Digital Commons Network^™

The Effect Of Biologic Therapy For Immune-Mediated Inflammatory Diseases On Clinical Outcomes Of Covid-19 In The Greater Houston Area: A Retrospective Chart Review, Michela Tinelli, Raphael Wittenberg, Michelle Cornes, Robert W Aldridge, Michael Clark, Richard Byng, Graham Foster, James Fuller, Andrew Hayward, Nigel Hewett, Alan Kilmister, Jill Manthorpe, Joanne Neale, Elizabeth Biswell, Martin Whiteford

Faculty, Staff and Student Publications

There are long-standing concerns that people experiencing homelessness may not recover well if left unsupported after a hospital stay. This study reports on a study investigating the cost-effectiveness of three different 'in patient care coordination and discharge planning' configurations for adults experiencing homelessness who are discharged from hospitals in England. The first configuration provided a clinical and housing in-reach service during acute care and discharge coordination but with no 'step-down' care. The second configuration provided clinical and housing in-reach, discharge coordination and 'step-down' intermediate care. The third configuration consisted of housing support workers providing in-reach and discharge coordination as well …

Comparison Of Setup Accuracy And Efficiency Between The Klarity System And Bodyfix System For Spine Stereotactic Body Radiation Therapy, Enzhuo Quan, Shane P Krafft, Tina M Briere, Marissa J Vaccarelli, Amol J Ghia, Andrew J Bishop, Debra N Yeboa, Todd A Swanson, Eun Young Han

Faculty, Staff and Student Publications

BACKGROUND: Spine stereotactic body radiation therapy (SBRT) uses highly conformal dose distributions and sharp dose gradients to cover targets in proximity to the spinal cord or cauda equina, which requires precise patient positioning and immobilization to deliver safe treatments.

AIMS: Given some limitations with the BodyFIX system in our practice, we sought to evaluate the accuracy and efficiency of the Klarity SBRT patient immobilization system in comparison to the BodyFIX system.

METHODS: Twenty-three patients with 26 metastatic spinal lesions (78 fractions) were enrolled in this prospective observational study with one of two systems - BodyFIX (n = 11) or Klarity …

Inhibition Of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance To Programmed Cell Death 1 Blockade In Malignant Mesothelioma, Hee-Jin Jang, Cynthia Y Truong, Eric M Lo, Hudson M Holmes, Daniela Ramos, Maheshwari Ramineni, Ju-Seog Lee, Daniel Y Wang, Massimo Pietropaolo, R Taylor Ripley, Bryan M Burt, Hyun-Sung Lee

Faculty, Staff and Student Publications

BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with programmed cell death 1 (PD-1) blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.

METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 nonresponders). We used The Cancer Genome Atlas MPM cohort (n = 73) to determine what genomic alterations were associated with the resistance signature. We tested …

Investigation Of Murine Host Sex As A Biological Variable In Epithelial Barrier Function And Muscle Contractility In Human Intestinal Organoids, Brooke T Beanland, Eoin P Mcneill, David J Sequeira, Hasen Xue, Noah F Shroyer, Allison L Speer

Faculty, Staff and Student Publications

Intestinal failure (IF) occurs when intestinal surface area or function is not sufficient to support digestion and nutrient absorption. Human intestinal organoid (HIO)-derived tissue-engineered intestine is a potential cure for IF. Research to date has demonstrated successful HIO transplantation (tHIO) into mice with significant in vivo maturation. An area lacking in the literature is exploration of murine host sex as a biological variable (SABV) in tHIO function. In this study, we investigate murine host SABV in tHIO epithelial barrier function and muscle contractility. HIOs were generated in vitro and transplanted into nonobese diabetic, severe combined immunodeficiency gamma chain deficient male …

Combined Regulatory T-Lymphocyte And Il-2 Treatment Is Safe, Tolerable, And Biologically Active For 1 Year In Persons With Amyotrophic Lateral Sclerosis, Jason R Thonhoff, James D Berry, Eric A Macklin, David R Beers, Patricia A Mendoza, Weihua Zhao, Aaron D Thome, Fabio Triolo, James J Moon, Sabrina Paganoni, Merit Cudkowicz, Stanley H Appel

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.

METHODS: Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 10

RESULTS: The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive …

Differential Integrated Stress Response And Asparagine Production Drive Symbiosis And Therapy Resistance Of Pancreatic Adenocarcinoma Cells, Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy Mccarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca Di Magliano, Claus Jorgensen, Costas A Lyssiotis

Faculty, Staff and Student Publications

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive …

The Equilibrium Of Tumor Suppression: Dubs As Active Regulators Of Pten, Audrey Christine, Mi Kyung Park, Su Jung Song, Min Sup Song

Faculty, Staff and Student Publications

PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have …

Molecular Mechanisms Of Resistance To Kinase Inhibitors And Redifferentiation In Thyroid Cancers, Marie-Claude Hofmann, Muthusamy Kunnimalaiyaan, Jennifer R Wang, Naifa L Busaidy, Steven I Sherman, Stephen Y Lai, Mark Zafereo, Maria E Cabanillas

Faculty, Staff and Student Publications

Protein kinases play critical roles in cell survival, proliferation and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies. However, despite satisfactory early responses, these drugs are not curative and most patients inevitably progress due to drug resistance. This review summarizes up-to-date knowledge on various mechanisms that thyroid cancer cells develop to bypass protein kinase inhibition and outlines strategies that are being explored to overcome …

A Semi-Mechanistic Dose-Finding Design In Oncology Using Pharmacokinetic/Pharmacodynamic Modeling, Xiao Su, Yisheng Li, Peter Müller, Chia-Wei Hsu, Haitao Pan, Kim-Anh Do

Faculty, Staff and Student Publications

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting …

Molecular Map Of Chronic Lymphocytic Leukemia And Its Impact On Outcome, Binyamin A Knisbacher, Ziao Lin, Cynthia K Hahn, Ferran Nadeu, Martí Duran-Ferrer, Kristen E Stevenson, Eugen Tausch, Julio Delgado, Alex Barbera-Mourelle, Amaro Taylor-Weiner, Pablo Bousquets-Muñoz, Ander Diaz-Navarro, Andrew Dunford, Shankara Anand, Helene Kretzmer, Jesus Gutierrez-Abril, Sara López-Tamargo, Stacey M Fernandes, Clare Sun, Mariela Sivina, Laura Z Rassenti, Christof Schneider, Shuqiang Li, Laxmi Parida, Alexander Meissner, François Aguet, Jan A Burger, Adrian Wiestner, Thomas J Kipps, Jennifer R Brown, Michael Hallek, Chip Stewart, Donna S Neuberg, José I Martín-Subero, Xose S Puente, Stephan Stilgenbauer, Catherine J Wu, Elias Campo, Gad Getz

Faculty, Staff and Student Publications

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. …

T Cells Specific For Α-Myosin Drive Immunotherapy-Related Myocarditis, Margaret L Axelrod, Wouter C Meijers, Elles M Screever, Juan Qin, Mary Grace Carroll, Xiaopeng Sun, Elie Tannous, Yueli Zhang, Ayaka Sugiura, Brandie C Taylor, Ann Hanna, Shaoyi Zhang, Kaushik Amancherla, Warren Tai, Jordan J Wright, Spencer C Wei, Susan R Opalenik, Abigail L Toren, Jeffrey C Rathmell, P Brent Ferrell, Elizabeth J Phillips, Simon Mallal, Douglas B Johnson, James P Allison, Javid J Moslehi, Justin M Balko

Faculty, Staff and Student Publications

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, …

Impact Of Conditioning Chemotherapy On Lymphocyte Kinetics And Outcomes In Lbcl Patients Treated With Car T-Cell Therapy, Paolo Strati, Andrew P Jallouk, Ryan Sun, Jaihee Choi, Kaberi Das, Hua-Jay Cherng, Sairah Ahmed, Hun J Lee, Swaminathan P Iyer, Ranjit Nair, Loretta J Nastoupil, Raphael E Steiner, Chad D Huff, Yao Yu, Haleigh Mistry, Brittany Pulsifer, Mansoor Noorani, Neeraj Saini, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Jason R Westin, Michelle A T Hildebrandt, Sattva S Neelapu

Faculty, Staff and Student Publications

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 109/L (range, 0.01-2.75 × 109/L) and was significantly higher in patients who achieved complete response (p = 0.04). On …

Image Analysis Reveals Differences In Tumor Multinucleations In Black And White Patients With Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma, Can F Koyuncu, Reetoja Nag, Cheng Lu, Germán Corredor, Vidya S Viswanathan, Vlad C Sandulache, Pingfu Fu, Kailin Yang, Quintin Pan, Zelin Zhang, Jun Xu, Deborah J Chute, Wade L Thorstad, Farhoud Faraji, Justin A Bishop, Mitra Mehrad, Patricia D Castro, Andrew G Sikora, Lester D R Thompson, Rebecca D Chernock, Krystle A Lang Kuhs, Jay K Wasman, Jingqin R Luo, David J Adelstein, Shlomo A Koyfman, James S Lewis, Anant Madabhushi

Faculty, Staff and Student Publications

BACKGROUND: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies.

METHODS: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin-eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same …

Structural Brain Alterations Associated With Suicidal Thoughts And Behaviors In Young People: Results From 21 International Studies From The Enigma Suicidal Thoughts And Behaviours Consortium, Laura S Van Velzen, Maria R Dauvermann, Lejla Colic, Luca M Villa, Hannah S Savage, Yara J Toenders, Alyssa H Zhu, Joanna K Bright, Adrián I Campos, Lauren E Salminen, Sonia Ambrogi, Rosa Ayesa-Arriola, Nerisa Banaj, Zeynep Başgöze, Jochen Bauer, Karina Blair, Robert James Blair, Katharina Brosch, Yuqi Cheng, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Baptiste Couvy-Duchesne, Benedicto Crespo-Facorro, Kathryn R Cullen, Udo Dannlowski, Christopher G Davey, Katharina Dohm, Janice M Fullerton, Ali Saffet Gonul, Ian H Gotlib, Dominik Grotegerd, Tim Hahn, Ben J Harrison, Mengxin He, Ian B Hickie, Tiffany C Ho, Frank Iorfino, Andreas Jansen, Fabrice Jollant, Tilo Kircher, Bonnie Klimes-Dougan, Melissa Klug, Elisabeth J Leehr, Elizabeth T C Lippard, Katie A Mclaughlin, Susanne Meinert, Adam Bryant Miller, Philip B Mitchell, Benson Mwangi, Igor Nenadić, Amar Ojha, Bronwyn J Overs, Julia-Katharina Pfarr, Fabrizio Piras, Kai G Ringwald, Gloria Roberts, Georg Romer, Marsal Sanches, Margaret A Sheridan, Jair C Soares, Gianfranco Spalletta, Frederike Stein, Giana I Teresi, Diana Tordesillas-Gutiérrez, Aslihan Uyar-Demir, Nic J A Van Der Wee, Steven J Van Der Werff, Robert R J M Vermeiren, Alexandra Winter, Mon-Ju Wu, Tony T Yang, Paul M Thompson, Miguel E Rentería, Neda Jahanshad, Hilary P Blumberg, Anne-Laura Van Harmelen, Enigma Suicidal Thoughts And Behaviours Consortium, Lianne Schmaal

Faculty, Staff and Student Publications

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample …

Genome-Wide Meta-Analyses Reveal Novel Loci For Verbal Short-Term Memory And Learning, Jari Lahti, Samuli Tuominen, Qiong Yang, Giulio Pergola, Shahzad Ahmad, Najaf Amin, Nicola J Armstrong, Alexa Beiser, Katharina Bey, Joshua C Bis, Eric Boerwinkle, Jan Bressler, Archie Campbell, Harry Campbell, Qiang Chen, Janie Corley, Simon R Cox, Gail Davies, Philip L De Jager, Eske M Derks, Jessica D Faul, Annette L Fitzpatrick, Alison E Fohner, Ian Ford, Myriam Fornage, Zachary Gerring, Hans J Grabe, Francine Grodstein, Vilmundur Gudnason, Eleanor Simonsick, Elizabeth G Holliday, Peter K Joshi, Eero Kajantie, Jaakko Kaprio, Pauliina Karell, Luca Kleineidam, Maria J Knol, Nicole A Kochan, John B Kwok, Markus Leber, Max Lam, Teresa Lee, Shuo Li, Anu Loukola, Tobias Luck, Riccardo E Marioni, Karen A Mather, Sarah Medland, Saira S Mirza, Mike A Nalls, Kwangsik Nho, Adrienne O'Donnell, Christopher Oldmeadow, Jodie Painter, Alison Pattie, Simone Reppermund, Shannon L Risacher, Richard J Rose, Vijay Sadashivaiah, Markus Scholz, Claudia L Satizabal, Peter W Schofield, Katharina E Schraut, Rodney J Scott, Jeannette Simino, Albert V Smith, Jennifer A Smith, David J Stott, Ida Surakka, Alexander Teumer, Anbupalam Thalamuthu, Stella Trompet, Stephen T Turner, Sven J Van Der Lee, Arno Villringer, Uwe Völker, Robert S Wilson, Katharina Wittfeld, Eero Vuoksimaa, Rui Xia, Kristine Yaffe, Lei Yu, Habil Zare, Wei Zhao, David Ames, John Attia, David A Bennett, Henry Brodaty, Daniel I Chasman, Aaron L Goldman, Caroline Hayward, M Arfan Ikram, J Wouter Jukema, Sharon L R Kardia, Todd Lencz, Markus Loeffler, Venkata S Mattay, Aarno Palotie, Bruce M Psaty, Alfredo Ramirez, Paul M Ridker, Steffi G Riedel-Heller, Perminder S Sachdev, Andrew J Saykin, Martin Scherer, Peter R Schofield, Stephen Sidney, John M Starr, Julian Trollor, William Ulrich, Michael Wagner, David R Weir, James F Wilson, Margaret J Wright, Daniel R Weinberger, Stephanie Debette, Johan G Eriksson, Thomas H Mosley, Lenore J Launer, Cornelia M Van Duijn, Ian J Deary, Sudha Seshadri, Katri Räikkönen

Faculty, Staff and Student Publications

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during …

Estimation Of Tumor Cell Total Mrna Expression In 15 Cancer Types Predicts Disease Progression, Shaolong Cao, Jennifer R Wang, Shuangxi Ji, Peng Yang, Yaoyi Dai, Shuai Guo, Matthew D Montierth, John Paul Shen, Xiao Zhao, Jingxiao Chen, Jaewon James Lee, Paola A Guerrero, Nicholas Spetsieris, Nikolai Engedal, Sinja Taavitsainen, Kaixian Yu, Julie Livingstone, Vinayak Bhandari, Shawna M Hubert, Najat C Daw, P Andrew Futreal, Eleni Efstathiou, Bora Lim, Andrea Viale, Jianjun Zhang, Matti Nykter, Bogdan A Czerniak, Powel H Brown, Charles Swanton, Pavlos Msaouel, Anirban Maitra, Scott Kopetz, Peter Campbell, Terence P Speed, Paul C Boutros, Hongtu Zhu, Alfonso Urbanucci, Jonas Demeulemeester, Peter Van Loo, Wenyi Wang

Faculty, Staff and Student Publications

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene …

Stat6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis And Asthma, A Model Of Unified Airway Disease, Meng Lin, Amy T Ku, Jie Dong, Fei Yue, Weiyu Jiang, Ahmed Atef Ibrahim, Fanglue Peng, Chad J Creighton, Chandandeep Nagi, Carolina Gutierrez, Jeffrey M Rosen, Xiang H-F Zhang, Susan G Hilsenbeck, Xi Chen, Yi-Chieh Nancy Du, Shixia Huang, Aiping Shi, Zhimin Fan, Yi Li

Faculty, Staff and Student Publications

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5aca) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5aca reduced the migratory and invasive ability of human breast cancer cell lines in …

Assessment Of Bubble Activity Generated By Histotripsy Combined With Echogenic Liposomes, Aarushi Bhargava, Shaoling Huang, David D Mcpherson, Kenneth B Bader

Faculty, Staff and Student Publications

No abstract provided.

Altering Brain Amyloidosis By Intra-Lingual And Extra-Nasal Exposure Of Aβ Aggregates, Nazaret Gamez, Javiera Bravo-Alegria, Yumeng Huang, Nelson Perez-Urrutia, Deepa Dongarwar, Claudio Soto, Rodrigo Morales

Faculty, Staff and Student Publications

Extensive experimental and human-derived evidence suggest that misfolded Aβ particles spread similarly to infectious prions. Moreover, peripheral administration of Aβ seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aβ from the periphery to the brain are not fully understood, although circulation and retrograde axonal transport have been proposed. Here, we demonstrate that injection of Aβ seeds in the tongue, a highly innervated organ, substantially accelerates the appearance of plaques in Tg2576 mice. In addition, the extra-nasal exposure of Aβ aggregates increased amyloid pathology in the olfactory bulb. Our …

Naphthoquinones Oxidize H2s To Polysulfides And Thiosulfate, Implications For Therapeutic Applications, Kenneth R Olson, Kasey J Clear, Paul J Derry, Yan Gao, Zhilin Ma, Nathaniel M Cieplik, Alyssa Fiume, Dominic J Gaziano, Stephen M Kasko, Kathleen Narloch, Cecilia L Velander, Ifeyinwa Nwebube, Collin J Pallissery, Ella Pfaff, Brian P Villa, Thomas A Kent, Gang Wu, Karl D Straub

Faculty, Staff and Student Publications

1,4-Napththoquinones (NQs) are clinically relevant therapeutics that affect cell function through production of reactive oxygen species (ROS) and formation of adducts with regulatory protein thiols. Reactive sulfur species (RSS) are chemically and biologically similar to ROS and here we examine RSS production by NQ oxidation of hydrogen sulfide (H2S) using RSS-specific fluorophores, liquid chromatography-mass spectrometry, UV-Vis absorption spectrometry, oxygen-sensitive optodes, thiosulfate-specific nanoparticles, HPLC-monobromobimane derivatization, and ion chromatographic assays. We show that NQs, catalytically oxidize H2S to per- and polysulfides (H2Sn, n = 2−6), thiosulfate, sulfite and sulfate in reactions that consume oxygen and are accelerated by superoxide dismutase (SOD) and …

A Machine Learning-Based Method For Automatically Identifying Novel Cells In Annotating Single-Cell Rna-Seq Data, Ziyi Li, Yizhuo Wang, Irene Ganan-Gomez, Simona Colla, Kim-Anh Do

Faculty, Staff and Student Publications

MOTIVATION: Single-cell RNA sequencing (scRNA-seq) has been widely used to decompose complex tissues into functionally distinct cell types. The first and usually the most important step of scRNA-seq data analysis is to accurately annotate the cell labels. In recent years, many supervised annotation methods have been developed and shown to be more convenient and accurate than unsupervised cell clustering. One challenge faced by all the supervised annotation methods is the identification of the novel cell type, which is defined as the cell type that is not present in the training data, only exists in the testing data. Existing methods usually …

Standards In Semen Examination: Publishing Reproducible And Reliable Data Based On High-Quality Methodology, Lars Björndahl, Christopher L R Barratt, David Mortimer, Ashok Agarwal, Robert J Aitken, Juan G Alvarez, Natalie Aneck-Hahn, Stefan Arver, Elisabetta Baldi, Lluís Bassas, Florence Boitrelle, Riana Bornman, Douglas T Carrell, José A Castilla, Gerardo Cerezo Parra, Jerome H Check, Patricia S Cuasnicu, Sally Perreault Darney, Christiaan De Jager, Christopher J De Jonge, Joël R Drevet, Erma Z Drobnis, Stefan S Du Plessis, Michael L Eisenberg, Sandro C Esteves, Evangelini A Evgeni, Alberto Ferlin, Nicolas Garrido, Aleksander Giwercman, Ilse G F Goovaerts, Trine B Haugen, Ralf Henkel, Lars Henningsohn, Marie-Claude Hofmann, James M Hotaling, Piotr Jedrzejczak, Pierre Jouannet, Niels Jørgensen, Jackson C Kirkman Brown, Csilla Krausz, Maciej Kurpisz, Ulrik Kvist, Dolores J Lamb, Hagai Levine, Kate L Loveland, Robert I Mclachlan, Ali Mahran, Liana Maree, Sarah Martins Da Silva, Michael T Mbizvo, Andreas Meinhardt, Roelof Menkveld, Sharon T Mortimer, Sergey Moskovtsev, Charles H Muller, Maria José Munuce, Monica Muratori, Craig Niederberger, Cristian O'Flaherty, Rafael Oliva, Willem Ombelet, Allan A Pacey, Michael A Palladino, Ranjith Ramasamy, Liliana Ramos, Nathalie Rives, Eduardo Rs Roldan, Susan Rothmann, Denny Sakkas, Andrea Salonia, Maria Cristina Sánchez-Pozo, Rosanna Sapiro, Stefan Schlatt, Peter N Schlegel, Hans-Christian Schuppe, Rupin Shah, Niels E Skakkebæk, Katja Teerds, Igor Toskin, Herman Tournaye, Paul J Turek, Gerhard Van Der Horst, Monica Vazquez-Levin, Christina Wang, Alex Wetzels, Theodosia Zeginiadou, Armand Zini

Faculty, Staff and Student Publications

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

Inhibition Of Colorectal Cancer Tumorigenesis By Ursolic Acid And Doxorubicin Is Mediated By Targeting The Akt Signaling Pathway And Activating The Hippo Signaling Pathway, Masashi Fujita, Mei-Ju May Chen, Doris Rieko Siwak, Shota Sasagawa, Ayako Oosawa-Tatsuguchi, Koji Arihiro, Atsushi Ono, Ryoichi Miura, Kazuhiro Maejima, Hiroshi Aikata, Masaki Ueno, Shinya Hayami, Hiroki Yamaue, Kazuaki Chayama, Ju-Seog Lee, Yiling Lu, Gordon B Mills, Han Liang, Satoshi S Nishizuka, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Primary liver cancer is a heterogeneous disease in terms of its etiology, histology, and therapeutic response. Concurrent proteomic and genomic characterization of a large set of clinical liver cancer samples can help elucidate the molecular basis of heterogeneity and thus serve as a valuable resource for personalized liver cancer treatment. In this study, we perform proteomic profiling of ~300 proteins on 259 primary liver cancer tissues with reverse-phase protein arrays, mutational analysis using whole genome sequencing and transcriptional analysis with RNA-Seq. Patients are of Japanese ethnic background and mainly HBV or HCV positive, providing insight into this important liver cancer …

Proteo-Genomic Characterization Of Virus-Associated Liver Cancers Reveals Potential Subtypes And Therapeutic Targets, Masashi Fujita, Mei-Ju May Chen, Doris Rieko Siwak, Shota Sasagawa, Ayako Oosawa-Tatsuguchi, Koji Arihiro, Atsushi Ono, Ryoichi Miura, Kazuhiro Maejima, Hiroshi Aikata, Masaki Ueno, Shinya Hayami, Hiroki Yamaue, Kazuaki Chayama, Ju-Seog Lee, Yiling Lu, Gordon B Mills, Han Liang, Satoshi S Nishizuka, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Primary liver cancer is a heterogeneous disease in terms of its etiology, histology, and therapeutic response. Concurrent proteomic and genomic characterization of a large set of clinical liver cancer samples can help elucidate the molecular basis of heterogeneity and thus serve as a valuable resource for personalized liver cancer treatment. In this study, we perform proteomic profiling of ~300 proteins on 259 primary liver cancer tissues with reverse-phase protein arrays, mutational analysis using whole genome sequencing and transcriptional analysis with RNA-Seq. Patients are of Japanese ethnic background and mainly HBV or HCV positive, providing insight into this important liver cancer …

Range-Bounded Adaptive Therapy In Metastatic Prostate Cancer, Renee Brady-Nicholls, Heiko Enderling

Faculty, Staff and Student Publications

Adaptive therapy with abiraterone acetate (AA), whereby treatment is cycled on and off, has been presented as an alternative to continuous therapy for metastatic castration resistant prostate cancer (mCRPC). It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for whom this competition can be enhanced through slight modifications. Here, we investigate how adaptive AA can be modified to extend time to progression using a simple mathematical model of stem cell, non-stem cell, and …

Characterization Of A Bioactive Peptide T14 In The Human And Rodent Substantia Nigra: Implications For Neurodegenerative Disease, Susan Adele Greenfield, Giovanni Ferrati, Clive W Coen, Auguste Vadisiute, Zoltan Molnár, Sara Garcia-Rates, Sally Frautschy, Gregory M Cole

Faculty, Staff and Student Publications

The substantia nigra is generally considered to show significant cell loss not only in Parkinson's but also in Alzheimer's disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, …

Challenges And Opportunities Associated With The Md Anderson Impact2 Randomized Study In Precision Oncology, Henry Hiep Vo, Siqing Fu, David S Hong, Daniel D Karp, Sarina Piha-Paul, Vivek Subbiah, Filip Janku, Aung Naing, Timothy A Yap, Jordi Rodon, Jaffer A Ajani, Carrie Cartwright, Amber Johnson, I-Wen Song, Jennifer Beck, Michael Kahle, Graciela M Nogueras-Gonzalez, Vincent Miller, Calvin Chao, David J Vining, Donald A Berry, Funda Meric-Bernstam, Apostolia-Maria Tsimberidou

Faculty, Staff and Student Publications

We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of …

Loneliness And Alcohol-Related Problems Among College Students Who Report Binge Drinking Behavior: The Moderating Role Of Food And Alcohol Disturbance, Luke Herchenroeder, Stacy M Post, Michelle L Stock, Ellen W Yeung

Faculty, Staff and Student Publications

Loneliness and alcohol misuse are common among college students and pose a threat to public health. To better understand the longitudinal association between these public health concerns we examined food and alcohol disturbance (FAD; i.e., restricting one's caloric intake prior to drinking) as a moderator in the association between loneliness and alcohol-related problems. Participants were 456 college students from a mid-sized university who engaged in past 30-day binge drinking. The majority of participants identified as being White (67.1%), female (78.1%), and reported a mean age of 19.61 (SD = 1.54) years. Participants completed two surveys (3 weeks apart) over the …

Prodrugs Of A 1-Hydroxy-2-Oxopiperidin-3-Yl Phosphonate Enolase Inhibitor For The Treatment Of Eno1-Deleted Cancers, Victoria C Yan, Cong-Dat Pham, Elliot S Ballato, Kristine L Yang, Kenisha Arthur, Sunada Khadka, Yasaman Barekatain, Prakriti Shrestha, Theresa Tran, Anton H Poral, Mykia Washington, Sudhir Raghavan, Barbara Czako, Federica Pisaneschi, Yu-Hsi Lin, Nikunj Satani, Naima Hammoudi, Jeffrey J Ackroyd, Dimitra K Georgiou, Steven W Millward, Florian L Muller

Faculty, Staff and Student Publications

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma …

Pathologic Predictors Of Response To Treatment Of Immune Checkpoint Inhibitor-Induced Kidney Injury, Ala Abudayyeh, Liye Suo, Heather Lin, Omar Mamlouk, Noha Abdel-Wahab, Amanda Tchakarov

Faculty, Staff and Student Publications

Background: Immune-related adverse events are a management challenge in patients receiving immune checkpoint inhibitors (ICIs). The most common renal immune-related adverse event, acute interstitial nephritis (AIN), is associated with patient morbidity and mortality. AIN, characterized by infiltration of renal tissue with immune cells, may be analogous to kidney transplant rejection. We evaluated clinical variables and pathologic findings to identify predictors of renal response and overall survival (OS) in patients with ICI-induced AIN. Design, setting, participants, and measurements: We reviewed the records and biopsy specimens of all 35 patients treated for ICI-induced AIN at our institution, between August 2007 and August …