Medical Sciences Commons^™

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 …

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 …

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 …

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 …

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 …

Histone Chaperone Asf1 Acts With Rif1 To Promote Dna End Joining In Brca1-Deficient Cells, Mengfan Tang, Zhen Chen, Chao Wang, Xu Feng, Namsoo Lee, Min Huang, Huimin Zhang, Siting Li, Yun Xiong, Junjie Chen

Faculty, Staff and Student Publications

Replication timing regulatory factor 1 (RIF1) acts downstream of p53-binding protein 53BP1 to inhibit the resection of DNA broken ends, which plays critical roles in determining the DNA double-strand break repair pathway choice between nonhomologous end joining and homologous recombination (HR). However, the mechanism by which this choice is made is not yet clear. In this study, we identified that histone chaperone protein ASF1 associates with RIF1 and regulates RIF1-dependent functions in the DNA damage response. Similar to loss of RIF1, we found that loss of ASF1 resulted in resistance to poly (ADP-ribose) polymerase (PARP) inhibition in BRCA1-deficient cells with …

A Phase 1 Trial Of 8-Chloro-Adenosine In Relapsed/Refractory Acute Myeloid Leukemia: An Evaluation Of Safety And Pharmacokinetics, Rong Chen, Yuling Chen, Ping Xiong, Daniella Zheleva, David Blake, Michael J Keating, William G Wierda, William Plunkett

Faculty, Staff and Student Publications

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and …

Atf4/Txnip/Redd1/Mtor Signaling Mediates The Antitumor Activities Of Liver X Receptor In Pancreatic Cancers, Zhikang Chen, Xiaobo Lai, Hui Ding, Aijun Zhang, Yufei Sun, Jianhua Ling, Paul J Chiao, Zihua Chen, Xuefeng Xia

Faculty, Staff and Student Publications

Background: Limited by difficulties in early detection and availabilities of effective treatments, pancreatic cancer is a highly malignant disease with poor prognosis. Nuclear receptors are a family of ligand-dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development, including cancer. In this study, we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor (LXR) agonist GW3965 in pancreatic cancer.

Methods: Soft-agar colony formation assay, xenograft tumors, Oligonucleotide microarray, Reverse transcription real-time polymerase chain reaction, Western immunoblotting and Immunohistochemistry were used in this study.

Results: We demonstrated pleotropic …

Factors Impacting Adolescent And Young Adult Cancer Patients’ Decision To Pursue Genetic Counseling And Testing, Megan Morand, Michael Roth, Susan K Peterson, Erica M Bednar, Aarti Ramdaney, J Andrew Livingston, Angela Yarbrough, Jessica Corredor

Faculty, Staff and Student Publications

Purpose: Adolescent and young adult (AYA) cancer patients face challenges when navigating cancer treatment and survivorship. Many are at risk for cancer predisposition syndromes; however, factors influencing pursuit of genetic counseling and testing have not been reported. We describe AYA cancer patients' decision-making process, including motivational factors and barriers, as it relates to utilization of genetic services.

Methods: Thirty AYAs diagnosed with cancer previously referred for cancer predisposition genetic counseling completed semi-structured interviews via audio-only Zoom calls. Thematic analysis was used to perform qualitative analysis and identify major themes.

Results: The sample comprised 21 AYAs who had genetic counseling and …

Obif: An Omics-Based Interaction Framework To Reveal Molecular Drivers Of Synergy, Jezreel Pantaleón García, Vikram V Kulkarni, Tanner C Reese, Shradha Wali, Saima J Wase, Jiexin Zhang, Ratnakar Singh, Mauricio S Caetano, Humam Kadara, Seyed Javad Moghaddam, Faye M Johnson, Jing Wang, Yongxing Wang, Scott E Evans

Faculty, Staff and Student Publications

Bioactive molecule library screening may empirically identify effective combination therapies, but molecular mechanisms underlying favorable drug-drug interactions often remain unclear, precluding further rational design. In the absence of an accepted systems theory to interrogate synergistic responses, we introduce Omics-Based Interaction Framework (OBIF) to reveal molecular drivers of synergy through integration of statistical and biological interactions in synergistic biological responses. OBIF performs full factorial analysis of feature expression data from single versus dual exposures to identify molecular clusters that reveal synergy-mediating pathways, functions and regulators. As a practical demonstration, OBIF analyzed transcriptomic and proteomic data of a dyad of immunostimulatory molecules …

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 …

Comprehensive Quantitative Evaluation Of Variability In Magnetic Resonance-Guided Delineation Of Oropharyngeal Gross Tumor Volumes And High-Risk Clinical Target Volumes: An R-Ideal Stage 0 Prospective Study, Carlos E Cardenas, Sanne E Blinde, Abdallah S R Mohamed, Sweet Ping Ng, Cornelis Raaijmakers, Marielle Philippens, Alexis Kotte, Abrahim A Al-Mamgani, Irene Karam, David J Thomson, Jared Robbins, Kate Newbold, Clifton D Fuller, Chris Terhaard

Faculty, Staff and Student Publications

Purpose: Tumor and target volume manual delineation remains a challenging task in head and neck cancer radiation therapy. The purpose of this study was to conduct a multi-institutional evaluation of manual delineations of gross tumor volume (GTV), high-risk clinical target volume (CTV), parotids, and submandibular glands on treatment simulation magnetic resonance scans of patients with oropharyngeal cancer.

Methods and materials: We retrospectively collected pretreatment T1-weighted, T1-weighted with gadolinium contrast, and T2-weighted magnetic resonance imaging scans for 4 patients with oropharyngeal cancer under an institution review board-approved protocol. We provided the scans to 26 radiation oncologists from 7 international cancer centers …

Maximal Activation Of Apoptosis Signaling By Cotargeting Antiapoptotic Proteins In Bh3 Mimetic-Resistant Aml And Aml Stem Cells, Bing Z Carter, Po Yee Mak, Wenjing Tao, Qi Zhang, Vivian Ruvolo, Vinitha M Kuruvilla, Xiangmeng Wang, Duncan H Mak, Venkata L Battula, Marina Konopleva, Elias J Jabbour, Paul E Hughes, Xiaoyue Chen, Phuong K Morrow, Michael Andreeff

Faculty, Staff and Student Publications

MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Cotargeting BCL-2 and MCL-1 was highly synergistic in AML cell lines …

Androgen Receptor Blockade Promotes Response To Braf/Mek-Targeted Therapy, Christopher P Vellano, Michael G White, Miles C Andrews, Manoj Chelvanambi, Russell G Witt, Joseph R Daniele, Mark Titus, Jennifer L Mcquade, Fabio Conforti, Elizabeth M Burton, Matthew J Lastrapes, Gabriel Ologun, Alexandria P Cogdill, Golnaz Morad, Peter Prieto, Alexander J Lazar, Yanshuo Chu, Guangchun Han, M A Wadud Khan, Beth Helmink, Michael A Davies, Rodabe N Amaria, Jeffrey J Kovacs, Scott E Woodman, Sapna Patel, Patrick Hwu, Michael Peoples, Jeffrey E Lee, Zachary A Cooper, Haifeng Zhu, Guang Gao, Hiya Banerjee, Mike Lau, Jeffrey E Gershenwald, Anthony Lucci, Emily Z Keung, Merrick I Ross, Laura Pala, Eleonora Pagan, Rossana Lazcano Segura, Qian Liu, Mikayla S Borthwick, Eric Lau, Melinda S Yates, Shannon N Westin, Khalida Wani, Michael T Tetzlaff, Lauren E Haydu, Mikhila Mahendra, Xiaoyan Ma, Christopher Logothetis, Zachary Kulstad, Sarah Johnson, Courtney W Hudgens, Ningping Feng, Lorenzo Federico, Georgina V Long, P Andrew Futreal, Swathi Arur, Hussein A Tawbi, Amy E Moran, Linghua Wang, Timothy P Heffernan, Joseph R Marszalek, Jennifer A Wargo

Faculty, Staff and Student Publications

Treatment with BRAF/MEK-targeted therapy has revolutionized care in melanoma and other cancers, however therapeutic resistance is common and innovative treatment strategies are needed1,2. We studied a group of melanoma patients treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51), and observed significantly higher rates of major pathologic response (MPR= <10% viable tumor at resection) and improved recurrence-free survival (RFS) in females versus males (MPR-66% versus 14%, p=0.001; RFS-64% versus 32% at 2 years, p=0.021). Findings were validated in a several additional cohorts2–4 patients with unresectable metastatic melanoma treated with BRAF and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival (PFS) and overall survival (OS) in females versus males in several of these studies. Studies in pre-clinical models demonstrated significantly impaired anti-tumor activity in male …

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 …

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 …

Comprehensive Characterization Of Tumor Immune Landscape Following Oncolytic Virotherapy By Single-Cell Rna Sequencing, Divya Ravirala, Guangsheng Pei, Zhongming Zhao, Xiaoliu Zhang

Faculty, Staff and Student Publications

An important mechanism of oncolytic virotherapy in ameliorating cancer immunotherapy is by inducing significant changes in the immune landscape in the tumor microenvironment (TME). Despite this notion and the potential therapeutic implications, a comprehensive analysis of the immune changes in carcinomas induced by virotherapy has not yet been elucidated. We conducted single-cell RNA sequencing analysis on carcinomas treated with an HSV-2-based oncolytic virus to characterize the immunogenic changes in the TME. We specifically analyzed and compared the immune cell composition between viral treated and untreated tumors. We also applied CellChat to analyze the complex interactions among the infiltrated immune cells. …

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 …

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 …

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 …

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 …

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 …

A Crosstalk Between Gut And Brain In Sepsis-Induced Cognitive Decline\, Vijayasree V Giridharan, Jaqueline S Generoso, Leonardo Lence, Gabriela Candiotto, Emílio Streck, Fabricia Petronilho, Anilkumar Pillai, Tarek Sharshar, Felipe Dal-Pizzol, Tatiana Barichello

Faculty, Staff and Student Publications

BACKGROUND: Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota-gut-brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors.

METHODS: To test our hypothesis, adult Wistar rats were subjected to cecal-ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [

RESULTS: Compared to the control …

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 …

Dedifferentiation-Mediated Stem Cell Niche Maintenance In Early-Stage Ductal Carcinoma In Situ Progression: Insights From A Multiscale Modeling Study, Joseph D Butner, Prashant Dogra, Caroline Chung, Javier Ruiz-Ramírez, Sara Nizzero, Marija Plodinec, Xiaoxian Li, Ping-Ying Pan, Shu-Hsia Chen, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is …

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 …

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 …

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 …

Pirtobrutinib Inhibits Wild-Type And Mutant Bruton’S Tyrosine Kinase-Mediated Signaling In Chronic Lymphocytic Leukemia, Burcu Aslan, Gorkem Kismali, Lakesla R Iles, Ganiraju C Manyam, Mary L Ayres, Lisa S Chen, Mihai Gagea, Maria Teresa Sabrina Bertilaccio, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Pirtobrutinib (LOXO-305), a reversible inhibitor of Bruton's tyrosine kinase (BTK), was designed as an alternative strategy to treat ibrutinib-resistant disease that develops due to C481 kinase domain mutations. The clinical activity of pirtobrutinib has been demonstrated in CLL, but the mechanism of action has not been investigated. We evaluated pirtobrutinib in 4 model systems: first, MEC-1, a CLL cell line overexpressing BTKWT, BTKC481S, or BTKC481R; second, murine models driven by MEC-1 overexpressing BTKWT or BTKC481S; third, in vitro incubations of primary CLL cells; and finally, CLL patients during pirtobrutinib therapy (NCT03740529, ClinicalTrials.gov). Pirtobrutinib inhibited BTK activation as well …