Medicine and Health Sciences Commons^™

Kras G12c Inhibitor Combination Therapies: Current Evidence And Challenge, Hirotaka Miyashita, Shumei Kato, David S Hong

Faculty, Staff and Student Publications

Although KRAS G12C inhibitors have proven that KRAS is a "druggable" target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical …

Aspiring Toward Equitable Benefits From Genomic Advances To Individuals Of Ancestrally Diverse Backgrounds, Ying Wang, Yixuan He, Yue Shi, David C Qian, Kathryn J Gray, Robert Winn, Alicia R Martin

Faculty, Staff and Student Publications

Advancements in genomic technologies have shown remarkable promise for improving health trajectories. The Human Genome Project has catalyzed the integration of genomic tools into clinical practice, such as disease risk assessment, prenatal testing and reproductive genomics, cancer diagnostics and prognostication, and therapeutic decision making. Despite the promise of genomic technologies, their full potential remains untapped without including individuals of diverse ancestries and integrating social determinants of health (SDOHs). The NHGRI launched the 2020 Strategic Vision with ten bold predictions by 2030, including "individuals from ancestrally diverse backgrounds will benefit equitably from advances in human genomics." Meeting this goal requires a …

Tsyn-Seq: A T-Cell Synapse-Based Antigen Identification Platform, Yimei Jin, Takahiko Miyama, Alexandria Brown, Tomo Hayase, Xingzhi Song, Anand K Singh, Licai Huang, Ivonne I Flores, Lauren K Mcdaniel, Israel Glover, Taylor M Halsey, Rishika Prasad, Valerie Chapa, Saira Ahmed, Jianhua Zhang, Kunal Rai, Christine B Peterson, Gregory Lizee, Jennifer Karmouch, Eiko Hayase, Jeffrey J Molldrem, Chia-Chi Chang, Wen-Bin Tsai, Robert R Jenq

Faculty, Staff and Student Publications

Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen …

Fam86a Methylation Of Eef2 Links Mrna Translation Elongation To Tumorigenesis, Joel William Francis, Simone Hausmann, Sabeen Ikram, Kunlun Yin, Robert Mealey-Farr, Natasha Mahealani Flores, Annie Truc Trinh, Tourkian Chasan, Julia Thompson, Pawel Karol Mazur, Or Gozani

Faculty, Staff and Student Publications

eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression …

Mdm2 Inhibitors For Cancer Therapy: The Past, Present, And Future, Wei Wang, Najah Albadari, Yi Du, Josef F Fowler, Hannah T Sang, Wa Xian, Frank Mckeon, Wei Li, Jia Zhou, Ruiwen Zhang

Faculty, Staff and Student Publications

Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are …

Community-Acquired Pneumonia: A Us Perspective On The Guideline Gap, Maricar Malinis, Lilian Abbo, Jose A Vazquez, Luis Ostrosky-Zeichner

Faculty, Staff and Student Publications

Community-acquired pneumonia continues to be one of the most common causes of morbidity and mortality due to infectious disease. The aetiologies, clinical presentations, diagnostic modalities and therapeutic options are changing and outpacing the creation of management guidelines. This educational article summarizes a roundtable activity sponsored by an unrestricted educational grant by Paratek that included US experts discussing these changes and identifying gaps in the current guidelines.

Examining The Association Between Abstinence From Smoking And Healthcare Costs Among Patients With Cancer, George Kypriotakis, Seokhun Kim, Maher Karam-Hage, Jason D Robinson, Jennifer A Minnix, Janice A Blalock, Yong Cui, Diane Beneventi, Bumyang Kim, I-Wen Pan, Ya-Chen Tina Shih, Paul M Cinciripini

Faculty, Staff and Student Publications

Continuous tobacco use in cancer patients is linked to substantial healthcare costs due to increased risks and complications, whereas quitting smoking leads to improved treatment outcomes and cost reductions. Addressing the need for empirical evidence on the economic impact of smoking cessation, this study examined the association between smoking cessation and healthcare cost utilization among a sample of 930 cancer patients treated at The University of Texas MD Anderson Cancer Center’s Tobacco Research and Treatment Program (TRTP). Applying conditional quantile regression and propensity scores to address confounding, our findings revealed that abstinence achieved through the TRTP significantly reduced the median …

Response Of Treatment-Naive Brain Metastases To Stereotactic Radiosurgery, Chibawanye I Ene, Christina Abi Faraj, Thomas H Beckham, Jeffrey S Weinberg, Clark R Andersen, Ali S Haider, Ganesh Rao, Sherise D Ferguson, Christopher A Alvarez-Brenkenridge, Betty Y S Kim, Amy B Heimberger, Ian E Mccutcheon, Sujit S Prabhu, Chenyang Michael Wang, Amol J Ghia, Susan L Mcgovern, Caroline Chung, Mary Frances Mcaleer, Martin C Tom, Subha Perni, Todd A Swanson, Debra N Yeboa, Tina M Briere, Jason T Huse, Gregory N Fuller, Frederick F Lang, Jing Li, Dima Suki, Raymond E Sawaya

Faculty, Staff and Student Publications

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) …

A Genetic Association Study Of Circulating Coagulation Factor Viii And Von Willebrand Factor Levels, Paul S De Vries, Paula Reventun, Michael R Brown, Adam S Heath, Jennifer E Huffman, Ngoc-Quynh Le, Allison Bebo, Jennifer A Brody, Gerard Temprano-Sagrera, Laura M Raffield, Ayse Bilge Ozel, Florian Thibord, Deepti Jain, Joshua P Lewis, Benjamin A T Rodriguez, Nathan Pankratz, Kent D Taylor, Ozren Polasek, Ming-Huei Chen, Lisa R Yanek, German D Carrasquilla, Riccardo E Marioni, Marcus E Kleber, David-Alexandre Trégouët, Jie Yao, Ruifang Li-Gao, Peter K Joshi, Stella Trompet, Angel Martinez-Perez, Mohsen Ghanbari, Tom E Howard, Alex P Reiner, Marios Arvanitis, Kathleen A Ryan, Traci M Bartz, Igor Rudan, Nauder Faraday, Allan Linneberg, Lynette Ekunwe, Gail Davies, Graciela E Delgado, Pierre Suchon, Xiuqing Guo, Frits R Rosendaal, Lucija Klaric, Raymond Noordam, Frank Van Rooij, Joanne E Curran, Marsha M Wheeler, William O Osburn, Jeffrey R O'Connell, Eric Boerwinkle, Andrew Beswick, Bruce M Psaty, Ivana Kolcic, Juan Carlos Souto, Lewis C Becker, Torben Hansen, Margaret F Doyle, Sarah E Harris, Angela P Moissl, Jean-François Deleuze, Stephen S Rich, Astrid Van Hylckama Vlieg, Harry Campbell, David J Stott, Jose Manuel Soria, Moniek P M De Maat, Laura Almasy, Lawrence C Brody, Paul L Auer, Braxton D Mitchell, Yoav Ben-Shlomo, Myriam Fornage, Caroline Hayward, Rasika A Mathias, Tuomas O Kilpeläinen, Leslie A Lange, Simon R Cox, Winfried März, Pierre-Emmanuel Morange, Jerome I Rotter, Dennis O Mook-Kanamori, James F Wilson, Pim Van Der Harst, J Wouter Jukema, M Arfan Ikram, John Blangero, Charles Kooperberg, Karl C Desch, Andrew D Johnson, Maria Sabater-Lleal, Charles J Lowenstein, Nicholas L Smith, Alanna C Morrison

Faculty, Staff and Student Publications

Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was …

Comparable Cigarette Consumption Data Collected Using Timeline Follow-Back And Digital Diary Among Treatment-Seeking Smokers, Yong Cui, Jason D Robinson, George Kypriotakis, Jennifer A Minnix, Charles E Green, Seokhun Kim, Maher Karam-Hage, Paul M Cinciripini

Faculty, Staff and Student Publications

Objective: The timeline follow-back interview is a common method of collecting daily cigarette consumption (cigarettes per day [CPD]) in smoking research. However, it may be subject to recall bias due to its reliance on retrospective reports. The increasing ownership of smartphones allows researchers to administer app-based digital diaries (DD) to collect CPD, which is expected to have less recall bias. Several studies have compared these two methods and found a noticeable discrepancy between them. However, these studies have mainly focused on the time window when smokers were smoking ad libitum. In this study, we wanted to determine the comparability of …

Ectopic Pregnancy Located At Pelvic Wall And Liver: Two Uncommon Case Reports From Vietnam And Mini-Review Literature, Thanh Hai Pham, Van Hoang Bui, Van Hung Nguyen, Phuc Nhon Nguyen

Faculty, Staff and Student Publications

INTRODUCTION AND IMPORTANCE: Abdominal ectopic pregnancy (AEP) located at hepatic region and pelvic-wall ectopic pregnancy (EP) are rare entities, that provoking a potentially life-threatening condition. Due to insufficient data, a proper management of non-specific types remains a challenge for all gynecologists worldwide.

CASE PRESENTATION: Two child-bearing age women were hospitalized due to delayed menstruation and a urine pregnancy test was positive without a determination of intrauterine pregnancy. The first EP case was located at the pelvic wall which identified incidentally during laparoscopy for a presumed tubal ectopic pregnancy on ultrasonography throughout. The second EP case was found at the hepatic …

Fatty Acid Concentrations In Preterm Infants Fed The Exclusive Human Milk Diet: A Prospective Cohort Study, Lindsay F Holzapfel, Jana P Unger, Pam Gordon, Heeju Yang, Joanne E Cluette-Brown, Laura A Gollins, Amy B Hair, Camilia R Martin

Faculty, Staff and Student Publications

OBJECTIVE: Quantify blood fatty acids and growth outcomes in preterm infants fed the exclusive human milk diet.

METHODS: A prospective cohort study of 30 infants 24-34 weeks gestation and ≤1250 g fed the exclusive human milk diet. Blood fatty acids were quantified at two time points. Comparisons were made using two-sample t-tests and Wilcoxon rank sum.

RESULTS: Donor human milk-fed (n = 12) compared to mother's own milk-fed infants (n = 18) from birth to after 28 days of life, had an increased interval change of linoleic to docosahexaenoic acid ratio (5.5 vs. -1.1 mole percent ratio, p = 0.034). …

Association Of Maternal Body Mass Index And Maternal Morbidity And Mortality, Mara J Dinsmoor, Lynda G Ugwu, Jennifer L Bailit, Uma M Reddy, Ronald J Wapner, Michael W Varner, John M Thorp, Steve N Caritis, Mona Prasad, Alan T N Tita, George R Saade, Yoram Sorokin, Dwight J Rouse, Sean C Blackwell, Jorge E Tolosa

Faculty, Staff and Student Publications

Objective: This study aimed to assess the association of maternal body mass index (BMI) with a composite of severe maternal outcomes.

Study design: Secondary analysis of a cohort of deliveries on randomly selected days at 25 hospitals from 2008 to 2011. Data on comorbid conditions, intrapartum events, and postpartum course were collected. The reference group (REF, BMI: 18.5-29.9kg/m2), obese (OB; BMI: 30-39.9kg/m2), morbidly obese (MO; BMI: 40-49.9kg/m2), and super morbidly obese (SMO; BMI ≥ 50kg/m2) women were compared. The composite of severe maternal outcomes was defined as death, intensive care unit (ICU) admission, ventilator use, deep venous thrombosis/pulmonary embolus (DVT/PE), …

Age At Lung Cancer Diagnosis In Females Versus Males Who Never Smoke By Race And Ethnicity, Batel Blechter, Jason Y Y Wong, Li-Hsin Chien, Kouya Shiraishi, Xiao-Ou Shu, Qiuyin Cai, Wei Zheng, Bu-Tian Ji, Wei Hu, Mohammad L Rahman, Hsin-Fang Jiang, Fang-Yu Tsai, Wen-Yi Huang, Yu-Tang Gao, Xijing Han, Mark D Steinwandel, Gong Yang, Yihe G Daida, Su-Ying Liang, Scarlett L Gomez, Mindy C Derouen, W Ryan Diver, Ananya G Reddy, Alpa V Patel, Loïc Le Marchand, Christopher Haiman, Takashi Kohno, Iona Cheng, I-Shou Chang, Chao Agnes Hsiung, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke.

METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes.

RESULTS: We found that among Chinese individuals diagnosed with lung cancer …

Retention, Adherence, And Acceptability Testing Of A Digital Health Intervention In A 3-Group Randomized Controlled Trial For Chronic Musculoskeletal Pain, Jennifer Kawi, Chao Hsing Yeh, Lauren Grant, Xinran Huang, Hulin Wu, Chunyan Hua, Paul Christo

Faculty, Staff and Student Publications

OBJECTIVES: Evaluate a digital health intervention using Auricular Point Acupressure (APA) for chronic musculoskeletal pain in terms of participant retention, adherence, acceptability, and satisfaction. Chronic musculoskeletal pain is a global concern and there are persistent challenges in pain management. Despite the value of digital health interventions, these interventions need to be fully evaluated for feasibility.

METHODS: We conducted a 3-group, longitudinal, randomized controlled trial (RCT). After Institutional Review Board approval, we posted recruitment flyers in a university, healthcare clinics, and community settings. Participants were randomized into an in-person + app group (n = 8), virtual + app group (n = …

Development And Validation Of A Rule-Based Algorithm To Identify Periodontal Diagnosis Using Structured Electronic Health Record Data, Bunmi Tokede, Ryan Brandon, Chun-Teh Lee, Guo-Hao Lin, Joel White, Alfa Yansane, Xiaoqian Jiang, Elsbeth Kalenderian, Muhammad Walji

Faculty, Staff and Student Publications

AIM: To develop and validate an automated electronic health record (EHR)-based algorithm to suggest a periodontal diagnosis based on the 2017 World Workshop on the Classification of Periodontal Diseases and Conditions.

MATERIALS AND METHODS: Using material published from the 2017 World Workshop, a tool was iteratively developed to suggest a periodontal diagnosis based on clinical data within the EHR. Pertinent clinical data included clinical attachment level (CAL), gingival margin to cemento-enamel junction distance, probing depth, furcation involvement (if present) and mobility. Chart reviews were conducted to confirm the algorithm's ability to accurately extract clinical data from the EHR, and then …

The Constitutively Active Form Of A Key Cholesterol Synthesis Enzyme Is Lipid Droplet-Localized And Upregulated In Endometrial Cancer Tissues, Hudson W Coates, Tina B Nguyen, Ximing Du, Ellen M Olzomer, Rhonda Farrell, Frances L Byrne, Hongyuan Yang, Andrew J Brown

Faculty, Staff and Student Publications

Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we …

Profiling The Activity Of The Para-Caspase Malt1 In B-Cell Acute Lymphoblastic Leukemia For Potential Targeted Therapeutic Application, Firas M Safa, Terri Rasmussen, Lorena Fontan, Min Xia, Ari Melnick, Adrian Wiestner, Patricia Lobelle-Rich, Jan A Burger, Yara Mouawad, Hana Safah, Erik K Flemington, Nakhle S Saba

Faculty, Staff and Student Publications

B-cell acute lymphoblastic leukemia (B-ALL) remains a hard-to-treat disease with a poor prognosis in adults. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a para-caspase required for B-cell receptor (BCR)-mediated NF-κB activation. Inhibition of MALT1 in preclinical models has proven efficacious in many B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B-cell lymphoma. We sought to examine the role of MALT1 in B-ALL and determine the biological consequences of its inhibition. Targeting MALT1 with both Z-VRPR-fmk and MI-2 efficiently kills B-ALL cells independent of the cell-of-origin (pro, pre, mature) or the presence of the Philadelphia …

Dlk-Mapk Signaling Coupled With Dna Damage Promotes Intrinsic Neurotoxicity Associated With Non-Mutated Tau, Sanming Li, Ethan R Roy, Yanyu Wang, Trent Watkins, Wei Cao

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine …

Neoadjuvant Chemoimmunotherapy For Nsclc: A Systematic Review And Meta-Analysis, Mark Sorin, Connor Prosty, Louis Ghaleb, Kathy Nie, Khaled Katergi, Muhammad H Shahzad, Laurie-Rose Dubé, Aline Atallah, Anikka Swaby, Matthew Dankner, Trafford Crump, Logan A Walsh, Pierre O Fiset, Boris Sepesi, Patrick M Forde, Tina Cascone, Mariano Provencio, Jonathan D Spicer

Faculty, Staff and Student Publications

IMPORTANCE: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%.

OBJECTIVE: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials.

DATA SOURCES: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of …

Natural Language Processing Of Clinical Notes Enables Early Inborn Error Of Immunity Risk Ascertainment, Kirk Roberts, Aaron T Chin, Klaus Loewy, Lisa Pompeii, Harold Shin, Nicholas L Rider

Faculty, Staff and Student Publications

BACKGROUND: There are now approximately 450 discrete inborn errors of immunity (IEI) described; however, diagnostic rates remain suboptimal. Use of structured health record data has proven useful for patient detection but may be augmented by natural language processing (NLP). Here we present a machine learning model that can distinguish patients from controls significantly in advance of ultimate diagnosis date.

OBJECTIVE: We sought to create an NLP machine learning algorithm that could identify IEI patients early during the disease course and shorten the diagnostic odyssey.

METHODS: Our approach involved extracting a large corpus of IEI patient clinical-note text from a major …

Improvements In Appropriate Placement Of Dental Sealants After Implementation Of A Clinical Decision Support System, Joanna Mullins, Ryan Brandon, Nicholas Skourtes, Elsbeth Kalenderian, Muhammad Walji

Faculty, Staff and Student Publications

BACKGROUND: Dental sealants are effective for the prevention of caries in children at elevated risk levels, and increasing the proportion of children and adolescents who have dental sealants on 1 or more molars is a Healthy People 2030 objective. Electronic health record (EHR)-based clinical decision support systems (CDSSs) have the ability to improve patient care. A dental quality measure related to dental sealant placement for children at elevated risk of caries was targeted for improvement using a CDSS.

METHODS: A validated dental quality measure was adapted to assess a patient's need for dental sealant placement. A CDSS was implemented to …

The Intrinsic Substrate Specificity Of The Human Tyrosine Kinome, Tomer M Yaron-Barir, Brian A Joughin, Emily M Huntsman, Alexander Kerelsky, Daniel M Cizin, Benjamin M Cohen, Amit Regev, Junho Song, Neil Vasan, Ting-Yu Lin, Jose M Orozco, Christina Schoenherr, Cari Sagum, Mark T Bedford, R Max Wynn, Shih-Chia Tso, David T Chuang, Lei Li, Shawn S-C Li, Pau Creixell, Konstantin Krismer, Mina Takegami, Harin Lee, Bin Zhang, Jingyi Lu, Ian Cossentino, Sean D Landry, Mohamed Uduman, John Blenis, Olivier Elemento, Margaret C Frame, Peter V Hornbeck, Lewis C Cantley, Benjamin E Turk, Michael B Yaffe, Jared L Johnson

Faculty, Staff and Student Publications

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of …

Bacteria Synergized With Pd-1 Blockade Enhance Positive Feedback Loop Of Cancer Cells-M1 Macrophages-T Cells In Glioma, Qi Chen, Yuyi Zheng, Xiaojie Chen, Yuan Xing, Jiajie Zhang, Xinyi Yan, Qi Zhang, Di Wu, Zhong Chen

Faculty, Staff and Student Publications

Cancer immunotherapy is an attractive strategy because it stimulates immune cells to target malignant cells by regulating the intrinsic activity of the immune system. However, due to lacking many immunologic markers, it remains difficult to treat glioma, a representative "cold" tumor. Herein, to wake the "hot" tumor immunity of glioma, Porphyromonas gingivalis (Pg) is customized with a coating to create an immunogenic tumor microenvironment and further prove the effect in combination with the immune checkpoint agent anti-PD-1, exhibiting elevated therapeutic efficacy. This is accomplished not by enhancing the delivery of PD-1 blockade to enhance the effect of immunotherapy, but by …

Enhanced Ctla-4 Blockade Anti-Tumor Immunity With Apg-157 Combination In A Murine Head And Neck Cancer, Daniel Sanghoon Shin, Saroj Basak, Mysore S Veena, Begoña Comin-Anduix, Arjun Bhattacharya, Tien S Dong, Albert Ko, Philip Han, Jonathan Jacobs, Neda A Moatamed, Luis Avila, Matteo Pellegrini, Marilene Wang, Eri S Srivatsan

Faculty, Staff and Student Publications

BACKGROUND: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors.

METHODS: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed …

Leveraging Logical Definitions And Lexical Features To Detect Missing Is-A Relations In Biomedical Terminologies, Rashmie Abeysinghe, Fengbo Zheng, Jay Shi, Samden D Lhatoo, Licong Cui

Faculty, Staff and Student Publications

Biomedical terminologies play a vital role in managing biomedical data. Missing IS-A relations in a biomedical terminology could be detrimental to its downstream usages. In this paper, we investigate an approach combining logical definitions and lexical features to discover missing IS-A relations in two biomedical terminologies: SNOMED CT and the National Cancer Institute (NCI) thesaurus. The method is applied to unrelated concept-pairs within non-lattice subgraphs: graph fragments within a terminology likely to contain various inconsistencies. Our approach first compares whether the logical definition of a concept is more general than that of the other concept. Then, we check whether the …

Mechanical Venous Thrombectomy For Deep Venous Thrombosis In Cancer Patients: A Single-Center Retrospective Study, Riya M Patel, Koustav Pal, Syed Hadi Ahmed, Joshua D Kuban, Milan Patel, Ketan Shah, Peiman Habibollahi, Zeyad Metwalli, Varshana Gurusamy, Sanjay Gupta, Cristhiam M Rojas-Hernandez, Vahid Afshar-Kharghan, Michael H Kroll, Rahul A Sheth

Faculty, Staff and Student Publications

PURPOSE: Venous thromboembolism (VTE) is a major contributor to the mortality of cancer patients. Mechanical thrombectomy (MT) is an endovascular technique that physically removes a thrombus without thrombolytics. The purpose of this study was to evaluate safety, efficacy, and clinical outcomes following MT for lower extremity DVT in cancer patients.

METHODS: This single-center, retrospective study evaluated outcomes following MT of lower extremity DVT in cancer patients from November 2019 to May 2023. The primary outcome measure was clinical success, defined as a decrease in Villalta score by at least 2 points following the intervention. Secondary outcomes included repeat intervention-free survival …

Montelukast As A Repurposable Additive Drug For Standard-Efficacy Multiple Sclerosis Treatment: Emulating Clinical Trials With Retrospective Administrative Health Claims Data, Astrid M Manuel, Assaf Gottlieb, Leorah Freeman, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma or allergic rhinitis, may provide an additional therapeutic approach.

OBJECTIVE: The study aimed to evaluate the effects of montelukast on the relapses of people with MS (pwMS).

METHODS: In this retrospective case-control study, two independent longitudinal claims datasets were used to emulate randomized clinical trials (RCTs). We identified pwMS aged 18-65 years, on MS disease-modifying therapies concomitantly, in de-identified claims from Optum's Clinformatics

RESULTS: pwMS treated with montelukast demonstrated a statistically significant 23.6% reduction in relapses compared …

Serial Cytoreductive Surgery And Survival Outcomes In Recurrent Adult-Type Ovarian Granulosa Cell Tumors, Jeffrey A How, Alejandra Flores Legarreta, Katelyn F Handley, Bryan Fellman, Katherine I Foster, Deanna Glassman, Veena K Vuttaradhi, Allison L Brodsky, Barrett Lawson, Michael Frumovitz, Shannon N Westin, Lois M Ramondetta, David M Gershenson, Anil K Sood, R Tyler Hillman

Faculty, Staff and Student Publications

BACKGROUND: Few studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared with systemic therapy alone following the first recurrence and subsequent disease progressions.

OBJECTIVE: This study aimed to determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary.

STUDY …

Mr-Guided Stereotactic Radiation Therapy For Head And Neck Cancers, He Wang, Jinzhong Yang, Anna Lee, Jack Phan, Tze Yee Lim, Clifton D Fuller, Eun Young Han, Dong Joo Rhee, Travis Salzillo, Yao Zhao, Nitish Chopra, Mary Pham, Pam Castillo, Angela Sobremonte, Amy C Moreno, Jay P Reddy, David Rosenthal, Adam S Garden, Xin Wang

Faculty, Staff and Student Publications

PURPOSE: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT.

METHOD: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were …