Genetic Phenomena Commons^™

A 3d Dual-Echo Spiral Sequence For Simultaneous Dynamic Susceptibility Contrast And Dynamic Contrast-Enhanced Mri With Single Bolus Injection, Zhiqiang Li, Dinghui Wang, Melvyn B Ooi, Poonam Choudhary, Sudarshan Ragunathan, John P Karis, James G Pipe, C Chad Quarles, Ashley M Stokes

Faculty, Staff and Student Publications

Purpose: Perfusion MRI reveals important tumor physiological and pathophysiologic information, making it a critical component in managing brain tumor patients. This study aimed to develop a dual-echo 3D spiral technique with a single-bolus scheme to simultaneously acquire both dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) data and overcome the limitations of current EPI-based techniques.

Methods: A 3D spiral-based technique with dual-echo acquisition was implemented and optimized on a 3T MRI scanner with a spiral staircase trajectory and through-plane SENSE acceleration for improved speed and image quality, in-plane variable-density undersampling combined with a sliding-window acquisition and reconstruction approach for increased …

Circuit-Specific Deep Brain Stimulation Provides Insights Into Movement Control., Aryn H Gittis, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Deep brain stimulation (DBS), a method in which electrical stimulation is delivered to specific areas of the brain, is an effective treatment for managing symptoms of a number of neurological and neuropsychiatric disorders. Clinical access to neural circuits during DBS provides an opportunity to study the functional link between neural circuits and behavior. This review discusses how the use of DBS in Parkinson's disease and dystonia has provided insights into the brain networks and physiological mechanisms that underlie motor control. In parallel, insights from basic science about how patterns of electrical stimulation impact plasticity and communication within neural circuits are …

Cerebellar Functions Beyond Movement And Learning, Linda H Kim, Detlef H Heck, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural …

A Randomised, Parallel-Group, Double-Blind, Placebo-Controlled Phase 3 Study To Determine The Effectiveness Of The Type I Interferon Receptor Antibody, Anifrolumab, In Systemic Sclerosis: Daisy Study Design And Rationale, Dinesh Khanna, Christopher P Denton, Shervin Assassi, Masataka Kuwana, Yannick Allanore, Robyn T Domsic, Christi Kleoudis, John Xu, Eszter Csomor, Caroline Seo, Marius Albulescu, Raj Tummala, Hussein Al-Mossawi, Rubana N Kalyani, Francesco Del Galdo

Faculty, Staff and Student Publications

Objectives: The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY).

Methods: DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, …

Ephb2 Receptor Promotes Dermal Fibrosis In Systemic Sclerosis, Erika S A Egal, Severin Donald Kamdem, Masaaki Yoshigi, Ching-Chu Yang, Sarah Pellizzari, Ernest M Kameni, My N Helms, Shervin Assassi, Mark Henkemeyer, Tracy M Frech, Patrice N Mimche

Faculty, Staff and Student Publications

Objective: Erythropoietin-producing hepatocellular (Eph)/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc).

Methods: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models of skin fibrosis. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In …

Electrical Stimulation Of The Dorsal Motor Nucleus Of The Vagus In Male Mice Can Regulate Inflammation Without Affecting The Heart Rate, Aidan Falvey, Santhoshi P Palandira, Sangeeta S Chavan, Michael Brines, Robert Dantzer, Kevin J Tracey, Valentin A Pavlov

Faculty, Staff and Student Publications

Background: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide …

Collaborative Filtering For The Imputation Of Patient Reported Outcomes, Eric Ababio Anyimadu, Clifton David Fuller, Xinhua Zhang, G Elisabeta Marai, Guadalupe Canahuate

Faculty, Staff and Student Publications

This study addresses the prevalent issue of missing data in patient-reported outcome datasets, particularly focusing on head and neck cancer patient symptom ratings sourced from the MD Anderson Symptom Inventory. Given that many data mining and machine learning algorithms necessitate complete datasets, the accurate imputation of missing data as an initial step becomes crucial. In this study we propose, for the first time, the use of collaborative filtering for imputing missing head and neck cancer patient symptom ratings. Two configurations of collaborative filtering, namely patient-based and symptom-based, leverage known ratings to infer the missing ones. Additionally, this study compares the …

Targeting Adenosine A2b Receptor Promotes Penile Rehabilitation Of Refractory Erectile Dysfunction, Yang Xiong, Feng Qin, Shanzun Wei, Xingliang Yang, Jun Li, Changjing Wu, Fuxun Zhang, Jiuhong Yuan

Faculty, Staff and Student Publications

The mechanisms of adenosine and specific adenosine receptor subtypes in promoting penile rehabilitation remain unclear. Single‐cell RNA sequencing of human corpus cavernosum,  adenosine deaminase (ADA) and adenosine receptors knock‐out mice (ADA−/−, A1−/−, A2a−/−, A2b−/−, and A3−/−), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine‐induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age‐related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus‐induced ED. In single‐cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, …

Candida Albicans Natural Diversity: A Resource To Dissect Fungal Commensalism And Pathogenesis, Elena Lindemann-Perez, J Christian Perez

Faculty, Staff and Student Publications

Candida albicans is a ubiquitous fungus of humans. It is not only a component of the oral and intestinal microbiota of most healthy adults but also a major cause of mucosal disorders and life-threatening disseminated infections. Until recently, research on the biology and pathogenesis of the fungus was largely based on a single clinical isolate. We review investigations that have started to dissect a diverse set of C. albicans strains. Using different approaches to leverage the species' phenotypic and/or genetic diversity, these studies illuminate the wide range of interactions between fungus and host. While connecting genetic variants to phenotypes of …

A Qualitative Narrative Study Of Rescue And Recovery Workers Responding To The Terrorist Bombing Of Oklahoma City's Murrah Building, E Whitney Pollio, Jennifer Wang, Edward Randle, David E Pollio, Carol S North

Faculty, Staff and Student Publications

OBJECTIVE: Much of disaster mental health research uses quantitative methods, focusing on numerical prevalence, services, and outcomes.

METHODS: Qualitative methods can provide more detailed, rich, and spontaneous insights into personal disaster experiences, yielding important insights beyond deductive methods. This large-scale qualitative narrative study examined experiences of 181 Oklahoma City bombing rescue/recovery workers.

RESULTS: Thematic narrative content of the bombing experience arose from personal accounts of the bomb blast by rescue/recovery workers proceeding chronologically from initial awareness and deployment to harrowing onsite search and rescue/recovery missions to the aftermath with reflections on the bombing.

CONCLUSIONS: Beyond disaster recovery/rescue worker stories published …

Patient-Derived Organoids As Therapy Screening Platforms In Cancer Patients, Danial Khorsandi, Jia-Wei Yang, Samuel Foster, Safoora Khosravi, Negar Hosseinzadeh Kouchehbaghi, Fahimeh Zarei, Yun Bin Lee, Farhana Runa, Ankit Gangrade, Leon Voskanian, Darbaz Adnan, Yangzhi Zhu, Zhaohui Wang, Vadim Jucaud, Mehmet Remzi Dokmeci, Xiling Shen, Faraz Bishehsari, Jonathan A Kelber, Ali Khademhosseini, Natan Roberto De Barros

Faculty, Staff and Student Publications

Patient-derived organoids (PDOs) developed ex vivo and in vitro are increasingly used for therapeutic screening. They provide a more physiologically relevant model for drug discovery and development compared to traditional cell lines. However, several challenges remain to be addressed to fully realize the potential of PDOs in therapeutic screening. This paper summarizes recent advancements in PDO development and the enhancement of PDO culture models. This is achieved by leveraging materials engineering and microfabrication technologies, including organs-on-a-chip and droplet microfluidics. Additionally, this work discusses the application of PDOs in therapy screening to meet diverse requirements and overcome bottlenecks in cancer treatment. …

Social Determinants Of Long-Term Opioid Use Following Total Knee Arthroplasty, Katherine Hadlandsmyth, Brian C Lund, Yubo Gao, Andrea L Strayer, Heather Davila, Leslie R M Hausmann, Susanne Schmidt, Paula K Shireman, Michael A Jacobs, Michael J Mader, Robert A Tessler, Carly A Duncan, Daniel E Hall, Mary Vaughan Sarrazin

Faculty, Staff and Student Publications

Total knee arthroplasty (TKA) risks persistent pain and long-term opioid use (LTO). The role of social determinants of health (SDoH) in LTO is not well established. We hypothesized that SDoH would be associated with postsurgical LTO after controlling for relevant demographic and clinical variables. This study utilized data from the Veterans Affairs Surgical Quality Improvement Program, VA Corporate Data Warehouse, and Centers for Medicare and Medicaid Services, including Veterans aged ≥ 65 who underwent elective TKA between 2013 and 2019 with no postsurgical complications or history of significant opioid use. LTO was defined as > 90 days of opioid use beginning …

Care Fragmentation, Social Determinants Of Health, And Postoperative Mortality In Older Veterans, Carly A Duncan, Michael A Jacobs, Yubo Gao, Michael Mader, Susanne Schmidt, Heather Davila, Katherine Hadlandsmyth, Paula K Shireman, Leslie R M Hausmann, Robert A Tessler, Andrea Strayer, Mary Vaughan Sarrazin, Daniel E Hall

Faculty, Staff and Student Publications

Introduction: Veterans Affairs Surgical Quality Improvement Program (VASQIP) benchmarking algorithms helped the Veterans Health Administration (VHA) reduce postoperative mortality. Despite calls to consider social risk factors, these algorithms do not adjust for social determinants of health (SDoH) or account for services fragmented between the VHA and the private sector. This investigation examines how the addition of SDoH change model performance and quantifies associations between SDoH and 30-d postoperative mortality.

Methods: VASQIP (2013-2019) cohort study in patients ≥65 y old with 2-30-d inpatient stays. VASQIP was linked to other VHA and Medicare/Medicaid data. 30-d postoperative mortality was examined using multivariable logistic …

Molecular Pathways And Cellular Subsets Associated With Adverse Clinical Outcomes In Overlapping Immune-Related Myocarditis And Myositis, Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meenakshi B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses …

Combination Of Dasatinib And Venetoclax In Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia, Elias Jabbour, Fadi G Haddad, Koji Sasaki, Bing Z Carter, Yesid Alvarado, Cedric Nasnas, Lewis Nasr, Lucia Masarova, Naval Daver, Naveen Pemmaraju, Nicholas J Short, Jeffrey Skinner, Tapan Kadia, Gautam Borthakur, Guillermo Garcia-Manero, Farhad Ravandi, Ghayas C Issa, Michael Andreeff, Hagop Kantarjian

Faculty, Staff and Student Publications

Background: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL-2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML-CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax.

Methods: In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 …

Trends In Outcomes After Upfront Autologous Transplant For Multiple Myeloma Over Three Decades, Oren Pasvolsky, Curtis Marcoux, Jianliang Dai, Denái R Milton, Mark R Tanner, Naureen Syed, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Yosra Aljawai, Hans C Lee, Mahmoud R Gaballa, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), …

Why Do Patients With Cancer Die?, Adrienne Boire, Katy Burke, Thomas R Cox, Theresa Guise, Mariam Jamal-Hanjani, Tobias Janowitz, Rosandra Kaplan, Rebecca Lee, Charles Swanton, Matthew G Vander Heiden, Erik Sahai

Faculty, Staff and Student Publications

Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this …

Inhibition Of Lysine Acetyltransferase Kat6 In Er+Her2− Metastatic Breast Cancer: A Phase 1 Trial, Toru Mukohara, Yeon Hee Park, David Sommerhalder, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Jee Hyun Kim, Hiroji Iwata, Toshinari Yamashita, Rachel M Layman, Monica Mita, Timothy Clay, Yee Soo Chae, Catherine Oakman, Fengting Yan, Gun Min Kim, Seock-Ah Im, Geoffrey J Lindeman, Hope S Rugo, Marlon Liyanage, Michelle Saul, Christophe Le Corre, Athanasia Skoura, Li Liu, Meng Li, Patricia M Lorusso

Faculty, Staff and Student Publications

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2−) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as …

Metronidazole May Display Anti-Inflammatory Features In Periodontitis Treatment: A Scoping Review, Lina J Suárez, Roger M Arce, Cristiane Gonçalves, Camila Pinheiro Furquim, Nidia Castro Dos Santos, Belén Retamal-Valdes, Magda Feres

Faculty, Staff and Student Publications

Aim: Metronidazole (MTZ) is an antimicrobial agent used to treat anaerobic infections. It has been hypothesized that MTZ may also have anti-inflammatory properties, but the evidence is limited and has not been previously reviewed. Thus, this scoping review aimed to answer the following question: "What is the evidence supporting anti-inflammatory properties of metronidazole that are not mediated by its antimicrobial effects?"

Methods: A scoping review was conducted according to the PRISMA-ScR statement. Five databases were searched up to January 2023 for studies evaluating the anti-inflammatory properties of MTZ used as monotherapy for treating infectious and inflammatory diseases.

Results: A total …

Estimating The Direct Effects Of The Genetic Liabilities To Bipolar Disorder, Schizophrenia, And Behavioral Traits On Suicide Attempt Using A Multivariable Mendelian Randomization Approach, Brenda Cabrera-Mendoza, Necla Aydin, Gabriel R Fries, Anna R Docherty, Consuelo Walss-Bass, Renato Polimanti

Faculty, Staff and Student Publications

Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect …

Markov Models For Clinical Decision-Making In Radiation Oncology: A Systematic Review, Lucas B Mccullum, Aysenur Karagoz, Cem Dede, Raul Garcia, Fatemeh Nosrat, Mehdi Hemmati, Seyedmohammadhossein Hosseinian, Andrew J Schaefer, Clifton D Fuller

Faculty, Staff and Student Publications

The intrinsic stochasticity of patients' response to treatment is a major consideration for clinical decision-making in radiation therapy. Markov models are powerful tools to capture this stochasticity and render effective treatment decisions. This paper provides an overview of the Markov models for clinical decision analysis in radiation oncology. A comprehensive literature search was conducted within MEDLINE using PubMed, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies published from 2000 to 2023 were considered. Selected publications were summarized in two categories: (i) studies that compare two (or more) fixed treatment policies using Monte Carlo simulation …

Pb-05204, A Supercritical Co2 Extract Of Nerium Oleander, Suppresses Glioblastoma Stem Cells By Inhibiting Grp78 And Inducing Programmed Necroptotic Cell Death, Sharmistha Chakraborty, Daoyan Wei, Megan Tran, Frederick F Lang, Robert A Newman, Peiying Yang

Faculty, Staff and Student Publications

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression …

Pharmacodynamic Activity Of [18f]-Fluorthanatrace Poly(Adp-Ribose) Polymerase Positron Emission Tomography In Patients With Brca1/2-Mutated Breast Cancer Receiving Talazoparib, Lilie L Lin, Franklin Wong, Ruitao Lin, Timothy Yap, Jennifer K Litton

Faculty, Staff and Student Publications

Purpose: We tested the ability of [18F] fluorthanatrace (FTT), a radiolabeled analog of poly(ADP-ribose) polymerase (PARP)-1 inhibitors, to demonstrate target engagement on positron emission tomography (PET) scans from patients with newly diagnosed primary breast cancer receiving the PARP inhibitor (PARPi) talazoparib.

Methods: Seven patients with germline BRCA1/2 pathogenic variants underwent [18F]FTT PET-computed tomography scanning at baseline, and five underwent repeat scanning 14 days after talazoparib initiation. Maximum uptake on PET was quantified in the primary tumor, involved nodes, contralateral pectoralis muscle, and lumbar vertebra body level 3, and compared between the two time points.

Results: Blocking of [18F]FTT was observed …

Patient Education Practices And Preferences Of Radiation Oncologists And Interprofessional Radiation Therapy Care Teams: A Mixed-Methods Study Exploring Strategies For Effective Patient Education Delivery, Jie Jane Chen, Anna M Brown, Allison E Garda, Ellen Kim, Sarah A Mcavoy, Subha Perni, Michael K Rooney, Kevin Shiue, Kristi L Tonning, Laura E Warren, Daniel W Golden, Jennifer M Croke

Faculty, Staff and Student Publications

Purpose: Patients' understanding of radiation therapy (RT) and data regarding optimal approaches to patient education (PE) within radiation oncology (RO) are limited. We aimed to evaluate PE practices of radiation oncologists and interprofessional RT care team members to inform recommendations for delivering inclusive and accessible PE.

Methods and materials: An anonymous survey was administered to all Radiation Oncology Education Collaborative Study Group members (10/5/22-11/23/22). Respondent demographics, individual practices/preferences, and institutional practices were collected. Qualitative items explored strategies, challenges, and desired resources for PE. Descriptive statistics summarized survey responses. The Fisher exact test compared PE practices by respondent role and PE …

Proteomics In Orthopedic Research: Recent Studies And Their Translational Implications, George Li, Argyrios Stampas, Yoshihiro Komatsu, Xueqin Gao, Johnny Huard, Sheng Pan

Faculty, Staff and Student Publications

Proteomics is a growing field that offers insights into various aspects of disease processes and therapy responses. Within the field of orthopedics, there are a variety of diseases that have a poor prognosis due to a lack of targeted curative therapy or disease modifying therapy. Other diseases have been difficult to manage in part due to lack of clinical biomarkers that offer meaningful insight into disease progression or severity. As an emerging technology, proteomics has been increasingly applied in studying bone biology and an assortment of orthopedics related diseases, such as osteoarthritis, osteosarcoma and bone tumors, osteoporosis, traumatic bone injury, …

A First-In-Class Selective Inhibitor Of Egfr And Pi3k Offers A Single-Molecule Approach To Targeting Adaptive Resistance, Christopher E Whitehead, Elizabeth K Ziemke, Christy L Frankowski-Mcgregor, Rachel A Mumby, June Chung, Jinju Li, Nathaniel Osher, Oluwadara Coker, Veerabhadran Baladandayuthapani, Scott Kopetz, Judith S Sebolt-Leopold

Faculty, Staff and Student Publications

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal …

Perioperative Nivolumab Versus Observation In Patients With Renal Cell Carcinoma Undergoing Nephrectomy (Prosper Ecog-Acrin Ea8143): An Open-Label, Randomised, Phase 3 Study, Mohamad E Allaf, Se-Eun Kim, Viraj Master, David F Mcdermott, Lauren C Harshman, Suzanne M Cole, Charles G Drake, Sabina Signoretti, Mahmut Akgul, Nicholas Baniak, Elsa Li-Ning, Matthew B Palmer, Hamid Emamekhoo, Nabil Adra, Hristos Kaimakliotis, Yasser Ged, Phillip M Pierorazio, E Jason Abel, Mehmet A Bilen, Kenneth Ogan, Helen H Moon, Krishna A Ramaswamy, Eric A Singer, Tina M Mayer, Jay Lohrey, Vitaly Margulis, Jessie Gills, Scott E Delacroix, Mark J Waples, Andrew C James, Peng Wang, Toni Choueiri, M Dror Michaelson, Anil Kapoor, Daniel Y Heng, Brian Shuch, Bradley C Leibovich, Primo N Lara, Judith Manola, Deborah Maskens, Dena Battle, Robert Uzzo, Gennady Bratslavsky, Naomi B Haas, Michael A Carducci

Faculty, Staff and Student Publications

Background: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only.

Methods: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or …

Updated Understanding Of The Protein-Dna Recognition Code Used By C2h2 Zinc Finger Proteins, Xing Zhang, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

C2H2 zinc-finger (ZF) proteins form the largest family of DNA-binding transcription factors coded by mammalian genomes. In a typical DNA-binding ZF module, there are twelve residues (numbered from -1 to -12) between the last zinc-coordinating cysteine and the first zinc-coordinating histidine. The established C2H2-ZF "recognition code" suggests that residues at positions -1, -4, and -7 recognize the 5', central, and 3' bases of a DNA base-pair triplet, respectively. Structural studies have highlighted that additional residues at positions -5 and -8 also play roles in specific DNA recognition. The presence of bulky and either charged or polar residues at these five …

Structural Dynamics In Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptor Gating, Cuauhtemoc U Gonzalez, Vasanthi Jayaraman

Faculty, Staff and Student Publications

The ionotropic glutamate receptors (iGluRs) are comprised of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate receptor, kainate, and delta subtypes and are pivotal in neuronal plasticity. Recent structural studies on AMPA receptors reveal intricate conformational changes during activation and desensitization elucidating the steps from agonist binding to channel opening and desensitization. Additionally, interactions with auxiliary subunits, including transmembrane AMPA-receptor regulatory proteins, germ-cell-specific gene 1-like protein, and cornichon homologs, intricately modulate AMPA receptors. We discuss the recent high-resolution structures of these complexes that unveil stoichiometry, subunit positioning, and differences in specific side-chain interactions that influence these functional modulations.

Mc-Keyboard: A Practical Phase I Trial Design For Targeted Therapies And Immunotherapies Integrating Multiple-Grade Toxicities, Liyun Jiang, Zhulin Yin, Fangrong Yan, Ying Yuan

Faculty, Staff and Student Publications

In targeted therapies and immunotherapies, the occurrence of low-grade (e.g., grade 1-2) toxicities (LGT) is common, while dose-limiting toxicities (DLT) are relatively rare. As a result, conventional phase I trial designs, solely based on DLTs and disregarding milder toxicities, are problematic when evaluating these novel therapies.

Methods: To address this issue, we propose a novel phase I design called a multiple-constraint keyboard (MC-Keyboard) that integrates multiple toxicity constraints, accounting for both DLT and LGT, for precise dose escalation and de-escalation, and identification of the maximum tolerated dose (MTD). As a model-assisted design, an important feature of MC-Keyboard is that its …