophagosomes. By screening for cells that divert one or more Toll-like receptor agonist and/or one or more molecular chaperones to the harvested …

Using Medical Claims Database To Develop A Population Disease Progression Model For Leuprorelin-Treated Subjects With Hormone-Sensitive Prostate Cancer, Yixuan Zou, Fei Tang, Jeffery C. Talbert, Chee M. Ng

Pharmacy Practice and Science Faculty Publications

Androgen deprivation therapy (ADT) is a widely used treatment for patients with hormone-sensitive prostate cancer (PCa). However, duration of treatment response varies, and most patients eventually experience disease progression despite treatment. Leuprorelin is a luteinizing hormone-releasing hormone (LHRH) agonist, a commonly used form of ADT. Prostate-specific antigen (PSA) is a biomarker for monitoring disease progression and predicting treatment response and survival in PCa. However, time-dependent profile of tumor regression and growth in patients with hormone-sensitive PCa on ADT has never been fully characterized. In this analysis, nationwide medical claims database provided by Humana from 2007 to 2011 was used to …

Dietary Alterations Modulate The Microrna 29/30 And Igf-1/Akt Signaling Axis In Breast Cancer Liver Metastasis., Anuradha A. Shastri, Anthony Saleh, Jason E. Savage, Tiziana Deangelis, Kevin Camphausen, Nicole L. Simone

Department of Radiation Oncology Faculty Papers

Background: Metastatic cancer is incurable and understanding the molecular underpinnings is crucial to improving survival for our patients. The IGF-1/Akt signaling pathway is often impaired in cancer leading to its progression and metastases. Diet modification is known to alter the IGF-1/Akt pathway and affect the expression of microRNA involved in tumor initiation, growth and metastases. Liver metastases are one of the most common type of metastases in breast and colon cancer. In the present study, we looked at the effect of diet modification on the expression of microRNA in normal liver and liver with breast cancer metastases using in vivo …

Design And Analysis Of A Novel Long-Distance Double Tendon-Sheath Transmission Device For Breast Intervention Robots Under Mri Field, Xiaohong Jia, Yongde Zhang, Jingang Jiang, Haiyan Du, Yan Yu

Department of Radiation Oncology Faculty Papers

Cancer represents a major threat to human health. Magnetic resonance imaging (MRI) provides superior performance to other imaging-based examination methods in the detection of tumors and offers distinct advantages in biopsy and seed implantation. However, because of the MRI environment, the material requirements for actuating devices for the medical robots used in MRI are incredibly demanding. This paper describes a novel double tendon-sheath transmission device for use in MRI applications. LeBus grooves are used in the original transmission wheels, thus enabling the system to realize long-distance and large-stroke transmission with improved accuracy. The friction model of the transmission system and …

Metabolic Reprogramming By C-Met Inhibition As A Targetable Vulnerability In Glioblastoma, Trang Thi Thu Nguyen, Enyuan Shang, Georg Karpel-Massler, Markus D. Siegelin

Publications and Research

The elucidation of better treatments for solid tumors and especially malignant glial tumors is a priority. Better understanding of the molecular underpinnings of treatment response and resistance are critical determinants in the success for this endeavor. Recently, a battery of novel tools have surfaced that allow to interrogate tumor cell metabolism to more precise extent than this was possible in the earlier days. At the forefront of these developments are the extracellular flux and carbon tracing analyses. Through utilization of these techniques our group made the recent observation that acute and chronic c-MET inhibition drives fatty acid oxidation that in …

Osteoblastoma In The Occipital Bone: A Case Report Of A Rare Tumor In The Calvarium, Lukas M. Trunz, Scott H. Faro, Richard J. Gorniak

Department of Radiology Faculty Papers

Osteoblastomas infrequently occur in the calvarium, displaying a preference for temporal and frontal bones when it does. We present an unusual case of a large, expansile osteoblastoma in the occipital bone of a 23-year-old man who presented with a nontender lump at the back of his head. Initial computed tomography scan showed a large occipital bone mass, and after additional imaging, a gross total resection was performed. Histopathological examination revealed an osteoblastoma. Although these tumors are benign, overlapping imaging characteristics of lesions affecting the calvarium often present a diagnostic dilemma. This case emphasizes the importance of imaging in the management …

Proteins Inform Survival-Based Differences In Patients With Glioblastoma, L. C. Stetson, Daniela M. Schlatzer, Peter Liao, Karen Devine, Kristin Waite, Marta E. Couce, Andrew E. Sloan, Mark R. Chance, Jill S. Barnholtz-Sloan

Faculty Scholarship

Background: Improving the care of patients with glioblastoma (GB) requires accurate and reliable predictors of patient prognosis. Unfortunately, while protein markers are an effective readout of cellular function, proteomics has been underutilized in GB prognostic marker discovery. Methods: For this study, GB patients were prospectively recruited and proteomics discovery using liquid chromatography-mass spectrometry analysis (LC-MS/MS) was performed for 27 patients including 13 short-term survivors (STS) (≤10 months) and 14 long-term survivors (LTS) (≥18 months). Results: Proteomics discovery identified 11 941 peptides in 2495 unique proteins, with 469 proteins exhibiting significant dysregulation when comparing STS to LTS. We verified the differential …

Atrx Loss In Pediatric Glioma Results In Epigenetic Dysregulation Of G2/M Checkpoint Maintenance And Sensitivity To Atm Inhibition, Brendan Mullan, Tingting Qin, Ruby Siada, Carla Danussi, Jacqueline Brosnan-Cashman, Drew Pratt, Taylor Garcia, Viveka Nand Yadav, Xinyi Zhao, Meredith Morgan, Sriram Venneti, Alan Meeker, Alnawaz Rehemtulla, Pedro Lowenstein, Maria Castro, Carl Koschmann

Medical Student Research Symposium

ATRX is a histone chaperone protein recurrently mutated in pediatric glioma. The mechanism which mediates the proliferative advantage of ATRX loss in pediatric glioma remains unexplained. Recent data revealed a distinct pattern of DNA binding sites of the ATRX protein using ChIP-seq in mouse neuronal precursor cells (mNPCs). Using the ATRX peaks identified in p53^-/- mNPCs, we confirmed that ATRX binding sites were significantly enriched in gene promoters (p < 0.0001) and CpG islands (p < 0.0001) compared with random regions. Gene set enrichment (GSE) analysis identified that cell cycle and regulation of cell cycle were among the most significantly enriched gene sets (p=2.52e-16 and 1.61e-9, respectively). We found that ATRX loss resulted in dysfunction of G2/M checkpoint maintenance: (1) ATRX-deficient pediatric glioblastoma (GBM) cells exhibited a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation, and (2) murine GBM cells with ATRX knockdown demonstrated impaired pChk1 signaling on western blot at multiple time points after radiation compared to controls (p=0.0187). Notably, the ATM signaling (pChk2) remained intact in those cells, suggesting a potential therapeutic target. ATRX-deficient mouse cells were uniquely sensitive to ATM inhibitors at 1 uM alongside 8 Gy radiation compared to controls with intact ATRX (AZD0156: p=0.0027 and AZD01390: p=0.0436). Mice intra-cranially implanted with ATRX-deficient GBM cells showed improved survival (n=10, p=0.0018) when treated with AZD0156 combined with radiation. Our findings suggest that ATRX loss in glioma results in unique sensitivity to ATM inhibition via epigenetic dysregulation of G2/M checkpoint maintenance.