Medical Genetics Commons^™

The Androgen Receptor Is A Therapeutic Target In Desmoplastic Small Round Cell Sarcoma, Salah-Eddine Lamhamedi-Cherradi, Mayinuer Maitituoheti, Brian A Menegaz, Sandhya Krishnan, Amelia M Vetter, Pamela Camacho, Chia-Chin Wu, Hannah C Beird, Robert W Porter, Davis R Ingram, Vandhana Ramamoorthy, Sana Mohiuddin, David Mccall, Danh D Truong, Branko Cuglievan, P Andrew Futreal, Alejandra Ruiz Velasco, Nazanin Esmaeili Anvar, Budi Utama, Mark Titus, Alexander J Lazar, Wei-Lien Wang, Cristian Rodriguez-Aguayo, Ravin Ratan, J Andrew Livingston, Kunal Rai, A Robert Macleod, Najat C Daw, Andrea Hayes-Jordan, Joseph A Ludwig

Faculty, Staff and Student Publications

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the …

A Roadmap To Clinical Trials For Flash, Paige A Taylor, Jean M Moran, David A Jaffray, Jeffrey C Buchsbaum

Faculty, Staff and Student Publications

While FLASH radiation therapy is inspiring enthusiasm to transform the field, it is neither new nor well understood with respect to the radiobiological mechanisms. As FLASH clinical trials are designed, it will be important to ensure we can deliver dose consistently and safely to every patient. Much like hyperthermia and proton therapy, FLASH is a promising new technology that will be complex to implement in the clinic and similarly will require customized credentialing for multi-institutional clinical trials. There is no doubt that FLASH seems promising, but many technologies that we take for granted in conventional radiation oncology, such as rigorous …

Statins Enhance The Chemosensitivity Of R-Chop In Diffuse Large B-Cell Lymphoma, Sushanth Gouni, Paolo Strati, Gokce Toruner, Akanksha Aradhya, Ralf Landgraf, Daniel Bilbao, Francisco Vega, Nitin Kumar Agarwal

Faculty, Staff and Student Publications

The beneficial effect of statins on the anti-lymphoma activity of the rituximab-based chemotherapy regimen is controversial. Here, we retrospectively reviewed patients with naïve-treated advanced diffuse large B-cell lymphoma (DLBCL) receiving frontline R-CHOP, and for whom data regarding differential statins use was available at the time of initiation of treatment. We observe that patients treated with statins and R-CHOP experienced a significantly higher CR rate as compared to those who received R-CHOP only. We further show that patients receiving medium or high intensity statins and R-CHOP experienced a significantly higher CR as compared to those treated with R-CHOP. Six-year progression free …

Assessment Of Clinical Response Following Atezolizumab And Bevacizumab Treatment In Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial, Daniel M Halperin, Suyu Liu, Arvind Dasari, David Fogelman, Priya Bhosale, Armeen Mahvash, Jeannelyn S Estrella, Laura Rubin, Ajaykumar C Morani, Mark Knafl, Tim A Overeem, Szu-Chin Fu, Luisa M Solis, Edwin Parra Cuentas, Anuj Verma, Hong-Lei Chen, Swati Gite, Priya Subashchandrabose, Shannon Dervin, Katja Schulze, Walter C Darbonne, Cindy Yun, Ignacio I Wistuba, P Andrew Futreal, Scott E Woodman, James C Yao

Faculty, Staff and Student Publications

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing.

Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs.

Design, setting, and participants: This single-arm, open-label …

Integrating Mechanism-Based Modeling With Biomedical Imaging To Build Practical Digital Twins For Clinical Oncology, Chengyue Wu, Guillermo Lorenzo, David A Hormuth, Ernesto A B F Lima, Kalina P Slavkova, Julie C Dicarlo, John Virostko, Caleb M Phillips, Debra Patt, Caroline Chung, Thomas E Yankeelov

Faculty, Staff and Student Publications

Digital twins employ mathematical and computational models to virtually represent a physical object (e.g., planes and human organs), predict the behavior of the object, and enable decision-making to optimize the future behavior of the object. While digital twins have been widely used in engineering for decades, their applications to oncology are only just emerging. Due to advances in experimental techniques quantitatively characterizing cancer, as well as advances in the mathematical and computational sciences, the notion of building and applying digital twins to understand tumor dynamics and personalize the care of cancer patients has been increasingly appreciated. In this review, we …

Diversity Of Two-Pore Channels And The Accessory Naadp Receptors In Intracellular Ca2+ Signaling, Kunal R Shah, Xin Guan, Jiusheng Yan

Faculty, Staff and Student Publications

Intracellular Ca2+ signaling via changes or oscillation in cytosolic Ca2+ concentration controls almost every aspect of cellular function and physiological processes, such as gene transcription, cell motility and proliferation, muscle contraction, and learning and memory. Two-pore channels (TPCs) are a class of eukaryotic cation channels involved in intracellular Ca2+ signaling, likely present in a multitude of organisms from unicellular organisms to mammals. Accumulated evidence indicates that TPCs play a critical role in Ca2+ mobilization from intracellular stores mediated by the second messenger molecule, nicotinic acid adenine dinucleotide phosphate (NAADP). In recent years, significant progress has been made regarding our understanding …

Non-Coding Rnas And Ferroptosis: Potential Implications For Cancer Therapy, Amar Balihodzic, Felix Prinz, Michael A Dengler, George A Calin, Philipp J Jost, Martin Pichler

Faculty, Staff and Student Publications

Ferroptosis is a recently defined form of regulated cell death, which is biochemically and morphologically distinct from traditional forms of programmed cell death such as apoptosis or necrosis. It is driven by iron, reactive oxygen species, and phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage and breakdown of membrane integrity. Numerous cellular signaling pathways and molecules are involved in the regulation of ferroptosis, including enzymes that control the cellular redox status. Alterations in the ferroptosis-regulating network can contribute to the development of various diseases, including cancer. Evidence suggests that ferroptosis is commonly suppressed in cancer cells, allowing them …

Knowledge-Based Planning For The Radiation Therapy Treatment Plan Quality Assurance For Patients With Head And Neck Cancer, Wenhua Cao, Mary Gronberg, Adenike Olanrewaju, Thomas Whitaker, Karen Hoffman, Carlos Cardenas, Adam Garden, Heath Skinner, Beth Beadle, Laurence Court

Faculty, Staff and Student Publications

This study aimed to investigate the feasibility of using a knowledge-based planning technique to detect poor quality VMAT plans for patients with head and neck cancer. We created two dose-volume histogram (DVH) prediction models using a commercial knowledge-based planning system (RapidPlan, Varian Medical Systems, Palo Alto, CA) from plans generated by manual planning (MP) and automated planning (AP) approaches. DVHs were predicted for evaluation cohort 1 (EC1) of 25 patients and compared with achieved DVHs of MP and AP plans to evaluate prediction accuracy. Additionally, we predicted DVHs for evaluation cohort 2 (EC2) of 25 patients for which we intentionally …

Distinct Immune Gene Programs Associated With Host Tumor Immunity, Neoadjuvant Chemotherapy, And Chemoimmunotherapy In Resectable Nsclc, Pedro Rocha, Jiexin Zhang, Raquel Laza-Briviesca, Alberto Cruz-Bermúdez, Neus Bota-Rabassedas, Beatriz Sanchez-Espiridon, Katsuhiro Yoshimura, Carmen Behrens, Wei Lu, Ximing Tang, Apar Pataer, Edwin R Parra, Cara Haymaker, Junya Fujimoto, Stephen G Swisher, John V Heymach, Don L Gibbons, J Jack Lee, Boris Sepesi, Tina Cascone, Luisa M Solis, Mariano Provencio, Ignacio I Wistuba, Humam Kadara

Faculty, Staff and Student Publications

Purpose: Our understanding of the immunopathology of resectable non-small cell lung cancer (NSCLC) is still limited. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.

Experimental design: Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n = 190), neoadjuvant chemotherapy (n = 38), and neoadjuvant chemoimmunotherapy (n = 21). Tumor immune microenvironment (TIME) phenotypes were based on the location of CD8+ T cells (inflamed, cold, excluded), tumoral PD-L1 expression (<1% and ≥1%), and tumor-infiltrating lymphocytes (TIL). Immune programs and signatures were statistically analyzed on the basis of tumoral PD-L1 expression, immune phenotypes, and pathologic response and were cross-compared across the three cohorts.

Results: PD-L1-positive tumors exhibited increased …

Cooking After Cancer: The Structure And Implementation Of A Community-Based Cooking Program For Cancer Survivors, Margaret Raber, Molly Costigan, Joya Chandra, Karen Basen-Engquist

Faculty, Staff and Student Publications

Cancer survivors are a growing population that may particularly benefit from nutrition and lifestyle interventions. Community-based programs teaching healthy cooking skills are increasingly popular and offer an opportunity to support survivors within communities. The objective of this study is to describe the curriculum and implementation of a cooking class program designed for cancer survivors, housed within an established community-based organization. First, we evaluated the class curriculum for specific constructs. An evidence-based measure of healthy cooking constructs, the Healthy Cooking Index (HCI), was used to analyze included recipes and revealed both summative cooking quality scores and individual constructs underlying the overall …

Success And Outcomes Following A Second Salvage Attempt For Free Flap Compromise In Patients Undergoing Head And Neck Reconstruction, Allison A Slijepcevic, Gavin Young, Justin Shinn, Steven B Cannady, Matthew Hanasono, Matthew Old, Jeewanjot S Grewal, Tamer Ghanem, Yadranko Ducic, Joseph M Curry, Mark K Wax

Faculty, Staff and Student Publications

Importance: Incidence of perioperative free flap compromise is low, with successful salvage in up to 70%. When the flap is compromised a second time, the value of intervening is unknown.

Objective: To assess the outcomes of a second revascularization attempt for compromised free flaps.

Design, setting, and participants: This multicenter retrospective medical record review included patients undergoing head and neck reconstruction with free flaps at 6 US medical centers from January 1, 2000, through December 30, 2020. Patients were 18 years or older with a history of head and neck defects from cancer, osteoradionecrosis, or other wounds. Of 3510 flaps …

Association Of Driver Oncogene Variations With Outcomes In Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation And Consolidative Durvalumab, Yufei Liu, Zhe Zhang, Waree Rinsurongkawong, Carl M Gay, Xiuning Le, Matthew S Ning, Jeff Lewis, Vadeerat Rinsurongkawong, J Jack Lee, Jack Roth, Stephen Swisher, Saumil Gandhi, Percy P Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Jianjun Zhang, Steven H Lin

Faculty, Staff and Student Publications

Importance: Consolidative durvalumab after definitive chemoradiation for unresectable locally advanced non-small cell lung cancer (NSCLC) can significantly improve progression-free survival (PFS) and overall survival (OS), as shown in the PACIFIC trial. However, whether patients with driver variations derive equal benefit from this regimen remains unclear.

Objectives: To compare outcomes of patients with locally advanced NSCLC with and without driver variations treated with the PACIFIC regimen.

Design, setting, and participants: This cohort study examined 104 patients with unresectable locally advanced NSCLC with mutational profiling treated at a tertiary cancer center with definitive chemoradiation and consolidative durvalumab from June 2017 through May …

Outcomes After Definitive Surgery For Mandibular Osteoradionecrosis, Kevin J Contrera, Steven B Chinn, Randal S Weber, Dianna Roberts, Jeffery N Myers, Stephen Y Lai, Carol M Lewis, Amy C Hessel, Ann M Gillenwater, Collin F Mulcahy, Peirong Yu, Matthew M Hanasono, Clifton D Fuller, Mark S Chambers, Mark E Zafereo

Faculty, Staff and Student Publications

Objectives: To analyze charges, complications, survival, and functional outcomes for definitive surgery of mandibular osteoradionecrosis (ORN).

Materials and methods: Retrospective analysis of 76 patients who underwent segmental mandibulectomy with reconstruction from 2000 to 2009.

Results: Complications occurred in 49 (65%) patients and were associated with preoperative drainage (odds ratio [OR] 4.40, 95% confidence interval [CI] 1.01-19.27). The adjusted median charge was $343 000, and higher charges were associated with double flap reconstruction (OR 8.15, 95% CI 2.19-30.29) and smoking (OR 5.91, 95% CI 1.69-20.72). Improved swallow was associated with age <67 years (OR 3.76, 95% CI 1.16-12.17) and preoperative swallow (OR 3.42, 95% CI 1.23-9.51). Five-year ORN-recurrence-free survival was 93% while overall survival was 63% and associated with pulmonary disease (HR [hazard ratio] 3.57, 95% CI 1.43-8.94).

Conclusions: Although recurrence of ORN is rare, surgical complications are …

A Prospective Randomized Study Comparing Ceftolozane/Tazobactam To Standard Of Care In The Management Of Neutropenia And Fever In Patients With Hematological Malignancies, Anne-Marie Chaftari, Ray Hachem, Alexandre E Malek, Victor E Mulanovich, Ariel D Szvalb, Ying Jiang, Ying Yuan, Shahnoor Ali, Rita Deeba, Patrick Chaftari, Issam Raad

Faculty, Staff and Student Publications

Background: With increased use of antibiotics in high-risk patients, the investigation of new antibiotics to cover potentially resistant pathogens is warranted. In this prospective randomized trial, we compared ceftolozane/tazobactam (C/T), a new cephalosporin/β-lactamase inhibitor, to the standard of care (SOC) for the empiric treatment of neutropenia and fever in patients with hematological malignancies.

Methods: We enrolled 100 patients to receive intravenous (IV) C/T or SOC antibiotics (cefepime, piperacillin/tazobactam, or meropenem) in combination with gram-positive antibacterial agents. We evaluated responses at the end of IV therapy (EOIV), test of cure (TOC; days 21-28), and late follow-up (LFU; days 35-42).

Results: We …

Discovery Of Potent Bet Bromodomain 1 Stereoselective Inhibitors Using Dna-Encoded Chemical Library Selections, Ram K Modukuri, Zhifeng Yu, Zhi Tan, Hai Minh Ta, Melek Nihan Ucisik, Zhuang Jin, Justin L Anglin, Kiran L Sharma, Pranavanand Nyshadham, Feng Li, Kevin Riehle, John C Faver, Kevin Duong, Sureshbabu Nagarajan, Nicholas Simmons, Stephen S Palmer, Mingxing Teng, Damian W Young, Joanna S Yi, Choel Kim, Martin M Matzuk

Duncan NRI Faculty and Staff Publications

BRDT, BRD2, BRD3, and BRD4 comprise the bromodomain and extraterminal (BET) subfamily which contain two similar tandem bromodomains (BD1 and BD2). Selective BD1 inhibition phenocopies effects of tandem BET BD inhibition both in cancer models and, as we and others have reported of BRDT, in the testes. To find novel BET BD1 binders, we screened >4.5 billion molecules from our DNA-encoded chemical libraries with BRDT-BD1 or BRDT-BD2 proteins in parallel. A compound series enriched only by BRDT-BD1 was resynthesized off-DNA, uncovering a potent chiral compound, CDD-724, with >2,000-fold selectivity for inhibiting BRDT-BD1 over BRDT-BD2. CDD-724 stereoisomers exhibited remarkable differences in …

Differential Effects Of Dietary Macronutrients On The Development Of Oncogenic Kras-Mediated Pancreatic Ductal Adenocarcinoma, Liang Zhu, Juntao Ji, Jianjia Ma, Dan Wang, Muyun Liu, James Xianxing Du, Rong Chen, Wei Hou, James L Abbruzzese, Craig D Logsdon, Vincent W Yang, Yongde Luo, Weiqin Lu

Faculty, Staff and Student Publications

KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain …

Tumor Immunology And Immunotherapy Of Non-Small-Cell Lung Cancer, Tina Cascone, Jared Fradette, Monika Pradhan, Don L Gibbons

Faculty, Staff and Student Publications

Historically, non-small-cell lung cancer (NSCLC) has been regarded as a nonimmunogenic tumor; however, recent studies have shown that NSCLCs are among the most responsive cancers to monoclonal antibody immune checkpoint inhibitors (ICIs). ICIs have dramatically improved clinical outcomes for a subset of patients (∼20%) with locally advanced and metastatic NSCLC, and they have also demonstrated promise as neoadjuvant therapy for early-stage resectable disease. Nevertheless, the majority of patients with NSCLC are refractory to ICIs for reasons that are poorly understood. Thus, major questions are: how do we initially identify the patients most likely to derive significant clinical benefit from these …

Characteristics And Outcomes Of Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm Treated With Frontline Hcvad, Naveen Pemmaraju, Nathaniel R Wilson, Guillermo Garcia-Manero, Koji Sasaki, Joseph D Khoury, Nitin Jain, Gautam Borthakur, Farhad Ravandi, Naval Daver, Tapan Kadia, Courtney Dinardo, Elias Jabbour, Sherry Pierce, Muzaffar Qazilbash, Marina Konopleva, Hagop Kantarjian

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive blood cancer, often involving the skin, bone marrow, lymph nodes, and central nervous system (CNS) in 20% to 30% of patients. Despite significant progress in CD123- and BCL-2-targeted therapy, most patients are not cured without hematopoietic stem cell transplant (HSCT), and CNS relapses occur quite frequently. Combination approaches with targeted and chemotherapy agents plus incorporation of prophylactic CNS-directed therapy are urgently needed. In this setting, we sought to analyze outcomes using the cytotoxic chemotherapy backbone regimen hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (HCVAD). We conducted a retrospective analysis of patients …

Impact Of Estrogen Receptor Expression On Prognosis Of Ovarian Cancer According To Antibody Clone Used For Immunohistochemistry: A Meta-Analysis, Chun Wai Ng, Kwong-Kwok Wong

Faculty, Staff and Student Publications

Background: The prognostic value of the expression of estrogen receptor (ER) subtypes ER⍺ and ERβ in ovarian cancer has previously been evaluated by meta-analyses. However, the results are contradictory and controversial.

Methods: We conducted an updated meta-analysis with stringent inclusion criteria to ensure homogeneous studies to determine the effect of ER subtypes on ovarian cancer prognosis. Articles were retrieved by systematic search of PubMed and Web of Science for articles dated up to June 2021. Only studies with known hazard ratio (HR) and antibody clone for immunochemistry (IHC) were included. Pooled HRs with the corresponding 95% confidence intervals (CIs) were …

Enzymatic Characterization Of In Vitro Activity Of Rna Methyltransferase Pcif1 On Dna, Dan Yu, Jujun Zhou, Qin Chen, Tao Wu, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

PCIF1 and FTO are a pair of human mRNA cap-specific modification enzymes that have opposing activities. PCIF1 adds a methyl group to the N6-position of 2′O-methyladenosine (Am), generating N6, 2′O-dimethyladenosine (m6Am), when Am is the cap-proximal nucleotide. FTO removes the N6-methyl group from m6Am. In addition, FTO has a demethylase activity on a broad spectrum of various RNA substrates, as well as on DNA N6-methyldeoxyadenosine (m6dA). While the existence of m6dA in mammalian DNA remains controversial, we show here that PCIF1 has significant methylation activity on single stranded DNA deoxyadenosine, double stranded RNA/DNA hybrids, and double …

Tissue-Specific Variations In Transcription Factors Elucidate Complex Immune System Regulation, Hengwei Lu, Yi-Ching Tang, Assaf Gottlieb

Faculty, Staff and Student Publications

Gene expression plays a key role in health and disease. Estimating the genetic components underlying gene expression can thus help understand disease etiology. Polygenic models termed "transcriptome imputation" are used to estimate the genetic component of gene expression, but these models typically consider only the cis regions of the gene. However, these cis-based models miss large variability in expression for multiple genes. Transcription factors (TFs) that regulate gene expression are natural candidates for looking for additional sources of the missing variability. We developed a hypothesis-driven approach to identify second-tier regulation by variability in TFs. Our approach tested two models …

Mutational Activation Of The Nrf2 Pathway Upregulates Kynureninase Resulting In Tumor Immunosuppression And Poor Outcome In Lung Adenocarcinoma, Johannes F Fahrmann, Ichidai Tanaka, Ehsan Irajizad, Xiangying Mao, Jennifer B Dennison, Eunice Murage, Julian Casabar, Jeffrey Mayo, Qian Peng, Muge Celiktas, Jody V Vykoukal, Soyoung Park, Ayumu Taguchi, Oliver Delgado, Satyendra C Tripathi, Hiroyuki Katayama, Luisa Maren Solis Soto, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio Wistuba, Samir Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 …

Three-Dimensional Evaluation Of Isodose Radiation Volumes In Cases Of Severe Mandibular Osteoradionecrosis For The Prediction Of Recurrence After Segmental Resection, Haye H Glas, Joep Kraeima, Silke Tribius, Frank K J Leusink, Carsten Rendenbach, Max Heiland, Carmen Stromberger, Ashkan Rashad, Clifton D Fuller, Abdallah S R Mohamed, Stephen Y Lai, Max J H Witjes

Faculty, Staff and Student Publications

Background: Pre-operative margin planning for the segmental resection of affected bone in mandibular osteoradionecrosis (ORN) is difficult. The aim of this study was to identify a possible relation between the received RT dose, exposed bone volume and the progression of ORN after segmental mandibular resection.

Method: Patients diagnosed with grade 3-4 ORN for which a segmental resection was performed were included in the study. Three-dimensional reconstructions of RT isodose volumes were fused with postoperative imaging. The primary outcome was the recurrence of ORN after segmental resection. Subsequently, RT exposed mandibular bone volumes were calculated and the location of the bone …

Tite-Boin12: A Bayesian Phase I/Ii Trial Design To Find The Optimal Biological Dose With Late-Onset Toxicity And Efficacy, Yanhong Zhou, Ruitao Lin, J Jack Lee, Daniel Li, Li Wang, Ruobing Li, Ying Yuan

Faculty, Staff and Student Publications

In the era of immunotherapies and targeted therapies, the focus of early phase clinical trials has shifted from finding the maximum tolerated dose to identifying the optimal biological dose (OBD), which maximizes the toxicity-efficacy trade-off. One major impediment to using adaptive designs to find OBD is that efficacy or/and toxicity are often late-onset, hampering the designs’ real-time decision rules for treating new patients. To address this issue, we propose the model-assisted TITE-BOIN12 design to find OBD with late-onset toxicity and efficacy. As an extension of the BOIN12 design, the TITE-BOIN12 design also uses utility to quantify the toxicity-efficacy trade-off. We …

Gli1 Activates Pro-Fibrotic Pathways In Myelofibrosis Fibrocytes, Taghi Manshouri, Ivo Veletic, Ping Li, C Cameron Yin, Sean M Post, Srdan Verstovsek, Zeev Estrov

Faculty, Staff and Student Publications

Bone marrow (BM) fibrosis was thought to be induced exclusively by mesenchymal stromal cells (MSCs). However, we and others found that neoplastic fibrocytes induce BM fibrosis in myelofibrosis (MF). Because glioma-associated oncogene-1 (GLI1), an effector of the Hedgehog pathway, plays a role in the induction of BM fibrosis, we wondered whether GLI1 affects fibrocyte-induced BM fibrosis in MF. Multiplexed fluorescence immunohistochemistry analysis of MF patients' BM detected high levels of GLI1 in MF fibrocytes compared to MSCs or normal fibrocytes. Immunostaining, RNA in situ hybridization, gene expression analysis, and western immunoblotting detected high levels of GLI1 and GLI1-induced matrix metalloproteases …

Platelets Increase The Expression Of Pd-L1 In Ovarian Cancer, Min Soon Cho, Hani Lee, Ricardo Gonzalez-Delgado, Dan Li, Tomoyuki Sasano, Wendolyn Carlos-Alcalde, Qing Ma, Jinsong Liu, Anil K Sood, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

The interactions between platelets and cancer cells activate platelets and enhance tumor growth. Platelets increase proliferation and epithelial-mesenchymal transition in cancer cells, inhibit anoikis, enhance the extravasation of cancer cells, and protect circulating tumor cells against natural killer cells. Here, we have identified another mechanism by which platelets dampen the immune attack on cancer cells. We found that platelets can blunt the antitumor immune response by increasing the expression of inhibitory immune checkpoint (PD-L1) on ovarian cancer cells in vitro and in vivo. Platelets increased PD-L1 in cancer cells via contact-dependent (through NF-κB signaling) and contact-independent (through TFGβR1/Smad signaling) pathways. …

Genetic Origins Of Polycystic Ovarian Syndrome (Pcos): An Analysis Of The Genetic Correlation Between Pcos And Insulin Receptor Mutations, Lauren Henry

Undergraduate Theses

Polycystic Ovarian Syndrome (PCOS) remains an extremely common, yet understudied syndrome experienced by 6-12% of females of reproductive age. Not only does it cause painful side effects manifesting both physically and mentally, but it also poses a threat to the fertility of those affected. For this reason, a more in-depth analysis to better understand how to detect this condition early and prevent fertility complications later is certainly warranted. PCOS is suspected to be primarily genetic due to correlations among immediate female family members. Based on previous research, a good starting point for analysis is the INSR gene. Various mutations within …

Chronic Lymphocytic Leukemia Progression Diagnosis With Intrinsic Cellular Patterns Via Unsupervised Clustering, Pingjun Chen, Siba El Hussein, Fuyong Xing, Muhammad Aminu, Aparajith Kannapiran, John D Hazle, L Jeffrey Medeiros, Ignacio I Wistuba, David Jaffray, Joseph D Khoury, Jia Wu

Faculty, Staff and Student Publications

Identifying the progression of chronic lymphocytic leukemia (CLL) to accelerated CLL (aCLL) or transformation to diffuse large B-cell lymphoma (Richter transformation; RT) has significant clinical implications as it prompts a major change in patient management. However, the differentiation between these disease phases may be challenging in routine practice. Unsupervised learning has gained increased attention because of its substantial potential in data intrinsic pattern discovery. Here, we demonstrate that cellular feature engineering, identifying cellular phenotypes via unsupervised clustering, provides the most robust analytic performance in analyzing digitized pathology slides (accuracy = 0.925, AUC = 0.978) when compared to alternative approaches, such …

Rapid Acceleration Of Kras-Mutant Pancreatic Carcinogenesis Via Remodeling Of Tumor Immune Microenvironment By Pparδ, Yi Liu, Yasunori Deguchi, Daoyan Wei, Fuyao Liu, Micheline J Moussalli, Eriko Deguchi, Donghui Li, Huamin Wang, Lovie Ann Valentin, Jennifer K Colby, Jing Wang, Xiaofeng Zheng, Haoqiang Ying, Mihai Gagea, Baoan Ji, Jiaqi Shi, James C Yao, Xiangsheng Zuo, Imad Shureiqi

Faculty, Staff and Student Publications

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This …

Biliverdin Reductase Bridges Focal Adhesion Kinase To Src To Modulate Synaptic Signaling, Chirag Vasavda, Evan R Semenza, Jason Liew, Ruchita Kothari, Ryan S Dhindsa, Shruthi Shanmukha, Anthony Lin, Robert Tokhunts, Cristina Ricco, Adele M Snowman, Lauren Albacarys, Francesco Pastore, Cristian Ripoli, Claudio Grassi, Eugenio Barone, Michael D Kornberg, Xinzhong Dong, Bindu D Paul, Solomon H Snyder

Duncan NRI Faculty and Staff Publications

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity—the neuronal process of adapting to diverse and variable inputs—depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR-null (BVR−/−) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. …