Digital Commons Network^™

Overcoming Adaptive Resistance To Anti-Vegf Therapy By Targeting Cd5l, Christopher J Lafargue, Paola Amero, Kyunghee Noh, Lingegowda S Mangala, Yunfei Wen, Emine Bayraktar, Sujanitha Umamaheswaran, Elaine Stur, Santosh K Dasari, Cristina Ivan, Sunila Pradeep, Wonbeak Yoo, Chunhua Lu, Nicholas B Jennings, Vinod Vathipadiekal, Wei Hu, Anca Chelariu-Raicu, Zhiqiang Ku, Hui Deng, Wei Xiong, Hyun-Jin Choi, Min Hu, Takae Kiyama, Chai-An Mao, Rouba Ali-Fehmi, Michael J Birrer, Jinsong Liu, Ningyan Zhang, Gabriel Lopez-Berestein, Vittorio De Franciscis, Zhiqiang An, Anil K Sood

Faculty, Staff and Student Publications

Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. …

Bridging Clinic And Wildlife Care With Ai-Powered Pan-Species Computational Pathology, Khalid Abduljabbar, Simon P Castillo, Katherine Hughes, Hannah Davidson, Amy M Boddy, Lisa M Abegglen, Lucia Minoli, Selina Iussich, Elizabeth P Murchison, Trevor A Graham, Simon Spiro, Carlo C Maley, Luca Aresu, Chiara Palmieri, Yinyin Yuan

Faculty, Staff and Student Publications

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves …

Cloning A Profibrotic Stem Cell Variant In Idiopathic Pulmonary Fibrosis, Shan Wang, Wei Rao, Ashley Hoffman, Jennifer Lin, Justin Li, Tao Lin, Audrey-Ann Liew, Matthew Vincent, Tinne C J Mertens, Harry Karmouty-Quintana, Christopher P Crum, Mark L Metersky, David A Schwartz, Peter J A Davies, Clifford Stephan, Soma S K Jyothula, Ajay Sheshadri, Erik Eddie Suarez, Howard J Huang, John F Engelhardt, Burton F Dickey, Kalpaj R Parekh, Frank D Mckeon, Wa Xian

Faculty, Staff and Student Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell …

Modelling Radiation Cancer Treatment With A Death-Rate Term In Ordinary And Fractional Differential Equations, Nicole Wilson, Corina S Drapaca, Heiko Enderling, Jimmy J Caudell, Kathleen P Wilkie

Faculty, Staff and Student Publications

Fractional calculus has recently been applied to the mathematical modelling of tumour growth, but its use introduces complexities that may not be warranted. Mathematical modelling with differential equations is a standard approach to study and predict treatment outcomes for population-level and patient-specific responses. Here, we use patient data of radiation-treated tumours to discuss the benefits and limitations of introducing fractional derivatives into three standard models of tumour growth. The fractional derivative introduces a history-dependence into the growth function, which requires a continuous death-rate term for radiation treatment. This newly proposed radiation-induced death-rate term improves computational efficiency in both ordinary and …

Cdk5-Prmt1-Wdr24 Signaling Cascade Promotes Mtorc1 Signaling And Tumor Growth, Shasha Yin, Liu Liu, Lauren E Ball, Yalong Wang, Mark T Bedford, Stephen A Duncan, Haizhen Wang, Wenjian Gan

Faculty, Staff and Student Publications

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation …

Immune Cellular Patterns Of Distribution Affect Outcomes Of Patients With Non-Small Cell Lung Cancer, Edwin Roger Parra, Jiexin Zhang, Mei Jiang, Auriole Tamegnon, Renganayaki Krishna Pandurengan, Carmen Behrens, Luisa Solis, Cara Haymaker, John Victor Heymach, Cesar Moran, Jack J Lee, Don Gibbons, Ignacio Ivan Wistuba

Faculty, Staff and Student Publications

Studying the cellular geographic distribution in non-small cell lung cancer is essential to understand the roles of cell populations in this type of tumor. In this study, we characterize the spatial cellular distribution of immune cell populations using 23 makers placed in five multiplex immunofluorescence panels and their associations with clinicopathologic variables and outcomes. Our results demonstrate two cellular distribution patterns-an unmixed pattern mostly related to immunoprotective cells and a mixed pattern mostly related to immunosuppressive cells. Distance analysis shows that T-cells expressing immune checkpoints are closer to malignant cells than other cells. Combining the cellular distribution patterns with cellular …

Bone Marrow Endosteal Stem Cells Dictate Active Osteogenesis And Aggressive Tumorigenesis, Yuki Matsushita, Jialin Liu, Angel Ka Yan Chu, Chiaki Tsutsumi-Arai, Mizuki Nagata, Yuki Arai, Wanida Ono, Kouhei Yamamoto, Thomas L Saunders, Joshua D Welch, Noriaki Ono

Faculty, Staff and Student Publications

The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal …

Tumor Suppressor Candidate 2 (Tusc2): Discovery, Functions, And Cancer Therapy, Austin Arrigo, Angelina T Regua, Mariana K Najjar, Hui-Wen Lo

Faculty, Staff and Student Publications

Tumor Suppressor Candidate 2 (TUSC2) was first discovered as a potential tumor suppressor gene residing in the frequently deleted 3p21.3 chromosomal region. Since its discovery, TUSC2 has been found to play vital roles in normal immune function, and TUSC2 loss is associated with the development of autoimmune diseases as well as impaired responses within the innate immune system. TUSC2 also plays a vital role in regulating normal cellular mitochondrial calcium movement and homeostasis. Moreover, TUSC2 serves as an important factor in premature aging. In addition to TUSC2's normal cellular functions, TUSC2 has been studied as a tumor suppressor gene that …

Rapid Escape Of New Sars-Cov-2 Omicron Variants From Ba2-Directed Antibody Responses, Aiste Dijokaite-Guraliuc, Raksha Das, Daming Zhou, Helen M Ginn, Chang Liu, Helen M E Duyvesteyn, Jiandong Huo, Rungtiwa Nutalai, Piyada Supasa, Muneeswaran Selvaraj, Thushan I De Silva, Megan Plowright, Thomas A H Newman, Hailey Hornsby, Alexander J Mentzer, Donal Skelly, Thomas G Ritter, Nigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J Dunachie, Optic Consortium, Cornelius Roemer, Thomas P Peacock, Neil G Paterson, Mark A Williams, David R Hall, Elizabeth E Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I Stuart, Gavin R Screaton

Faculty, Staff and Student Publications

In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent …

Bone Marrow Endosteal Stem Cells Dictate Active Osteogenesis And Aggressive Tumorigenesis, Yuki Matsushita, Jialin Liu, Angel Ka Yan Chu, Chiaki Tsutsumi-Arai, Mizuki Nagata, Yuki Arai, Wanida Ono, Kouhei Yamamoto, Thomas L Saunders, Joshua D Welch, Noriaki Ono

Faculty, Staff and Student Publications

The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to …

Nothing About Us Without Us: The Roles Of Diverse Stakeholders In Scientific Publishing, Diana M Proctor

Faculty, Staff and Student Publications

No abstract provided.

Point-Of-Care Ultrasound In Airway Evaluation And Management: A Comprehensive Review, Judy Lin, Ryan Bellinger, Andrew Shedd, Jon Wolfshohl, Jennifer Walker, Jack Healy, Jimmy Taylor, Kevin Chao, Yi-Hsuan Yen, Ching-Fang Tiffany Tzeng, Eric H Chou

Faculty, Staff and Student Publications

Airway management is a common and critical procedure in acute settings, such as the Emergency Department (ED) or Intensive Care Unit (ICU) of hospitals. Many of the traditional physical examination methods have limitations in airway assessment. Point-of-care ultrasound (POCUS) has emerged as a promising tool for airway management due to its familiarity, accessibility, safety, and non-invasive nature. It can assist physicians in identifying relevant anatomy of the upper airway with objective measurements of airway parameters, and it can guide airway interventions with dynamic real-time images. To date, ultrasound has been considered highly accurate for assessment of the difficult airway, confirmation …

Armo: Automated And Reliable Multi-Objective Model For Lymph Node Metastasis Prediction In Head And Neck Cancer, Zhiguo Zhou, Liyuan Chen, Michael Dohopolski, David Sher, Jing Wang

Faculty, Staff and Student Publications

Objective:

Accurate diagnosis of lymph node metastasis (LNM) is critical in treatment management for patients with head & neck cancer. Positron emission tomography (PET) and computed tomography (CT) are routinely used for identifying LNM status. However, for small or less fluorodeoxyglucose (FDG) avid nodes, there are always uncertainties in LNM diagnosis. We are aiming to develop a reliable prediction model is for identifying LNM.

Approach:

In this study, a new automated and reliable multi-objective learning model (ARMO) is proposed. In ARMO, a multi-objective model is introduced to obtain balanced sensitivity and specificity. Meanwhile, confidence is calibrated by introducing individual reliability, …

Review Of The Tumor Microenvironment In Basal And Squamous Cell Carcinoma, Elizabeth Chiang, Haleigh Stafford, Jane Buell, Uma Ramesh, Moran Amit, Priyadharsini Nagarajan, Michael Migden, Dan Yaniv

Faculty, Staff and Student Publications

It is widely known that tumor cells of basal and squamous cell carcinoma interact with the cellular and acellular components of the tumor microenvironment to promote tumor growth and progression. While this environment differs for basal and squamous cell carcinoma, the cellular players within both create an immunosuppressed environment by downregulating effector CD4+ and CD8+ T cells and promoting the release of pro-oncogenic Th2 cytokines. Understanding the crosstalk that occurs within the tumor microenvironment has led to the development of immunotherapeutic agents, including vismodegib and cemiplimab to treat BCC and SCC, respectively. However, further investigation of the TME will provide …

Analysis Of Adsorbed Polyphosphate Changes On Milled Titanium Dioxide, Using Low-Field Relaxation Nmr And Photoelectron Spectroscopy, Laura N Elliott, David Austin, Richard A Bourne, Ali Hassanpour, John Robb, John L Edwards, Stephen Sutcliffe, Timothy N Hunter

Faculty, Staff and Students Publications

In this study, changes in the adsorbed amount and surface structure of sodium hexametaphosphate (SHMP) were investigated for aluminum-doped TiO2 pigment undergoing milling. Relaxation NMR was utilized as a potential at-line technique to monitor the effect of milling on surface area and surface chemistry, while XPS was used primarily to consider the dispersant structure. Results showed that considerable amounts of weakly adsorbed SHMP could be removed with washing, and the level of dispersant removal increased with time, highlighting destructive effects of sustained high-energy milling. Nonetheless, there were no significant chemical changes to the dispersant, although increases to the bridging oxygen …

Barriers To Care In Juvenile Localized And Systemic Scleroderma: An Exploratory Survey Study Of Caregivers’ Perspectives, Leigh A Stubbs, Andrew M Ferry, Danielle Guffey, Christina Loccke, Erin Moriarty Wade, Pamela Pour, Kaveh Ardalan, Peter Chira, Ingrid M Ganske, Daniel Glaser, Gloria Higgins, Nadia Luca, Katharine F Moore, Vidya Sivaraman, Katie Stewart, Natalia Vasquez-Canizares, Raegan D Hunt, Renata S Maricevich, Kathryn S Torok, Suzanne C Li, Childhood Arthritis, Rheumatology Research Alliance (Carra) Scleroderma Workgroup

Faculty, Staff and Students Publications

BACKGROUND: Juvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child's scleroderma.

METHODS: In this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child's condition and factors affecting diagnosis and treatment.

RESULTS: The response rate was 61% (73/120), with …

Framing The Family: A Qualitative Exploration Of Factors That Shape Family-Level Experience Of Pediatric Genomic Sequencing, Hadley Stevens Smith, Emily S Bonkowski, Madison R Hickingbotham, Raymond Belanger Deloge, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Families of children with rare and undiagnosed conditions face many psychosocial and logistical challenges that may affect their approach to decisions about their child’s care and their family’s well-being. As genomic sequencing (GS) is increasingly incorporated into pediatric diagnostic workups, assessing the family-level characteristics that shape the experience of pediatric GS is crucial to understanding how families approach decision-making about the test and how they incorporate the results into their family life. We conducted semi-structured interviews with parents and other primary caregivers of pediatric patients who were evaluated for a suspected genetic condition and who were recommended to have GS …

Framing The Family: A Qualitative Exploration Of Factors That Shape Family-Level Experience Of Pediatric Genomic Sequencing, Hadley Stevens Smith, Emily S Bonkowski, Madison R Hickingbotham, Raymond Belanger Deloge, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Families of children with rare and undiagnosed conditions face many psychosocial and logistical challenges that may affect their approach to decisions about their child’s care and their family’s well-being. As genomic sequencing (GS) is increasingly incorporated into pediatric diagnostic workups, assessing the family-level characteristics that shape the experience of pediatric GS is crucial to understanding how families approach decision-making about the test and how they incorporate the results into their family life. We conducted semi-structured interviews with parents and other primary caregivers of pediatric patients who were evaluated for a suspected genetic condition and who were recommended to have GS …

Machine Learning Models For The Identification Of Prognostic And Predictive Cancer Biomarkers: A Systematic Review, Qasem Al-Tashi, Maliazurina B Saad, Amgad Muneer, Rizwan Qureshi, Seyedali Mirjalili, Ajay Sheshadri, Xiuning Le, Natalie I Vokes, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

The identification of biomarkers plays a crucial role in personalized medicine, both in the clinical and research settings. However, the contrast between predictive and prognostic biomarkers can be challenging due to the overlap between the two. A prognostic biomarker predicts the future outcome of cancer, regardless of treatment, and a predictive biomarker predicts the effectiveness of a therapeutic intervention. Misclassifying a prognostic biomarker as predictive (or vice versa) can have serious financial and personal consequences for patients. To address this issue, various statistical and machine learning approaches have been developed. The aim of this study is to present an in-depth …

Combined Inhibition Of Bcl-2 And Mcl-1 Overcomes Bax Deficiency-Mediated Resistance Of Tp53-Mutant Acute Myeloid Leukemia To Individual Bh3 Mimetics, Bing Z Carter, Po Yee Mak, Wenjing Tao, Edward Ayoub, Lauren B Ostermann, Xuelin Huang, Sanam Loghavi, Steffen Boettcher, Yuki Nishida, Vivian Ruvolo, Paul E Hughes, Phuong K Morrow, Torsten Haferlach, Steven Kornblau, Muharrem Muftuoglu, Michael Andreeff

Faculty, Staff and Student Publications

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced …

A Small Secreted Protein Nicol Regulates Lumicrine-Mediated Sperm Maturation And Male Fertility, Daiji Kiyozumi, Kentaro Shimada, Michael Chalick, Chihiro Emori, Mayo Kodani, Seiya Oura, Taichi Noda, Tsutomu Endo, Martin M Matzuk, Daniel H Wreschner, Masahito Ikawa

Faculty, Staff and Students Publications

The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the …

Comparative Study Of Adenosine Analogs As Inhibitors Of Protein Arginine Methyltransferases And A Clostridioides Difficile- Specific Dna Adenine Methyltransferase, Jujun Zhou, Youchao Deng, Iredia D Iyamu, John R Horton, Dan Yu, Taraneh Hajian, Masoud Vedadi, Dante Rotili, Antonello Mai, Robert M Blumenthal, Xing Zhang, Rong Huang, Xiaodong Cheng

Faculty, Staff and Student Publications

S-Adenosyl-l-methionine (SAM) analogs are adaptable tools for studying and therapeutically inhibiting SAM-dependent methyltransferases (MTases). Some MTases play significant roles in host–pathogen interactions, one of which is Clostridioides difficile-specific DNA adenine MTase (CamA). CamA is needed for efficient sporulation and alters persistence in the colon. To discover potent and selective CamA inhibitors, we explored modifications of the solvent-exposed edge of the SAM adenosine moiety. Starting from the two parental compounds (6e and 7), we designed an adenosine analog (11a) carrying a 3-phenylpropyl moiety at the adenine N6-amino group, and a 3-(cyclohexylmethyl guanidine)-ethyl moiety at the …

Identifying Signatures Of Ev Secretion In Metastatic Breast Cancer Through Functional Single-Cell Profiling, Mohsen Fathi, Melisa Martinez-Paniagua, Ali Rezvan, Melisa J Montalvo, Vakul Mohanty, Ken Chen, Sendurai A Mani, Navin Varadarajan

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) regulate the tumor microenvironment by facilitating transport of biomolecules. Despite extensive investigation, heterogeneity in EV secretion among cancer cells and the mechanisms that support EV secretion are not well characterized. We developed an integrated method to identify individual cells with differences in EV secretion and performed linked single-cell RNA-sequencing on cloned single cells from the metastatic breast cancer cells. Differential gene expression analyses identified a four-gene signature of breast cancer EV secretion: HSP90AA1, HSPH1, EIF5, and DIAPH3. We functionally validated this gene signature by testing it across cell lines with different metastatic potential …

Synaptic Scaling Of Corticostriatal Circuits Underlies Hyperactivity In Gaba Transporter-1 Deficient Mice, Yan-Jiao Wu, Xin Yi, Xue Gu, Qi Wang, Qin Jiang, Ying Li, Michael X Zhu, Jianqing Ding, Wei-Guang Li, Tian-Le Xu

Faculty, Staff and Student Publications

Homeostatic synaptic scaling entails adjustment of synaptic strength on a cell to prolonged changes of neuronal activity, which is postulated to participate in neuropsychiatric disorders in vivo. Here, we find that sustained elevation in ambient GABA levels, by either genetic deletion or pharmacological blockade of GABA transporter-1 (GAT1), leads to synaptic scaling up of corticostriatal pathways, which underlies locomotor hyperactivity. Meanwhile, medium spiny neurons of the dorsal striatum exhibit an aberrant increase in excitatory synaptic transmission and corresponding structural changes in dendritic spines. Mechanistically, GAT1 deficiency dampens the expression and function of metabotropic glutamate receptors (mGluRs) and endocannabinoid (eCB)-dependent …

Synthetic Errα/Β/Γ Agonist Induces An Errα-Dependent Acute Aerobic Exercise Response And Enhances Exercise Capacity, Cyrielle Billon, Sadichha Sitaula, Subhashis Banerjee, Ryan Welch, Bahaa Elgendy, Lamees Hegazy, Tae Gyu Oh, Melissa Kazantzis, Arindam Chatterjee, John Chrivia, Matthew E Hayes, Weiyi Xu, Angelica Hamilton, Janice M Huss, Lilei Zhang, John K Walker, Michael Downes, Ronald M Evans, Thomas P Burris

Faculty, Staff and Students Publications

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo. Here, we report the …

Nivolumab Plus Ipilimumab Versus Extreme Regimen As First-Line Treatment For Recurrent/Metastatic Squamous Cell Carcinoma Of The Head And Neck: The Final Results Of Checkmate 651, Robert I Haddad, Kevin Harrington, Makoto Tahara, Robert L Ferris, Maura Gillison, Jerome Fayette, Amaury Daste, Piotr Koralewski, Bogdan Zurawski, Miren Taberna, Nabil F Saba, Milena Mak, Andrzej Kawecki, Gustavo Girotto, Miguel Angel Alvarez Avitia, Caroline Even, Joaquin Gabriel Reinoso Toledo, Alexander Guminski, Urs Müller-Richter, Naomi Kiyota, Mustimbo Roberts, Tariq Aziz Khan, Karen Miller-Moslin, Li Wei, Athanassios Argiris

Faculty, Staff and Student Publications

PURPOSE: CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

METHODS: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration …

Consensus On The Ras Dimerization Hypothesis: Strong Evidence For Lipid-Mediated Clustering But Not For G-Domain-Mediated Interactions, Dhirendra K Simanshu, Mark R Philips, John F Hancock

Faculty, Staff and Student Publications

One of the open questions in RAS biology is the existence of RAS dimers and their role in RAF dimerization and activation. The idea of RAS dimers arose from the discovery that RAF kinases function as obligate dimers, which generated the hypothesis that RAF dimer formation might be nucleated by G-domain-mediated RAS dimerization. Here, we review the evidence for RAS dimerization and describe a recent discussion among RAS researchers that led to a consensus that the clustering of two or more RAS proteins is not due to the stable association of G-domains but, instead, is a consequence of RAS C-terminal …

An Altered Extracellular Matrix-Integrin Interface Contributes To Huntington’S Disease-Associated Cns Dysfunction In Glial And Vascular Cells, Sarah J Hernandez, Ryan G Lim, Tarik Onur, Mark A Dane, Rebecca Smith, Keona Wang, Grace En-Hway Jean, Andrea Reyes-Ortiz, Kaylyn Devlin, Ricardo Miramontes, Jie Wu, Malcolm Casale, David Kilburn, Laura M Heiser, James E Korkola, David Van Vactor, Juan Botas, Katherine L Thompson-Peer, Leslie M Thompson

Faculty, Staff and Students Publications

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may …

Health Disparities In Multiple Sclerosis Among Hispanic And Black Populations In The United States, Michael Z Moore, Carlos A Pérez, George J Hutton, Hemali Patel, Fernando X Cuascut

Faculty, Staff and Students Publications

Multiple sclerosis (MS) is an acquired demyelinating disease of the central nervous system (CNS). Historically, research on MS has focused on White persons with MS. This preponderance of representation has important possible implications for minority populations with MS, from developing effective therapeutic agents to understanding the role of unique constellations of social determinants of health. A growing body of literature involving persons of historically underrepresented races and ethnicities in the field of multiple sclerosis is assembling. Our purpose in this narrative review is to highlight two populations in the United States: Black and Hispanic persons with multiple sclerosis. We will …

Ppgpp And Rna-Polymerase Backtracking Guide Antibiotic-Induced Mutable Gambler Cells, Yin Zhai, P J Minnick, John P Pribis, Libertad Garcia-Villada, P J Hastings, Christophe Herman, Susan M Rosenberg

Faculty, Staff and Students Publications

Antibiotic resistance is a global health threat and often results from new mutations. Antibiotics can induce mutations via mechanisms activated by stress responses, which both reveal environmental cues of mutagenesis and are weak links in mutagenesis networks. Network inhibition could slow the evolution of resistance during antibiotic therapies. Despite its pivotal importance, few identities and fewer functions of stress responses in mutagenesis are clear. Here, we identify the Escherichia coli stringent starvation response in fluoroquinolone-antibiotic ciprofloxacin-induced mutagenesis. Binding of response-activator ppGpp to RNA polymerase (RNAP) at two sites leads to an antibiotic-induced mutable gambler-cell subpopulation. Each activates a stress response …