Digital Commons Network^™

Molecular Profiling Of Bladder Cancer Xenografts Defines Relevant Molecular Subtypes And Provides A Resource For Biomarker Discovery, Sharada Mokkapati, Ganiraju Manyam, Alexis R Steinmetz, Côme Tholomier, Alberto Martini, Woonyoung Choi, Bogdon Czerniak, Byron H Lee, Colin P Dinney, David J Mcconkey

Faculty, Staff and Student Publications

Bladder cancer (BLCA) genomic profiling has identified molecular subtypes with distinct clinical characteristics and variable sensitivities to frontline therapy. BLCAs can be categorized into luminal or basal subtypes based on their gene expression. We comprehensively characterized nine human BLCA cell lines (UC3, UC6, UC9, UC13, UC14, T24, SCaBER, RT4V6 and RT112) into molecular subtypes using orthotopic xenograft models. Patient-derived, luciferase-tagged BLCA cell lines were cultured in vitro and engrafted into bladders of NSG mice. Tumor growth was monitored using bioluminescence imaging and mRNA-based molecular classification was used to characterize xenografts into molecular subtypes. RNAseq analysis and basal, luminal, and epithelial-mesenchymal …

On The Acceptance, Commissioning, And Quality Assurance Of Electron Flash Units, Allison Palmiero, Kevin Liu, Julie Colnot, Nitish Chopra, Denae Neill, Luke Connell, Brett Velasquez, Albert C Koong, Steven H Lin, Peter Balter, Ramesh Tailor, Charlotte Robert, Jean-François Germond, Patrik Gonçalves Jorge, Reiner Geyer, Sam Beddar, Raphael Moeckli, Emil Schüler

Faculty, Staff and Student Publications

Background and purpose: FLASH or ultra-high dose rate (UHDR) radiation therapy (RT) has gained attention in recent years for its ability to spare normal tissues relative to conventional dose rate (CDR) RT in various preclinical trials. However, clinical implementation of this promising treatment option has been limited because of the lack of availability of accelerators capable of delivering UHDR RT. Commercial options are finally reaching the market that produce electron beams with average dose rates of up to 1000 Gy/s. We established a framework for the acceptance, commissioning, and periodic quality assurance (QA) of electron FLASH units and present an …

A Phase Ib Trial Of Selinexor In Combination With Immune Checkpoint Blockade In Patients With Advanced Renal Cell Carcinoma, Omar Alhalabi, Mohamed A Gouda, Denái R Milton, Hassan Ahmed Momin, Bulent Yilmaz, Bettzy Stephen, Chinenye Lynette Ejezie, Justin Tyler Moyers, Serdar A Gurses, Jeffrey How, Siqing Fu, Jordi Rodon, David S Hong, Sarina A Piha-Paul, Vivek Subbiah, Ecaterina Elena Dumbrava, Daniel D Karp, Filip Janku, Funda Meric-Bernstam, Nizar M Tannir, Aung Naing

Faculty, Staff and Student Publications

Background: Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy.

Methods: NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies. Arm M utilized twice weekly oral SEL and intravenous nivolumab (NIVO). Arm N utilized weekly oral SEL with NIVO plus ipilimumab (IPI). The primary objective of this study was to evaluate the safety of SEL + NIVO and SEL …

Frailty And Sleep In Adult Survivors Of Childhood Cancer: A Childhood Cancer Survivor Study Report, Lauren C Daniel, Margaret M Lubas, Huiqi Wang, Mariana Szklo-Coxe, Kirsten K Ness, Annalynn M Williams, Daniel A Mulrooney, Rebecca Howell, Wendy Leisenring, Yutaka Yasui, Leslie L Robison, Gregory T Armstrong, Eric J Chow, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Young adult survivors of childhood cancer exhibit rates of frailty similar to adults several decades older without a cancer history. Frailty has been associated with sleep disturbances in non-cancer populations, but the relationship has not been examined in childhood cancer survivors who are known to exhibit elevated rates of sleep problems.

Aims: Examine associations between frailty and poor sleep quality in long-term survivors of childhood cancer.

Methods: This study utilized data from 9044 participants (> 5 years from diagnosis, Mage = 40.8 years [SD = 9.5]) in the Childhood Cancer Survivor Study. Survivors' frailty status, chronic health conditions (CHC), …

Hsp90: Bringing It All Together, Georgios Ioannis Karras, Giorgio Colombo, Andrea N Kravats

Faculty, Staff and Student Publications

Heat-shock protein 90 (Hsp90) is an ancient and multifaceted protein-folding machine essential for most organisms. The past 40 years have uncovered remarkable complexity in the regulation and function of Hsp90, which dwarfs most other machines in the cell in sophistication. Here, we propose four analogies to illustrate Hsp90's sophistication: a multifunctional Swiss Army knife, an automobile engine and its controls, a switchboard acting as a hub and directing signals, and an orchestra conductor setting the tempo of a symphony. Although each of these analogies represents some key Hsp90 activities, none of them captures the entirety of Hsp90's complexity. Together, these …

Stereotactic Body Radiotherapy Vs Sorafenib Alone In Hepatocellular Carcinoma: The Nrg Oncology/Rtog 1112 Phase 3 Randomized Clinical Trial, Laura A Dawson, Kathryn A Winter, Jennifer J Knox, Andrew X Zhu, Sunil Krishnan, Chandan Guha, Lisa A Kachnic, Michael T Gillin, Theodore S Hong, Timothy D Craig, Terence M Williams, Ali Hosni, Eric Chen, Anne M Noonan, Eugene J Koay, Rishi Sinha, Michael I Lock, Nitin Ohri, Jennifer A Dorth, Guila Delouya, Anand Swaminath, Jennifer Moughan, Christopher H Crane

Faculty, Staff and Student Publications

Importance: Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.

Objective: To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.

Design, setting, and participants: This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, …

Molecular Classification Of Endometrial Cancers (Ec) And Association With Relapse-Free Survival (Rfs) And Overall Survival (Os) Outcomes: Ancillary Analysis Of Gog-0258, Aine Clements, Danielle Enserro, Kyle C Strickland, Rebecca Previs, Daniela Matei, David Mutch, Matthew Powell, Ann Klopp, David Scott Miller, William Small, Paul Disilvestro, Nick Spirtos, Casey Cosgrove, Greg Sfakianos, J Rebecca Liu, Roberto Vargas, Mark Shahin, Bradley Corr, Kimberly Dessources, Frederick Ueland, David Warshal, Jessica Gillen, Angeles Alvarez Secord

Faculty, Staff and Student Publications

Purpose: Determine if molecular classification using mismatch repair (MMR) and p53 protein expression predicts recurrence-free survival (RFS) and overall survival (OS) in endometrial cancer (EC) patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT).

Methods: GOG-0258, a phase III randomized trial (NCT00942357), compared CRT to CT. Immunohistochemistry assessed MMR and p53 status. Kaplan-Meier curves and adjusted Cox models analyzed survival outcomes by molecular subtype.

Results: ECs classified as deficient MMR (dMMR) (27 %), p53 abnormal (p53abn) (24 %), and p53 wild type (p53wt) (49 %). p53abn were more frequent in patients that were older, Black, and had …

Association Of Systemic Inflammation And Long-Term Dysfunction In Covid-19 Patients: A Prospective Cohort, Felipe Dal-Pizzol, Bruno Kluwe-Schiavon, Henrique Ritter Dal-Pizzol, Gabriele Da Silveira Prestes, Diogo Dominguini, Carolina Saibro Girardi, Lucas Santos, José Cláudio Fonseca Moreira, Daniel Pens Gelain, Roger Walz, Tatiana Barichello, Cristiane Ritter

Faculty, Staff and Student Publications

COVID-19 has significant long-term impacts, including a chronic syndrome known as long-COVID, characterized by persistent symptoms post-recovery. The inflammatory response during acute infection is hypothesized to influence long-term outcomes. This study aimed to identify inflammatory biomarkers predictive of functional outcomes one year after hospital discharge. A prospective cohort study was conducted with 213 COVID-19 patients admitted to ICUs in Southern Brazil between June and November 2020. After exclusions and follow-ups, 109 patients were evaluated for one-year post-discharge. Plasma levels of Th1 (TNF-α, INF-γ, IL-12), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), and Th17 (IL-17, IL-22) cytokines were measured. Functional outcomes in …

Somatic Copy Number Deletion Of Chromosome 22q In Papillary Thyroid Carcinoma, Olivia W Lee, Danielle M Karyadi, Stephen W Hartley, Weyin Zhou, Mitchell J Machiela, Shahriar A Zamani, Liudmyla Yu Zurnadzhy, John N Weinstein, Young Joo Park, Jeong-Sun Seo, Gerry A Thomas, Tetiana I Bogdanova, Mykola D Tronko, Lindsay M Morton, Stephen J Chanock

Faculty, Staff and Student Publications

Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC cases with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC cases with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm. Our analysis confirmed that 22qDEL occurs more frequently with RAS point …

Toward A Biological Definition Of Neuronal And Glial Synucleinopathies, Claudio Soto, Brit Mollenhauer, Oskar Hansson, Un Jung Kang, Roy N Alcalay, David Standaert, Claudia Trenkwalder, Kenneth Marek, Douglas Galasko, Kathleen Poston

Faculty, Staff and Student Publications

Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms. We underscore the utility of the αSyn seed amplification assay to detect aggregated αSyn in living …

Recurrence-Free Survival Prediction For Anal Squamous Cell Carcinoma After Chemoradiotherapy Using Planning Ct-Based Radiomics Model, Shanshan Tang, Kai Wang, David Hein, Gloria Lin, Nina N Sanford, Jing Wang

Faculty, Staff and Student Publications

Objectives: Approximately 30% of non-metastatic anal squamous cell carcinoma (ASCC) patients will experience recurrence after chemoradiotherapy (CRT), and currently available clinical variables are poor predictors of treatment response. We aimed to develop a model leveraging information extracted from radiation pretreatment planning CT to predict recurrence-free survival (RFS) in ASCC patients after CRT.

Methods: Radiomics features were extracted from planning CT images of 96 ASCC patients. Following pre-feature selection, the optimal feature set was selected via step-forward feature selection with a multivariate Cox proportional hazard model. The RFS prediction was generated from a radiomics-clinical combined model based on an optimal feature …

Brain Transcriptomics Of A Social Challenge And Maternal Aggression In Incubating Female Tree Swallows, Emily J. Levy, Elizabeth M. George, Douglas B. Rusch, Aaron Buechlein, Kimberly A. Rosvall

Biology Faculty Publications

Aggressive behavior is ubiquitous across many contexts, including defense of territories, mates, and offspring. For decades, researchers have detailed the effect of aggressive behavior on physiology, but our understanding of these mechanisms in females lags behind that of males, despite the fact that female aggression is widespread, particularly in the context of maternal defense of eggs or offspring (i.e., maternal aggression). Here, we measured effects of a social challenge on brain gene expression in free-living incubating females. We hypothesized that the social challenge would generate at least one of three transcriptomic effects: (1) sensitizing the brain to otherwise low levels …

Host Traits And Temperature Predict Biogeographical Variation In Seagrass Disease Prevalence, F.R. Schenck, J.K. Baum, K.E. Boyer, J.E. Duffy, F.J. Fodrie, J. Gaeckle, Torrie Hanley, C.M. Hereu, K.A. Hovel, P. Jorgensen, D.L. Martin, N.E. O’Connor, B.J. Peterson, J.J. Stachowicz, A.R. Hughes

Biology Faculty Publications

Diseases are ubiquitous in natural systems, with broad effects across populations, communities and ecosystems. However, the drivers of many diseases remain poorly understood, particularly in marine environments, inhibiting effective conservation and management measures. We examined biogeographical patterns of infection in the foundational seagrass Zostera marina by the parasitic protist Labyrinthula zosterae, the causative agent of seagrass wasting disease, across >20° of latitude in two ocean basins. We then identified and characterized relationships among wasting disease prevalence and a suite of host traits and environmental variables. Host characteristics and transmission dynamics explained most of the variance in prevalence across our survey, …

Sparse Seagrass Meadows Are Critical Dugong Habitat: A Novel Rapid Assessment Of Habitat-Wildlife Associations Using Paired Drone And In-Water Surveys, Nicole E. Said, Christophe Cleguer, Paul Lavery, Amanda J. Hodgson, Connor Gorham, Julian A. Tyne, Ankje Frouws, Simone Strydom, Johnny Lo, Holly C. Raudino, Kelly Waples, Kathryn Mcmahon

Research outputs 2022 to 2026

Understanding the fine-scale behavioural and feeding ecology of marine megafauna is imperative for effective management of their habitat areas; however, obtaining the relevant data can be both costly and challenging. Here we integrate the use of small drones for dugong surveys with underwater benthic habitat assessment techniques at the local spatial scale (∼30 km2), to determine the drivers of dugong (Dugong dugon) distribution across three locations in the Pilbara, Western Australia. Paired assessment data was collected three times over two years. Benthic habitat (percent cover), seagrass nutritional quality and environmental parameters (temperature, water clarity, water current, water depth) were tested …

Test Of Strategies For Production And Harvest Of Edible Roots From Hydroponic Plants, Mariam Yaslem Albreiki

Theses

Hydroponic plant cultivation is becoming increasingly popular in the UAE, especially for leafy greens and fruit vegetables. By the end of the growing cycle, the roots of hydroponic plants are usually treated as crop residues, even though roots of several species are potentially edible and could be processed into food or nutraceuticals. Root crops like sweet potato or carrot might even be grown in hydroponic systems for the primary purpose of producing edible fibrous or tuberous roots. However, the use of hydroponic systems for the production of root biomass is not yet common, and most farmers strive to produce plants …

Mutational And Co-Mutational Landscape Of Early Onset Colorectal Cancer, Jumanah Yousef Alshenaifi, Guglielmo Vetere, Giulia Maddalena, Mahmoud Yousef, Michael G White, John Paul Shen, Eduardo Vilar, Christine Parseghian, Arvind Dasari, Van Karlyle Morris, Ryan Huey, Michael J Overman, Robert Wolff, Kanwal P Raghav, Jason Willis, Kristin Alfaro, Andy Futreal, Y Nancy You, Scott Kopetz

Faculty, Staff and Student Publications

Introduction: Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades.

Methods: Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, < 50 years) compared to late-onset (LOCRC, ≥ 50 years).

Results: EOCRC was associated with a higher prevalence of Asian and Hispanic patients, rectal or left-sided tumors (72% vs. 59%), and advanced-stage disease. Molecular analyses revealed differences in mutation patterns, with EOCRC having higher frequencies of TP53 (74% vs. 68%, p < 0.01) and SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p < 0.001) and NOTCH1 (2.7% vs. 4.1%, p = 0.01) mutations …

The Dynamics Of Tubulogenesis In Development And Disease, Adrian Romero, Brandy L Walker, Vanja Krneta-Stankic, Kamryn Gerner-Mauro, Lydia Youmans, Rachel K Miller

Faculty, Staff and Student Publications

Tubes are crucial for the function of many organs in animals given their fundamental roles in transporting and exchanging substances to maintain homeostasis within an organism. Therefore, the development and maintenance of these tube-like structures within organs is a vital process. Tubes can form in diverse ways, and advances in our understanding of the molecular and cellular mechanisms underpinning these different modes of tubulogenesis have significant impacts in many biological contexts, including development and disease. This Review discusses recent progress in understanding developmental mechanisms underlying tube formation.

A Phase 2 Basket Study Of Talabostat, A Small-Molecule Inhibitor Of Dipeptidyl Peptidases, Administered In Combination With Pembrolizumab In Patients With Advanced Solid Cancers, Jibran Ahmed, Filip Janku, Daniel D Karp, Sarina A Piha-Paul, Apostolia M Tsimberidou, Timothy Anthony Yap, Bettzy Stephen, Yali Yang, Serdar Gurses, Qian Liu, Juhee Song, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

Background: Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients.

Methods: The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST …

Establishment Of The Nichols Strain As The Type Strain Of Treponema Pallidum, Steven J Norris

Faculty, Staff and Student Publications

In this article, it is proposed that the Nichols strain of Treponema pallidum be established as the type strain. T. pallidum was first identified as the causative agent of syphilis in 1905, and the Nichols strain was isolated in 1912 by inoculation of a rabbit with cerebrospinal fluid from a patient with neurosyphilis. The Nichols strain has been maintained by serial passage in rabbits for over a century, and historically most studies of T. pallidum have been conducted using this strain. In recent years, a procedure for continuous in vitro culture of T. pallidum in a tissue culture system has …

Challenges And Opportunities For Data Integration To Improve Estimation Of Migratory Connectivity, Jeffrey A. Hostetler, Emily B. Cohen, Christen M. Bossu, Amy L. Scarpignato, Kristen Ruegg, Andrea Contina, Clark S. Rushing, Michael T. Hallworth

School of Integrative Biological & Chemical Sciences Faculty Publications

1. Understanding migratory connectivity, or the linkage of populations between seasons, is critical for effective conservation and management of migratory wildlife. A growing number of tools are available for understanding where migratory individuals and populations occur throughout the annual cycle. Integration of the diverse measures of migratory movements can help elucidate migratory connectivity patterns with methodology that accounts for differences in sampling design, directionality, effort, precision and bias inherent to each data type.
2. The R package MigConnectivity was developed to estimate population-specific connectivity and the range-wide strength of those connections. New functions allow users to integrate intrinsic markers, tracking and long-distance …

A Multicenter Open-Label Randomized Phase Ii Study Of Osimertinib With And Without Ramucirumab In Tyrosine Kinase Inhibitor–Naïve Egfr-Mutant Metastatic Non–Small Cell Lung Cancer (Ramose Trial), Xiuning Le, Jyoti D Patel, Elaine Shum, Christina Baik, Rachel E Sanborn, Catherine A Shu, Chul Kim, Mary Jo Fidler, Richard Hall, Yasir Y Elamin, Janet Tu, George Blumenschein, Jianjun Zhang, Don Gibbons, Carl Gay, Nisha A Mohindra, Young Chae, Yanis Boumber, Joshua Sabari, Rafael Santana-Davila, Shane Rogosin, Benjamin Herzberg, Ben Creelan, Bruna Pellini, Tawee Tanvetyanon, Simon Heeke, Mike Hernandez, Jhanelle E Gray, Andreas Saltos, John V Heymach

Faculty, Staff and Student Publications

Purpose: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS).

Methods: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334, HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for …

Refining Diagnostic Subtypes Of Peripheral T-Cell Lymphoma Using A Multiparameter Approach, Catalina Amador, Dennis D Weisenburger, Ana Gomez, Alyssa Bouska, Ahmad Alshomrani, Sunandini Sharma, Ab Rauf Shah, Timothy C Greiner, Francisco Vega, Andreas Rosenwald, German Ott, Andrew L Feldman, Elaine S Jaffe, Neval Ozkaya, Sarah L Ondrejka, James R Cook, Philipp W Raess, Kerry J Savage, Graham W Slack, Joo Y Song, David W Scott, Elias Campo, Lisa M Rimsza, Joseph D Khoury, Louis M Staudt, Wing C Chan, Javeed Iqbal

Faculty, Staff and Student Publications

Peripheral T-cell lymphoma (PTCL) is a heterogeneous category, and many cases are unclassifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated two prognostic subtypes within PTCL-NOS, PTCL-TBX21, and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including TFH biomarkers) and GEP analyses, separating them into PTCL-NOS (n=63) and PTCL-TFH (a.k.a. nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n=38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n=22; 34%) …

Adipose Tissue Deficiency Impairs Transient Lipid Accumulation And Delays Liver Regeneration Following Partial Hepatectomy In Male Seipin Knockout Mice, Qianqian Dong, Ziwei Liu, Yidan Ma, Xin Chen, Xiaowei Wang, Jinye Tang, Kexin Ma, Chenxi Liang, Mengyu Wang, Xiaoqin Wu, Yang Liu, Yaru Zhou, Hongyuan Yang, Mingming Gao

Faculty, Staff and Student Publications

Background: Liver diseases pose significant health challenges, underscoring the importance of understanding liver regeneration mechanisms. Systemic adipose tissue is thought to be a primary source of lipids and energy during this process; however, empirical data on the effects of adipose tissue deficiency are limited. This study investigates the role of adipose tissue in liver regeneration, focusing on transient regeneration-associated steatosis (TRAS) and hepatocyte proliferation using a Seipin knockout mouse model that mimics severe human lipodystrophy. Additionally, the study explores therapeutic strategies through adipose tissue transplantation.

Methods: Male Seipin knockout (Seipin-/-) and wild-type (WT) mice underwent 2/3 partial hepatectomy (PHx). Liver …

Taming Biological Complexity Through The Use Of Symmetries, Luis A. Álvarez-García

Dissertations, Theses, and Capstone Projects

The study of biological systems is, inherently, the study of very complex systems. This is essentially due to the fact that they are made up of numerous, often very complicated, interactions between an extensive number of components. Often necessitating an abundance of quantitative parameters and details for a precise description. The human brain for ex- ample, consisting of ∼ 80 billion neurons with ∼ 800 to 100 trillion connections between them, each of them depending on a large set of parameters. Even simpler examples such as bacterial organisms, such as E. coli and B. subtilis, which we focus on …

Immunogenomic Determinants Of Exceptional Response To Immune Checkpoint Inhibition In Renal Cell Carcinoma, Tejas Jammihal, Renee Maria Saliby, Chris Labaki, Hanna Soulati, Juan Gallegos, Arnau Peris, Dustin Mccurry, Chunlei Yu, Valisha Shah, Deepak Poduval, Talal El Zarif, Nourhan El Ahmar, Yasmin Nabil Laimon, Marc Eid, Aseman Bagheri Sheshdeh, Katherine M Krajewski, Florian A Büttner, Matthias Schwab, Daniel Heng, Rafael C Casellas, Kunal Rai, Niki M Zacharias Millward, Pavlos Msaouel, Jose Karam, Sabina Signoretti, Eliezer Van Allen, Toni K Choueiri, David A Braun, Sachet A Shukla

Faculty, Staff and Student Publications

Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with …

The Metabolic Basis Of Cancer-Related Fatigue, Robert Dantzer, Brandon Chelette, Elisabeth G Vichaya, A Phillip West, Aaron Grossberg

Faculty, Staff and Student Publications

Although we are all familiar with the sensation of fatigue, there are still profound divergences on what it represents and its mechanisms. Fatigue can take various forms depending on the condition in which it develops. Cancer-related fatigue is considered a symptom of exhaustion that is often present at the time of diagnosis, increases in intensity during cancer therapy, and does not always recede after completion of treatment. It is usually attributed to the inflammation induced by damage-associated molecular patterns released by tumor cells during cancer progression and in response to its treatment. In this review, we argue that it is …

Outcomes Of Patients With Treated Secondary Acute Myeloid Leukemia: A High-Risk Subtype That Warrants An Independent Prognostic Designation, Jayastu Senapati, Hagop M Kantarjian, Fadi G Haddad, Nicholas J Short, Gautam Borthakur, Rashmi Kanagal-Shamanna, Guilin Tang, Elias Jabbour, Courtney D Dinardo, Naval Daver, Guillermo Montalban-Bravo, Vishrut Shah, Amin Alousi, Elizabeth Shpall, Uday Popat, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M Kadia

Faculty, Staff and Student Publications

Patients who develop acute myeloid leukemia (AML) after having received treatment for myelodysplastic syndrome (MDS) or related conditions have particularly poor outcomes. This study analyzed adult patients with newly diagnosed AML who previously had MDS, chronic myelomonocytic leukemia (CMML), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome, and who had received hypomethylating agents, chemotherapy, and/or allogeneic stem cell transplantation (HSCT) for these antecedent disorders. From January 2012 to August 2023, we included 673 patients with a median age of 70 years (range, 19-94); 536 (80%) had transformed from MDS, and the remainder from CMML or MDS-MPN. Additionally, 149 patients (22%) had prior …

Preclinical And Clinical-Scale Magnetic Particle Imaging Of Natural Killer Cells: In Vitro And Ex Vivo Demonstration Of Cellular Sensitivity, Resolution, And Quantification, Olivia C Sehl, Yanwen Yang, Ariana R Anjier, Dmitry Nevozhay, Donghang Cheng, Kelvin Guo, Benjamin Fellows, Abdul Rahman Mohtasebzadeh, Erica E Mason, Toby Sanders, Petrina Kim, David Trease, Dimpy Koul, Patrick W Goodwill, Konstantin Sokolov, Max Wintermark, Nancy Gordon, Joan M Greve, Vidya Gopalakrishnan

Faculty, Staff and Student Publications

Purpose: Clinical adoption of NK cell immunotherapy is underway for medulloblastoma and osteosarcoma, however there is currently little feedback on cell fate after administration. We propose magnetic particle imaging (MPI) may have applications for the quantitative detection of NK cells.

Procedures: Human-derived NK-92 cells were labeled by co-incubation with iron oxide nanoparticles (VivoTrax™) for 24 h then excess nanoparticles were washed with centrifugation. Cytolytic activity of labeled versus unlabeled NK-92 cells was assessed after 4 h of co-incubation with medulloblastoma cells (DAOY) or osteosarcoma cells (LM7 or OS17). Labeled NK-92 cells at two different doses (0.5 or 1 × 106) …

Rezilient3: Randomized Phase Iii Study Of First-Line Zipalertinib Plus Chemotherapy In Patients With Egfr Exon 20 Insertion-Mutated Nsclc, John V Heymach, Helena A Yu, Benjamin Besse, Ying Cheng, Daniel Sw Tan, Li Wei, Volker Wacheck, Makoto Nishio

Faculty, Staff and Student Publications

There remains a significant unmet need for effective and tolerable treatments for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (

Selinexor (Kpt-330) In Combination With Immune Checkpoint Inhibition In Uveal Melanoma: A Phase 1b Trial, Mohamed A Gouda, Abdulrazzak Zarifa, Yali Yang, Bettzy Stephen, Serdar A Gurses, Ashabari Sprenger, Yanyan Tian, Mohamed H Derbala, Isabella Glitza Oliva, Funda Meric-Bernstam, Sapna P Patel

Faculty, Staff and Student Publications

Introduction: Uveal melanoma remains a disease with aggressive behavior and poor prognosis despite advances in clinical management. Because monotherapy with immune checkpoint inhibitors has led to limited improvement in response rates, combination with other agents that act on the biological basis of oncogenesis has been proposed as a possible therapeutic strategy.

Methods: We designed a phase 1b trial to test the safety and tolerability of selinexor in combination with immune checkpoint inhibitors in patients with advanced uveal melanoma. Patients received selinexor 60 mg PO twice weekly with standard of care, commercially available immune checkpoint inhibitor of the investigator's choice. In …