Biomedical Informatics Commons^™

Signal Detection Of Adverse Events Associated With Trastuzumab In A Cohort Of Elderly Patients With Breast Cancer, Efstathia Polychronopoulou, Sharon H Giordano, Lin-Na Chou, Xiaoying Yu, Yong-Fang Kuo

Faculty, Staff and Student Publications

AIM: Utilization of signal detection methods in longitudinal claims data can improve post-marketing drug surveillance, but to date there has been limited application. The aim of this study is to use 3 approaches, the proportional reporting ratio, Gamma Poisson Shrinker, and tree-based scan statistic in detecting adverse drug events (ADEs) attributed to trastuzumab using an administrative claims dataset.

METHODS: Using data from the Texas Cancer Registry and SEER linked to Medicare from 2010 to 2013, we conducted 1:2 propensity score matching. Breast cancer HER2+ patients treated with trastuzumab in addition to standard chemotherapy were matched to HER2- patients treated with …

Targeting Il-1Β As An Immunopreventive And Therapeutic Modality For K-Ras-Mutant Lung Cancer, Bo Yuan, Michael J Clowers, Walter V Velasco, Stephen Peng, Qian Peng, Yewen Shi, Marco Ramos-Castaneda, Melody Zarghooni, Shuanying Yang, Rachel L Babcock, Seon Hee Chang, John V Heymach, Jianjun Zhang, Edwin J Ostrin, Stephanie S Watowich, Humam Kadara, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

K-ras-mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1β, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D-mutant tumors (CC-LR mice). Here, we blocked IL-1β using an anti-IL-1β mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype …

Malinc1 An Immune-Related Long Non-Coding Rna Associated With Early-Stage Breast Cancer Progression, María Laura Fabre, Romina Canzoneri, Agustina Gurruchaga, Jaeho Lee, Pradeep Tatineni, Hyunsuk Kil, Ezequiel Lacunza, C Marcelo Aldaz, Martín Carlos Abba

Faculty, Staff and Student Publications

Simple Summary

Here we characterize the phenotypic and molecular effects of MALINC1, a long non-coding RNA (lncRNA) that we found significantly upregulated in premalignant ductal carcinoma in-situ lesions. We provide evidence that MALINC1 behaves as an oncogenic and immune-related lncRNA involved with early-stage breast cancer progression, showing prognostic and predictive value to immunotherapy in invasive breast carcinomas.

Abstract

Long non-coding RNAs are increasingly being recognized as cancer biomarkers in various malignancies, acting as either tumor suppressors or oncogenes. The long non-coding MALINC1 intergenic RNA was identified as significantly upregulated in breast ductal carcinoma in situ. The aim of this …

Phosphorylation And Stabilization Of Pd-L1 By Ck2 Suppresses Dendritic Cell Function, Xixi Zhao, Yongkun Wei, Yu-Yi Chu, Yintao Li, Jung-Mao Hsu, Zhou Jiang, Chunxiao Liu, Jennifer L Hsu, Wei-Chao Chang, Riyao Yang, Li-Chuan Chan, Jingkun Qu, Shuqun Zhang, Haoqiang Ying, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

UNLABELLED: Targeting immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has transformed cancer treatment, with durable clinical responses across a wide range of tumor types. However, a high percentage of patients fail to respond to anti-PD-1/PD-L1 treatment. A greater understanding of PD-L1 regulation is critical to improving the clinical response rate of PD-1/PD-L1 blockade. Here, we demonstrate that PD-L1 is phosphorylated and stabilized by casein kinase 2 (CK2) in cancer and dendritic cells (DC). Phosphorylation of PD-L1 at Thr285 and Thr290 by CK2 disrupted PD-L1 binding with speckle-type POZ protein, an adaptor …

Structural Characterization Of Dicyanopyridine Containing Dnmt1-Selective, Non-Nucleoside Inhibitors, John R Horton, Sarath Pathuri, Kristen Wong, Ren Ren, Lourdes Rueda, David T Fosbenner, Dirk A Heerding, Michael T Mccabe, Melissa B Pappalardi, Xing Zhang, Bryan W King, Xiaodong Cheng

Faculty, Staff and Student Publications

DNMT1 maintains the parental DNA methylation pattern on newly replicated hemimethylated DNA. The failure of this maintenance process causes aberrant DNA methylation that affects transcription and contributes to the development and progression of cancers such as acute myeloid leukemia. Here, we structurally characterized a set of newly discovered DNMT1-selective, reversible, non-nucleoside inhibitors that bear a core 3,5-dicyanopyridine moiety, as exemplified by GSK3735967, to better understand their mechanism of inhibition. All of the dicyanopydridine-containing inhibitors examined intercalate into the hemimethylated DNA between two CpG base pairs through the DNA minor groove, resulting in conformational movement of the DNMT1 active-site loop. In …

Predictive Performance Of Different Ntcp Techniques For Radiation-Induced Esophagitis In Nsclc Patients Receiving Proton Radiotherapy, Mei Chen, Zeming Wang, Shengpeng Jiang, Jian Sun, Li Wang, Narayan Sahoo, G Brandon Gunn, Steven J Frank, Cheng Xu, Jiayi Chen, Quynh-Nhu Nguyen, Joe Y Chang, Zhongxing Liao, X Ronald Zhu, Xiaodong Zhang

Faculty, Staff and Student Publications

This study aimed to compare the predictive performance of different modeling methods in developing normal tissue complication probability (NTCP) models for predicting radiation-induced esophagitis (RE) in non-small cell lung cancer (NSCLC) patients receiving proton radiotherapy. The dataset was composed of 328 NSCLC patients receiving passive-scattering proton therapy and 41.6% of the patients experienced ≥ grade 2 RE. Five modeling methods were used to build NTCP models: standard Lyman-Kutcher-Burman (sLKB), generalized LKB (gLKB), multivariable logistic regression using two variable selection procedures-stepwise forward selection (Stepwise-MLR), and least absolute shrinkage and selection operator (LASSO-MLR), and support vector machines (SVM). Predictive performance was internally …

Precision Combination Therapies Based On Recurrent Oncogenic Coalterations, Xubin Li, Elisabeth K Dowling, Gonghong Yan, Zeynep Dereli, Behnaz Bozorgui, Parisa Imanirad, Jacob H Elnaggar, Augustin Luna, David G Menter, Patrick G Pilié, Timothy A Yap, Scott Kopetz, Chris Sander, Anil Korkut

Faculty, Staff and Student Publications

UNLABELLED: Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Here, we provide a comprehensive resource of precision combination therapies tailored to oncogenic coalterations that are recurrent across patient cohorts. To generate the resource, we developed Recurrent Features Leveraged for Combination Therapy (REFLECT), which integrates machine learning and cancer informatics algorithms. Using multiomic data, the method maps recurrent coalteration signatures in patient cohorts to combination therapies. We validated the REFLECT pipeline using data from patient-derived xenografts, in vitro drug screens, and a combination therapy clinical trial. These validations demonstrate that REFLECT-selected combination therapies …

Identification Of Functional Heterogeneity Of Carcinoma-Associated Fibroblasts With Distinct Il6-Mediated Therapy Resistance In Pancreatic Cancer, Kathleen M Mcandrews, Yang Chen, J Kebbeh Darpolor, Xiaofeng Zheng, Sujuan Yang, Julienne L Carstens, Bingrui Li, Huamin Wang, Toru Miyake, Pedro Correa De Sampaio, Michelle L Kirtley, Mariangela Natale, Chia-Chin Wu, Hikaru Sugimoto, Valerie S Lebleu, Raghu Kalluri

Faculty, Staff and Student Publications

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Employing single-cell RNA-sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAFs) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs that leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAFs) and tumor-restraining αSMA+ CAFs (TR-CAFs) differentially regulate cancer-associated pathways and accumulation of Tregs. Improved efficacy of gemcitabine is observed when IL-6 is deleted from αSMA+ CAFs …

Pathological Response And Immune Biomarker Assessment In Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors, Frank Rojas, Edwin Roger Parra, Ignacio Ivan Wistuba, Cara Haymaker, Luisa Maren Solis Soto

Faculty, Staff and Student Publications

Lung cancer is the leading cause of cancer incidence and mortality worldwide. Adjuvant and neoadjuvant chemotherapy have been used in the perioperative setting of non-small-cell carcinoma (NSCLC); however, the five-year survival rate only improves by about 5%. Neoadjuvant treatment with immune checkpoint inhibitors (ICIs) has become significant due to improved survival in advanced NSCLC patients treated with immunotherapy agents. The assessment of pathology response has been proposed as a surrogate indicator of the benefits of neaodjuvant therapy. An outline of recommendations has been published by the International Association for the Study of Lung Cancer (IASLC) for the evaluation of pathologic …

External Validation Of A Laboratory Prediction Algorithm For The Reduction Of Unnecessary Labs In The Critical Care Setting, Linda T Li, Tongtong Huang, Elmer V Bernstam, Xiaoqian Jiang

Faculty, Staff and Student Publications

BACKGROUND: Unnecessary laboratory tests contribute to iatrogenic harm and are a major source of waste in the health care system. We previously developed a machine learning algorithm to help clinicians identify unnecessary laboratory tests, but it has not been externally validated. In this study, we externally validate our machine learning algorithm.

METHODS: To externally validate the machine learning algorithm that was originally trained on the Medical Information Mart for Intensive Care (MIMIC) III database, we tested the algorithm in a separate institution. We identified and abstracted data for all patients older than 18 years admitted to the intensive care unit …

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 …

Grief Symptoms Promote Inflammation During Acute Stress Among Bereaved Spouses, Ryan L Brown, Angie S Leroy, Michelle A Chen, Robert Suchting, Lisa M Jaremka, Jia Liu, Cobi Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

The death of a spouse is associated with maladaptive immune alterations; grief severity may exacerbate this link. We investigated whether high grief symptoms were associated with an amplified inflammatory response to subsequent stress among 111 recently bereaved older adults. Participants completed a standardized psychological stressor and underwent a blood draw before, 45 min after, and 2 hr after the stressor. Those experiencing high grief symptoms (i.e., scoring > 25 on the Inventory of Complicated Grief) experienced a 45% increase in interleukin-6 (IL-6; a proinflammatory cytokine) per hour, whereas those experiencing low grief symptoms demonstrated a 26% increase. In other words, high …

Experimental Models Of Undifferentiated Pleomorphic Sarcoma And Malignant Peripheral Nerve Sheath Tumor, Angela D Bhalla, Sharon M Landers, Anand K Singh, Jace P Landry, Michelle G Yeagley, Gabryella S B Myerson, Cristian B Delgado-Baez, Stephanie Dunnand, Theresa Nguyen, Xiaoyan Ma, Svetlana Bolshakov, Brian A Menegaz, Salah-Eddine Lamhamedi-Cherradi, Xizeng Mao, Xingzhi Song, Alexander J Lazar, Ian E Mccutcheon, John M Slopis, Joseph A Ludwig, Dina C Lev, Kunal Rai, Keila E Torres

Faculty, Staff and Student Publications

Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models available, we generated additional cell lines to study these rare cancers. Patient-derived tumors were used to establish 4 new UPS models, including one radiation-associated UPS-UPS271.1, UPS511, UPS0103, and RIS620, one unclassified spindle cell sarcoma-USC060.1, and 3 new models of …

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 …

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 …

A First-In-Human Phase I Trial Of The Oral P-Stat3 Inhibitor Wp1066 In Patients With Recurrent Malignant Glioma, John De Groot, Martina Ott, Jun Wei, Cynthia Kassab, Dexing Fang, Hinda Najem, Barbara O'Brien, Shiao-Pei Weathers, Carlos Kamiya Matsouka, Nazanin K Majd, Rebecca A Harrison, Gregory N Fuller, Jason T Huse, James P Long, Raymond Sawaya, Ganesh Rao, Tobey J Macdonald, Waldemar Priebe, Michael Decuypere, Amy B Heimberger

Faculty, Staff and Student Publications

No abstract provided.

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 …

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 …

Long-Term Outcomes Among Adolescent And Young Adult Survivors Of Acute Leukemia: A Surveillance, Epidemiology, And End Results Analysis, Amy M Berkman, Clark R Andersen, Branko Cuglievan, David C Mccall, Philip J Lupo, Susan K Parsons, Courtney D Dinardo, Nicholas J Short, Nitin Jain, Tapan M Kadia, J A Livingston, Michael E Roth

Faculty, Staff and Student Publications

Background: There is a growing population of adolescent and young adult (AYA, age 15-39 years) acute leukemia survivors in whom long-term mortality outcomes are largely unknown.

Methods: The current study utilized the Surveillance, Epidemiology, and End Results (SEER) registry to assess long-term outcomes of AYA acute leukemia 5-year survivors. The impact of diagnosis age, sex, race/ethnicity, socioeconomic status, and decade of diagnosis on long-term survival were assessed utilizing an accelerated failure time model.

Results: A total of 1,938 AYA acute lymphoblastic leukemia (ALL) and 2,350 AYA acute myeloid leukemia (AML) survivors diagnosed between 1980 and 2009 were included with a …

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 …

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 …

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 …

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 …

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 …

Axl/Mertk Inhibitor Ono-7475 Potently Synergizes With Venetoclax And Overcomes Venetoclax Resistance To Kill F Lt 3-Itd Acute Myeloid Leukemia, Sean M Post, Huaxian Ma, Prerna Malaney, Xiaorui Zhang, Marisa J L Aitken, Po Yee Mak, Vivian R Ruvolo, Tomoko Yasuhiro, Ryohei Kozaki, Lauren E Chan, Lauren B Ostermann, Marina Konopleva, Bing Z Carter, Courtney Dinardo, Michael D Andreeff, Joseph D Khoury, Peter P Ruvolo

Faculty, Staff and Student Publications

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that …

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 …

The Life Cycle Of Polyploid Giant Cancer Cells And Dormancy In Cancer: Opportunities For Novel Therapeutic Interventions, Jinsong Liu, Na Niu, Xiaoran Li, Xudong Zhang, Anil K Sood

Faculty, Staff and Student Publications

Recent data suggest that most genotoxic agents in cancer therapy can lead to shock of genome and increase in cell size, which leads whole genome duplication or multiplication, formation of polyploid giant cancer cells, activation of an early embryonic program, and dedifferentiation of somatic cells. This process is achieved via the giant cell life cycle, a recently proposed mechanism for malignant transformation of somatic cells. Increase in both cell size and ploidy allows cells to completely or partially restructures the genome and develop into a blastocyst-like structure, similar to that observed in blastomere-stage embryogenesis. Although blastocyst-like structures with reprogrammed genome …