Life Sciences Commons^™

Correlations Between Peripheral Levels Of Inflammatory Mediators And Frontolimbic Structures In Bipolar Disorder: An Exploratory Analysis, Satyajit Mohite, Haitham Salem, Thiago Cordeiro, Jonika Tannous, Benson Mwangi, Jair C Soares, Antonio L Teixeira

Faculty, Staff and Student Publications

BACKGROUND: Altered peripheral immune/inflammatory system and brain volumetric changes have been implicated in the pathophysiology of bipolar disorder (BD). This study aimed to evaluate how peripheral levels of cytokines are related to volumetric brain changes in euthymic patients with BD.

METHODS: Euthymic patients with BD (n = 21) and healthy controls (n = 22) were enrolled in this exploratory study. Blood samples were collected on the same day of clinical assessment and neuroimaging. Cytokines were measured through cytometric bead array method. Neuroimaging data were acquired using a sagittal three-dimensional magnetic resonance imaging T1-weighted fast field echo sequence and was processed …

The Hect Family Of E3 Ubiquitin Ligases And Pten, Min Sup Song, Pier Paolo Pandolfi

Faculty, Staff and Student Publications

Members of the HECT family of E3 ubiquitin ligases have emerged as prominent regulators of PTEN function, subcellular localization and levels. In turn this unfolding regulatory network is allowing for the identification of genes directly involved in both tumorigenesis at large and cancer susceptibility syndromes. While the complexity of this regulatory network is still being unraveled, these new findings are paving the way for novel therapeutic modalities for cancer prevention and therapy as well as for other diseases. Here we will review the signal transduction and therapeutic implications of the cross-talk between HECT family members and PTEN.

Detecting Förster Resonance Energy Transfer In Living Cells By Conventional And Spectral Flow Cytometry, Jared Henderson, Ondrej Havranek, Man Chun John Ma, Vaclav Herman, Kristyna Kupcova, Mariana Pacheco-Blanco, Justin M Comer, Tomasz Zal, Richard Eric Davis

Faculty, Staff and Student Publications

Assays based on Förster resonance energy transfer (FRET) can be used to study many processes in cell biology. Although this is most often done with microscopy for fluorescence detection, we report two ways to measure FRET in living cells by flow cytometry. Using a conventional flow cytometer and the "3-cube method" for intensity-based calculation of FRET efficiency, we measured the enzymatic activity of specific kinases in cells expressing a genetically-encoded reporter. For both AKT and protein kinase A, the method measured kinase activity in time-course, dose-response, and kinetic assays. Using the Cytek Aurora spectral flow cytometer, which applies linear unmixing …

Preconditioning By Voluntary Wheel Running Attenuates Later Neuropathic Pain Via Nuclear Factor E2-Related Factor 2 Antioxidant Signaling In Rats, Suzanne M Green-Fulgham, Michael E Harland, Jayson B Ball, Jiahe Li, Michael J Lacagnina, Renee A Dreher, Sabina A Lorca, Andrew J Kwilasz, Steven F Maier, Linda R Watkins, Peter M Grace

Faculty, Staff and Student Publications

Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases the formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury across both sexes. This attenuation was associated with reduced nitrotyrosine immunoreactivity-a marker for peroxynitrite-at the sciatic nerve injury site. Our data suggest …

T1 Signal Intensity Ratio Of The Pancreas As An Imaging Biomarker For The Staging Of Chronic Pancreatitis, Temel Tirkes, Anil K Dasyam, Zarine K Shah, Evan L Fogel, Santhi Swaroop Vege, Shuang Li, Carlos A Farinas, Joseph R Grajo, Kareem Mawad, Naoki Takahashi, Sudhakar K Venkatesh, Ashley Wachsman, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Stephen K Van Den Eeden, Yunlong Yang, Mark Topazian, Dana K Andersen, Jose Serrano, Darwin L Conwell, Dhiraj Yadav, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Purpose: Our purpose was to validate the T1 SIR (T1 score) as an imaging biomarker for the staging of CP in a large, multi-institutional, prospective study.

Methods: The prospective study population included 820 participants enrolled in the PROCEED study from nine clinical centers between June 2017 and December 2021. A radiologist at each institution used a standardized method to measure the T1 signal intensity of the pancreas and the reference organs (spleen, paraspinal muscle, liver), which was used to derive respective T1 scores. Participants were stratified according to the seven mechanistic stages of chronic pancreatitis (MSCP 0-6) based on their …

Spatiotemporal Microrna-Gene Expression Network Related To Orofacial Clefts, F Yan, L M Simon, A Suzuki, C Iwaya, P Jia, Z Zhao

Faculty, Staff and Student Publications

Craniofacial structures change dynamically in morphology during development through the coordinated regulation of various cellular molecules. However, it remains unclear how these complex mechanisms are regulated in a spatiotemporal manner. Here we applied natural cubic splines to model gene and microRNA (miRNA) expression from embryonic day (E) 10.5 to E14.5 in the proximal and distal regions of the maxillary processes to identify spatiotemporal patterns of gene and miRNA expression, followed by constructing corresponding regulatory networks. Three major groups of differentially expressed genes (DEGs) were identified, including 3,927 temporal, 314 spatial, and 494 spatiotemporal DEGs. Unsupervised clustering further resolved these spatiotemporal …

Comprehensive Multiplexed Immune Profiling Of The Ductal Carcinoma In Situ Immune Microenvironment Regarding Subsequent Ipsilateral Invasive Breast Cancer Risk, Mathilde M Almekinders, Tycho Bismeijer, Tapsi Kumar, Fei Yang, Bram Thijssen, Charlotte Van Rooijen, Baohua Sun, Edwin R Parra Cuentas, Ignacio I Wistuba, Savitri Krishnamurthy, Lindy L Visser, Iris M Seignette, Ingrid Hofland, Joyce Sanders, Annegien Broeks, Jason K Love, Brian Menegaz, Lodewyk Wessels, Alastair M Thompson, Karin E De Visser, Erik Hooijberg, Esther Lips, Andrew Futreal, Jelle Wesseling

Faculty, Staff and Student Publications

Background: Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.

Methods: Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8- T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with …

Selective Iga Deficiency In Spontaneously Hypertensive Rats With Gut Dysbiosis, Piu Saha, Blair Mell, Rachel M Golonka, Venugopal R Bovilla, Ahmed A Abokor, Beng San Yeoh, Andrew T Gewirtz, Bina Joe, Matam Vijay-Kumar

Faculty, Staff and Student Publications

BACKGROUND: The spontaneously hypertensive rat (SHR) is extensively used to study hypertension. Gut microbiota dysbiosis is a notable feature in SHR for reasons unknown. Immunoglobulin A (IgA) is a major host factor required for gut microbiota homeostasis. We hypothesized that inadequate IgA contributes to gut microbiota dysbiosis in SHR.

METHODS: IgA was measured in feces, cecum, serum, liver, gut-associated lymphoid tissue, and milk from SHR and Wistar Kyoto rats. IgA regulatory factors like IgM, IgG, and

RESULTS: Compared with Wistar Kyoto rats, SHR displayed remarkably near-deficient IgA levels accompanied by compensatory increases in serum IgM and IgG and gut-liver

CONCLUSIONS: …

Targeting The Alk-Cdk9-Tyr19 Kinase Cascade Sensitizes Ovarian And Breast Tumors To Parp Inhibition Via Destabilization Of The P-Tefb Complex, Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Clinton Yam, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N Westin, Sanghoon Lee, Anil K Sood, Liuqing Yang, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor …

Clinical Relevance Of Proteomic Profiling In De Novo Pediatric Acute Myeloid Leukemia: A Children’S Oncology Group Study, Fieke W Hoff, Anneke D Van Dijk, Yihua Qiu, Chenyue W Hu, Rhonda E Ries, Gaye N Jenkins, Alan S Gamis, Richard Aplenc, E Anders Kolb, Todd A Alonzo, Soheil Meshinchi, Amina A Qutub, Eveline S J M De Bont, Terzah M Horton, Steven M Kornblau

Faculty, Staff and Student Publications

Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patients' samples and 30 control CD34+ cell samples, using reverse phase protein arrays with 296 strictly validated antibodies. The multistep MetaGalaxy analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein …

First-In-Human Study Of An Ox40 (Ivuxolimab) And 4-1bb (Utomilumab) Agonistic Antibody Combination In Patients With Advanced Solid Tumors, Omid Hamid, Alberto A Chiappori, John A Thompson, Toshihiko Doi, Siwen Hu-Lieskovan, Willeke Ros, Jean-Philippe Spano, Naiyer A Rizvi, Jeffrey S Wasser, Eric Angevin, Patrick A Ott, Alison Forgie, Wenjing Yang, Cen Guo, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

Background: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.

Methods: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every …

Immunogenomic Profiling Of Lung Adenocarcinoma Reveals Poorly Differentiated Tumors Are Associated With An Immunogenic Tumor Microenvironment, Neal Akhave, Jiexin Zhang, Erin Bayley, Meredith Frank, Shin-Heng Chiou, Runzhe Chen, Edwin Roger Parra, Won-Chul Lee, Stephen Swisher, Luisa Solis, Annikka Weissferdt, Cesar Moran, Neda Kalhor, Jianhua Zhang, Paul Scheet, Ara A Vaporciyan, Boris Sepesi, Don L Gibbons, John V Heymach, Jack J Lee, Ignacio I Wistuba, P Andrew Futreal, Jianjun Zhang, Junya Fujimoto, Alexandre Reuben

Faculty, Staff and Student Publications

OBJECTIVES: Pathologists have routinely observed distinct histologic patterns of growth in early-stage lung adenocarcinoma (LUAD), which have been suggested to be associated with prognosis. Herein, we investigated the relationship between LUAD patterns of growth, as defined by the updated international association for the study of lung cancer (IASLC) grading criteria, and differences in the tumor immune microenvironment to identify predictors of response to immunotherapy.

METHODS: 174 resected stage I-III LUAD tumors were classified by histologic pattern of growth (i.e. solid, micropapillary, acinar, papillary, and lepidic) and then grouped as well differentiated, moderately differentiated, and poorly differentiated. Comprehensive multiplatform analysis including …

Clinical And Pathological Characteristics And Outcomes Among Patients With Subcutaneous Panniculitis-Like T-Cell Lymphoma And Related Adipotropic Lymphoproliferative Disorders, Joan Guitart, Aaron R Mangold, Maria Estela Martinez-Escala, Christina J Walker, Nneka I Comfere, Kerri E Rieger, Laura B Pincus, Erica S Kumar, Erica Bo Kyung Wang, Katherine E Park, Maria L Espinosa, Madeleine Duvic, Youn H Kim, Steven Horwitz

Faculty, Staff and Student Publications

IMPORTANCE: There is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date.

OBJECTIVE: To generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort …

Association Of Pd-L1 Expression And Other Variables With Benefit From Immune Checkpoint Inhibition In Advanced Gastroesophageal Cancer: Systematic Review And Meta-Analysis Of 17 Phase 3 Randomized Clinical Trials, Harry H Yoon, Zhaohui Jin, Oudom Kour, Lionel Aurelien Kankeu Fonkoua, Kohei Shitara, Larry J Prokop, Yoon-Koo Kang, Qian Shi, Jaffer A Ajani

Faculty, Staff and Student Publications

Importance: Approval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.

Objective: To systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability.

Data sources: MEDLINE, Embase, Scopus, Web of Science, Cochrane …

Monkeypox: What Do Dental Professionals Need To Know?, Charifa Zemouri, Edgar O Beltrán, Richard Holliday, Nicholas S Jakubovics, James R Allison

Faculty, Staff and Student Publications

Infection control is critical for the safe delivery of dental care. Infection control practices must be responsive to emerging and re-emerging infectious diseases and outbreaks, as was clearly seen during the peak of the COVID-19 pandemic. An emerging global outbreak of the monkeypox virus has again raised potential challenges for infection control in dentistry. Monkeypox is an infectious disease, characterised by a rash affecting the skin and soft tissues, including the oral cavity. Previously, cases were mostly seen following contact with infected animals in Central and West Africa, with limited human-to-human transmission within and outside of these areas. However, since …

The Circular Rna Edis Regulates Neurodevelopment And Innate Immunity, Xiao-Peng Xiong, Weihong Liang, Wei Liu, Shiyu Xu, Jian-Liang Li, Julia Situ, Chunlai Wu, Ranjan J Perera, Sheng Zhang, Rui Zhou

Faculty, Staff and Student Publications

Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset has been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis (circ_Ect4) causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotor activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective …

Effect Of Dexamethasone On Dyspnoea In Patients With Cancer (Abcd): A Parallel-Group, Double-Blind, Randomised, Controlled Trial, David Hui, Veronica Puac, Zeena Shelal, Rony Dev, Sandra K Hanneman, Hilary Ma, Sanjay Shete, Frank Fossella, Zhongxing Liao, George Blumenschein, Joe Y Chang, Michael O'Reilly, Saumil J Gandhi, Anne Tsao, Donald A Mahler, Eduardo Bruera

Faculty, Staff and Student Publications

BACKGROUND: Systemic corticosteroids are commonly prescribed for palliation of dyspnoea in patients with cancer, despite scarce evidence to support their use. We aimed to assess the effect of high-dose dexamethasone versus placebo on cancer-related dyspnoea.

METHODS: This double-blind, multi-site, parallel group randomized trial enrolled ambulatory patients with cancer, age ≥18, average dyspnea intensity over the past week ≥4/10 in a 0–10 point numeric rating scale and randomly assigned them to receive dexamethasone 8 mg orally every 12 hours for 7 days followed by 4 mg orally every 12 hours for 7 days or matching placebo capsules. Pharmacists conducted permuted block …

Stat3 Inhibits Autocrine Ifn Signaling In Type I Conventional Dendritic Cells, Taylor T Chrisikos, Yifan Zhou, Laura M Kahn, Bhakti Patel, Nina L Denne, Li Shen, Stephanie S Watowich

Faculty, Staff and Student Publications

Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli regulate cDC1 function remain unclear. We previously demonstrated that the cytokine-responsive transcriptional regulator STAT3 inhibits polyinosinic:polycytidylic acid [poly(I:C)]-induced cDC1 maturation and cDC1-mediated antitumor immunity in murine breast cancer, indicating an intrinsic, suppressive role for STAT3 in cDC1s. To probe transcriptional mechanisms regulating cDC1 function, we generated novel RNA sequencing datasets representing poly(I:C)-, IL-10-, and STAT3-mediated gene expression responses in murine cDC1s. Bioinformatics analyses …

Efficacy And Safety Of A Single Dose Of Casirivimab And Imdevimab For The Prevention Of Covid-19 Over An 8-Month Period: A Randomised, Double-Blind, Placebo-Controlled Trial, Gary A Herman, Meagan P O'Brien, Eduardo Forleo-Neto, Neena Sarkar, Flonza Isa, Kuo-Chen Chan, Ruanne V Barnabas, Dan H Barouch, Myron S Cohen, Christopher B Hurt, Dale R Burwen, Mary A Marovich, Bret J Musser, John D Davis, Kenneth C Turner, Adnan Mahmood, Andrea T Hooper, Jennifer D Hamilton, Janie Parrino, Danise Subramaniam, Alina Baum, Christos A Kyratsous, A Thomas Dicioccio, Neil Stahl, Ned Braunstein, George D Yancopoulos, David M Weinreich, Covid-19 Phase 3 Prevention Trial Team

Faculty, Staff and Student Publications

BACKGROUND: There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings.

METHODS: This was a randomised, …

Dosimetric Analysis Of Mr-Linac Treatment Plans For Salvage Spine Sbrt Re-Irradiation, Eun Young Han, Debra N Yeboa, Tina M Briere, Jinzhong Yang, He Wang

Faculty, Staff and Student Publications

PURPOSE: We investigated the feasibility of thoracic spine stereotactic body radiotherapy (SBRT) using the Elekta Unity magnetic resonance-guided linear accelerator (MRL) in patients who received prior radiotherapy. We hypothesized that Monaco treatment plans can improve the gross tumor volume minimum dose (GTVmin) with spinal cord preservation and maintain consistent plan quality during daily adaptation.

METHODS: Pinnacle clinical plans for 10 patients who underwent thoracic spine SBRT (after prior radiotherapy) were regenerated in the Monaco treatment planning system for the Elekta Unity MRL using 9 and 13 intensity-modulated radiotherapy (IMRT) beams. Monaco adapt-to-position (ATP) and adapt-to-shape (ATS) workflow plans were generated …

Targeting Hemoglobin To Reduce Delayed Cerebral Ischemia After Subarachnoid Hemorrhage, Hussein A Zeineddine, Pedram Honarpisheh, Devin Mcbride, Peeyush Kumar Thankamani Pandit, Ari Dienel, James Grotta

Faculty, Staff and Student Publications

Delayed cerebral ischemia (DCI) continues to be a sequela of aneurysmal subarachnoid hemorrhage (aSAH) that carries significant morbidity and mortality. Aside from nimodipine, no therapeutic agents are available to reduce the incidence of DCI. Pathophysiologic mechanisms contributing to DCI are poorly understood, but accumulating evidence over the years implicates several factors. Those have included microvessel vasoconstriction, microthrombosis, oxidative tissue damage, and cortical spreading depolarization as well as large vessel vasospasm. Common to these processes is red blood cell leakage into the cerebrospinal fluids (CSF) and subsequent lysis which releases hemoglobin, a central instigator in these events. This has led to …

Brequinar And Dipyridamole In Combination Exhibits Synergistic Antiviral Activity Against Sars-Cov-2 In Vitro: Rationale For A Host-Acting Antiviral Treatment Strategy For Covid-19, James F Demarest, Maryline Kienle, Ruthmabel Boytz, Mary Ayres, Eun Jung Kim, Donghoon Chung, Robert A Davey, David B Sykes, Nadim Shohdy, John C Pottage, Vikram S Kumar

Faculty, Staff and Student Publications

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the associated global pandemic resulting in >400 million infections worldwide and several million deaths. The continued evolution of SARS-CoV-2 to potentially evade vaccines and monoclonal antibody (mAb)-based therapies and the limited number of authorized small-molecule antivirals necessitates the need for development of new drug treatments. There remains an unmet medical need for effective and convenient treatment options for SARS-CoV-2 infection. SARS-CoV-2 is an RNA virus that depends on host intracellular ribonucleotide pools for its replication. Dihydroorotate dehydrogenase (DHODH) is a ubiquitous host …

Machine Learning Modeling Of Protein-Intrinsic Features Predicts Tractability Of Targeted Protein Degradation, Wubing Zhang, Shourya S Roy Burman, Jiaye Chen, Katherine A Donovan, Yang Cao, Boning Zhang, Shengqing Gu, Yi Zhang, Dian Li, Eric S Fischer, Collin Tokheim, X Shirley Liu

Faculty, Staff and Student Publications

Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell’s endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed “degradability”, is largely unknown. Here, we developed a machine learning model, model-free analysis of protein degradability (MAPD), to predict degradability from features intrinsic to protein targets. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds [with an area under the precision–recall curve (AUPRC) of 0.759 and an area under the receiver operating characteristic curve (AUROC) of 0.775] and is …

Lurbinectedin, A Selective Inhibitor Of Oncogenic Transcription, In Patients With Pretreated Germline Brca1/2 Metastatic Breast Cancer: Results From A Phase Ii Basket Study, V Boni, B Pistilli, I Braña, G I Shapiro, J Trigo, D Castellano, C Kahatt, V Alfaro, M Siguero, A Zeaiter, F Longo, K Zaman, A Antón, A Paredes, G Huidobro, V Subbiah

Faculty, Staff and Student Publications

Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer.

Patients and methods: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival …

A Randomized Controlled Trial Evaluating The Effects Of Social Networking On Chronic Disease Management In Rheumatoid Arthritis, Maria A Lopez-Olivo, Jessica T Foreman, Cheuk Leung, Heather Y Lin, Tiffany Westrich-Robertson, Jude K A Des Bordes, Amye Leong, Irmgard U Willcockson, Susan K Peterson, Maria E Suarez-Almazor

Faculty, Staff and Student Publications

OBJECTIVE: Social networking has been shown to improve health outcomes in certain patient populations. While patients with rheumatoid arthritis (RA) increasingly use social networking to communicate with peers, the effects of these interactions are largely unknown.

METHODS: In a randomized controlled trial, we compared RA patients who participated in a social networking group moderated by peer leaders and who had access to a static website offering RA materials with a control group, who only had access to the website. The primary outcomes were patients' RA knowledge, self-efficacy and empowerment. Secondary outcomes included participation in desired health behaviors, and satisfaction with …

First-In-Human Phase 1/1b Study To Evaluate Sitravatinib In Patients With Advanced Solid Tumors, Todd Bauer, Byong Chul Cho, Rebecca Heist, Lyudmila Bazhenova, Theresa Werner, Dong-Wan Kim, Richard D Carvajal, Ajjai Alva, Keith Eaton, Judy Wang, Yong Liu, Xiaohong Yan, Jamie Christensen, Saskia Neuteboom, Richard Chao, Shubham Pant

Faculty, Staff and Student Publications

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10-200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = …

Nerve Density And Neuronal Biomarkers In Cancer, Shahrukh R Ali, Madeleine Jordan, Priyadharsini Nagarajan, Moran Amit

Faculty, Staff and Student Publications

Certain histologic characteristics of neurons, novel neuronal biomarkers, and nerve density are emerging as important diagnostic and prognostic tools in several cancers. The tumor microenvironment has long been known to promote tumor development via promoting angiogenesis and cellular proliferation, but new evidence has shown that neural proliferation and invasion in the tumor microenvironment may also enable tumor growth. Specific neuronal components in peripheral nerves and their localization in certain tumor sites have been identified and associated with tumor aggressiveness. In addition, dense neural innervation has been shown to promote tumorigenesis. In this review, we will summarize the histological components of …

Use Of Breast Surveillance Between Women With Pathogenic Variants And Variants Of Uncertain Significance In Breast Cancer Susceptibility Genes, Sukh Makhnoon, Minxing Chen, Brooke Levin, Megan Ensinger, Kristin D Mattie, Sanjay Shete, Susan K Peterson

Faculty, Staff and Student Publications

BACKGROUND: Use of surveillance mammography and magnetic resonance imaging (MRI) has been understudied among women with variant of uncertain significance (VUS) compared to pathogenic and likely pathogenic variants (P/LP).

METHODS: Using data from two cancer settings, we calculated use of risk-reducing mastectomy (RRM) and surveillance during each 13-month span after genetic testing up to 6 years afterwards for a cohort of genetically elevated risk women.

RESULTS: Of 889 women, VUS carriers were less likely to undergo RRM compared to those with P/LP (hazard ratio [HR], 0.17; p =

CONCLUSION: The authors found that VUS, whether in high or moderate penetrance …

Response To Brentuximab Vedotin By Cd30 Expression In Non-Hodgkin Lymphoma, Deepa Jagadeesh, Steve Horwitz, Nancy L Bartlett, Youn Kim, Eric Jacobsen, Meredith Little, Keenan Fenton, Matthew Onsum, Julie Lisano, Ranjana Advani

Faculty, Staff and Student Publications

BACKGROUND: The safety and efficacy of brentuximab vedotin (BV), an antibody-drug conjugate directed to the CD30 antigen, has been assessed in several trials in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin lymphoma (NHL). The objective of this research was to examine the relationship between CD30 expression level and clinical response to BV.

PATIENTS AND METHODS: We analyzed response in patients treated with BV monotherapy in 5 prospective clinical studies in relapsed or refractory PTCL, CTCL, or B-cell NHL. CD30 expression was assessed by immunohistochemistry (IHC) using the Ber H2 antibody for 275 patients.

RESULTS: …

Aapm Report 373: The Content, Structure, And Value Of The Professional Doctorate In Medical Physics (Dmp), Jay W Burmeister, Charles W Coffey, John D Hazle, Neil Kirby, Yu Kuang, Brian Loughery

Faculty, Staff and Student Publications

The Professional Doctorate in Medical Physics (DMP) was originally conceived as a solution to the shortage of medical physics residency training positions. While this shortage has now been largely satisfied through conventional residency training positions, the DMP has expanded to multiple institutions and grown into an educational pathway that provides specialized clinical training and extends well beyond the creation of additional training spots. As such, it is important to reevaluate the purpose and the value of the DMP. Additionally, it is important to outline the defining characteristics of the DMP to assure that all existing and future programs provide this …