Digital Commons Network^™

Endorepellin Evokes An Angiostatic Stress Signaling Cascade In Endothelial Cells., Aastha Kapoor, Carolyn G Chen, Renato V Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980 Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex …

The Society For Immunotherapy Of Cancer Perspective On Regulation Of Interleukin-6 Signaling In Covid-19-Related Systemic Inflammatory Response, Fernanda I. Arnaldez, Steven J. O'Day, Charles G. Drake, Bernard A Fox, Bingqing Fu, Walter Urba, Vincenzo Montesarchio, Jeffrey S. Weber, Haiming Wei, Jon M. Wigginton, Paolo Antonio Ascierto

Articles, Abstracts, and Reports

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as ‘cytokine storm’. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes …

The Neurology Of Covid-19 Revisited: A Proposal From The Environmental Neurology Specialty Group Of The World Federation Of Neurology To Implement International Neurological Registries, Gustavo C. Román, Peter S. Spencer, Jacques Reis, Alain Buguet, Mostafa El Alaoui Faris, Sarosh M. Katrak, Miguel Láinez, Marco Tulio Medina, Chandrashekhar Meshram, Mohammad Wasay

Section of Neurology

A comprehensive review of the neurological disorders reported during the current COVID-19 pandemic demonstrates that infection with SARS-CoV-2 affects the central nervous system (CNS), the peripheral nervous system (PNS) and the muscle. CNS manifestations include: headache and decreased responsiveness considered initial indicators of potential neurological involvement; anosmia, hyposmia, hypogeusia, and dysgeusia are frequent early symptoms of coronavirus infection. Respiratory failure, the lethal manifestation of COVID-19, responsible for 264,679 deaths worldwide, is probably neurogenic in origin and may result from the viral invasion of cranial nerve I, progressing into rhinencephalon and brainstem respiratory centers. Cerebrovascular disease, in particular large-vessel ischemic strokes, …

Intraoperative Laser Speckle Contrast Imaging For Real-Time Visualization Of Cerebral Blood Flow In Cerebrovascular Surgery: Results From Pre-Clinical Studies., Antonella Mangraviti, Francesco Volpin, Jaepyeong Cha, Samantha I Cunningham, Karan Raje, M Jason Brooke, Henry Brem, Alessandro Olivi, Judy Huang, Betty M Tyler, Abhishek Rege

Pediatrics Faculty Publications

No abstract provided.

Analysis Of Different Characteristics Of Smile, Mehwish Khan, Syed Murtaza Raza Kazmi, Farhan Raza Khan, Imran Samejo

Section of Dental-Oral Maxillofacial Surgery

Introduction: Analysis of smile is imperative in the diagnosis and treatment planning phases of aesthetic dentistry.
Aim: To evaluate the components of smile among students of a dental institution.
Methods: Frontal view digital photographs with posed smile of 157 dental students were assessed using Adobe Photoshop7.0. Smile characteristics evaluated included; smile line, smile arc, smile design, upper lip curvature, labiodental relationship and number of teeth displayed. Data were analyzed using SPSS version 23.0. Pearson chi-square test was used to determine the gender based differences for various parameters.
Results: Average smile line (43.3%), consonant smile arcs (45.2%), cuspid smiles (45.9%), upward …

Gut Microbiome-Modified Polyphenolic Compounds Inhibit Α-Synuclein Seeding And Spreading In Α-Synucleinopathies, Tritia R. Yamasaki, Kenjiro Ono, Lap Ho, Giulio M. Pasinetti

Neurology Faculty Publications

Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson’s disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show in vitro ability to effectively modulate α-syn misfolding, oligomerization, and …

Nk Cell-Derived Gm-Csf Potentiates Inflammatory Arthritis And Is Negatively Regulated By Cis, Cynthia Louis, Fernando Souza-Fonseca-Guimaraes, Yuyan Yang, Damian D'Silva, Tobias Kratina, Laura Dagley, Soroor Hediyeh-Zadeh, Jai Rautela, Seth Lucian Masters, Melissa J Davis, Jeffrey J Babon, Bogoljub Ciric, Eric Vivier, Warren S Alexander, Nicholas D Huntington, Ian P Wicks

Department of Neurology Faculty Papers

Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18–dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also …

Otosclerosis: Experience With Stapes Surgery, Muhammad Shaheryar Ahmed Rajput, Asif Ali Arain, Arsalan A. Rajput, Mohammad Adeel, Anwar Suhail, Mohammad Sohail Awan

Section of Ophthalmology

Introduction: Otosclerosis is a disorder in which the footplate of the stapes is replaced by an abnormal bone, thereby affecting sound transmission to the inner ear at the level of the oval window. The solution to this condition is to reestablish this mechanism back to normal via the ossicular chain to the inner ear. The aim of stapes surgery is to improve the hearing level to thresholds appropriate enough to obviate the need for hearing aid. The hearing improvement achieved after surgery often lasts for many years. The purpose of the current study was to review our experience and find …

Evaluating The Effects Of Detergent Concentration On The Reendothelialization And Ultrastructure Of Porcine Internal Thoracic Artery Scaffolds, Jesse Bruce Kooistra

Graduate Theses

Cardiovascular disease exerts a consistent force of morbidity and mortality on the global population. This pressure has created a demand for reliable replacement vascular tissues. Current solutions include synthetic grafts and biological transplant options that are associated with a multitude of complications. Therefore, the continued innovation of vascular tissue replacement solutions is warranted. Decellularized vascular tissues have been previously utilized as scaffolds upon which recellularized tissue engineered vascular solutions are constructed. However the interplay between decellularization agent concentration and effective recellularization has not been well documented. Herein we investigate this relationship through a detail oriented research model that both qualifies …

What's All The Buzzy About? Using Cryotherapy And Vibration For Pain During Vaccinations In Children, Marta L. Byma

Evidence-Based Practice Project Reports

Vaccinations are the most common painful needle procedure, with an estimated 12 billion injections given per year (CDC, 2019). The usual method for administration of vaccinations is through needle puncture, which is often painful. Children often report receiving a shot as one of the most feared and painful experiences (McMurtry et al., 2015). The purpose of this evidence-based practice (EBP) project was to improve patient experiences by decreasing the pain that is associated with vaccinations through the use of a nonpharmacological method for comfort via the Buzzy® device. After thorough analysis and synthesis of the literature, the Buzzy® device that …

The Role Of Slc7a11 In Controlling Extracellular And Intracellular Redox Environments Of Lung Fibroblasts - Potential Targets For Intervention In Aging And Idiopathic Pulmonary Fibrosis., Yuxuan Zheng

Electronic Theses and Dissertations

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by extracellular matrix deposition by fibroblasts. Aging and oxidative stress increase the susceptibility to IPF. Redox couples, cysteine/cystine (Cys/CySS) and glutathione/glutathione disulfide (GSH/GSSG), and their redox potentials (E_h) quantify oxidative stress. Fibroblasts from old mice maintain more oxidized extracellular E_h(Cys/CySS) than young mice. Microarray shows down-regulation of Slc7a11 potentially mediates this age-related oxidation. Slc7a11 is the key component of system X_c^-, an antiporter that imports CySS and exports glutamate. The first aim of this dissertation is to investigate the mechanistic link between Slc7a11 …

Characterization Of Adnexal Masses Using Contrast-Enhanced Subharmonic Imaging: A Pilot Study., Lauren J. Delaney, Priscilla Machado, Mehnoosh Torkzaban, Andrej Lyshchik, Corinne Wessner, Christine H. Kim, Md, Norman G Rosenblum, Scott D. Richard, Kirk Wallace, Flemming Forsberg

Department of Radiology Faculty Papers

OBJECTIVES: This pilot study evaluated whether contrast-enhanced subharmonic imaging (SHI) could be used to characterize adnexal masses before surgical intervention.

METHODS: Ten women (with 12 lesions) scheduled for surgery of an ovarian mass underwent an SHI examination of their adnexal region using a modified LOGIQ E9 scanner (GE Healthcare, Waukesha, WI) with an endocavitary transducer, in which digital clips were acquired by pulse destruction-replenishment SHI across the lesions. Time-intensity curves were created offline to quantitatively evaluate SHI parameters (fractional tumor perfusion, peak contrast intensity, time to peak contrast enhancement, and area under the time-intensity curve), which were compared to pathologic …

A Needs Assessment For The Utilization Of Child Life Specialist Bereavement Support Services In An Emergency Veterinary Hospital Setting, Jared R. Negin-Fryers

Graduate Theses/Dissertations

Studies indicate that there is an affective attachment bond, and related emotional involvement that exists between the companion animal and their human owners. Patient companion-animal death within the veterinary hospital, is a daily occurrence, with death rates per patient being significantly higher than in human health care. This comparatively higher death rate is due to the commonplace utilization of professionally sanctioned euthanasia to relieve animal pain and suffering. Companion animal death, may elicit grief reactions that are identical to what is experienced upon the death of a family member. A void currently exists in family centered veterinary care in terms …

Provider-Led Intervention For Overweight Or Obese African American Women Ages 18-65 With A Bmi 25 Kg/ M₂, Tonya A. Harvey

Evidence-Based Practice Project Reports

Overweight and obese African American women tend to suffer most from the impacts of diseases, health disparities, disabilities, and decreased qualities of life (Sutton et al., 2016). Most weight loss programs are not culturally specific, despite the benefits of dietary changes and increased physical activity for all groups. The purpose of this EBP project was to implement a provider-led program including lifestyle, dietary, and activity components to decrease weight, BMI, waist circumference and blood pressure in African American women. The Iowa Model of Evidence-Based Practice to promote quality care was used to guide the EBP project, aimed to address obesity …

Estrogen Receptor-Α Expressing Neurons In The Ventrolateral Vmh Regulate Glucose Balance, Yanlin He, Pingwen Xu, Chunmei Wang, Yan Xia, Meng Yu, Yongjie Yang, Kaifan Yu, Xing Cai, Na Qu, Kenji Saito, Julia Wang, Ilirjana Hyseni, Matthew Robertson, Badrajee Piyarathna, Min Gao, Sohaib A Khan, Feng Liu, Rui Chen, Cristian Coarfa, Zhongming Zhao, Qingchun Tong, Zheng Sun, Yong Xu

Children’s Nutrition Research Center Staff Publications

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH …

Heterodimeric Il-15 Delays Tumor Growth And Promotes Intratumoral Ctl And Dendritic Cell Accumulation By A Cytokine Network Involving Xcl1, Ifn-Γ, Cxcl9 And Cxcl10., Cristina Bergamaschi, Hrishikesh Pandit, Bethany A Nagy, Dimitris Stellas, Shawn M. Jensen, Jenifer Bear, Maggie Cam, Antonio Valentin, Bernard A Fox, Barbara K Felber, George N Pavlakis

Articles, Abstracts, and Reports

BACKGROUND: Interleukin-15 (IL-15) promotes growth and activation of cytotoxic CD8

METHODS: The antitumor activity of hetIL-15 produced from mammalian cells was tested in mouse tumor models (MC38 colon carcinoma and TC-1 epithelial carcinoma). The functional diversity of the immune infiltrate and the cytokine/chemokine network within the tumor was evaluated by flow cytometry, multicolor immunohistochemistry (IHC), gene expression profiling by Nanostring Technologies, and protein analysis by electrochemiluminescence and ELISA assays.

RESULTS: hetIL-15 treatment resulted in delayed primary tumor growth. Increased NK and CD8

CONCLUSIONS: Our results show that hetIL-15 administration enhances T cell entry into tumors, increasing the success rate of …

Understanding The Importance Of Psychological Screenings For Patients Undergoing Elective, Invasive Cosmetic Surgery: A Literature Review, Jazmin N. Rush

Theses and Dissertations

All over the United States (U.S.), men and women alike are undergoing elective, invasive cosmetic surgery. Research has found there is an increasing number of patients choosing cosmetic surgery in hopes of alleviating psychological disorders such as body dysmorphic disorder and low self-esteem. The objective of this review is to analyze the literature available regarding cosmetic surgery and the psychological issues leading to the decision to undergo elective, invasive cosmetic surgery in order to understand and identify the possible benefits of psychological screenings. Information for this study was obtained from three electronic databases - Galileo, PubMed, and CINAHL. U.S. based …

Preclinical Studies Of A Novel Idh1 Inhibitor In Acute Myeloid Leukemia (Aml), Vivian Salama

Dissertations and Theses (Open Access)

LY3410738, a novel covalent Isocitrate Dehydrogenase 1 (IDH1) inhibitor in Acute Myeloid Leukemia, it is more effective than Ivosidenib (AG120) and has a potent anti-leukemic effect against IDH1 mutant acute myeloid leukemia in combination with Venetoclax (ABT-199).

Acute myeloid Leukemia (AML) is an aggressive neoplastic blood disorder characterized by proliferation of poorly differentiated cells of myeloid lineage. IDH1 is a cytoplasmic enzyme that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the citric acid cycle. Somatic gain-of-function mutations in IDH1 occur in ~10% of the newly diagnosed AML patients. The neo-enzymatic activity of mutant IDH1 results in accumulation …

Modulation Of Pi3k-Akt Pathway In Colorectal Cancer, Maliha Nusrat

Dissertations and Theses (Open Access)

The phosphatidylinositol-3-kinase (PI3K) signaling pathway is activated in 20-40% colorectal cancers (CRC) through PTEN loss (PTEN^loss) and PIK3CA mutations (PIK3CA^mut). Allosteric AKT inhibition with MK2206 monotherapy has been ineffective in CRC patients. We investigated the impact of MK2206 on pharmacodynamic (PD) markers and signaling pathways using reverse phase protein array (RPPA) on (1) paired tumor biopsies from a clinical trial of MK2206 in PI3K-altered metastatic CRC, (2) PTEN^lossCRC patient derived xenografts (PDX) treated with MK2206 or carrier, and (3) MK2206-treated cell lines. PD inhibition was deep in cell lines, less but significant in …

Dietary Fat And Sugar Differentially Affect Β-Adrenergic Stimulation Of Cardiac Erk And Akt Pathways In C57bl/6 Male Mice Subjected To High-Calorie Feeding, Sadia Ashraf, Gizem Yilmaz, Xu Chen, Romain Harmancey

Faculty, Staff and Student Publications

BACKGROUND: High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear.

OBJECTIVE: The goal of this study was to investigate the mechanisms by which high amounts of dietary fat and sugar affect cardiac growth regulatory pathways.

METHODS: Male C57BL/6 mice (9 wk old; n = 20/group) were fed a standard rodent diet (STD; kcal% protein-fat-carbohydrate, 29-17-54), a high-fat diet (HFD; 20-60-20), a high-fat and high-sugar Western diet (WD; 20-45-35), a high-sugar diet with mixed carbohydrates (HCD; 20-10-70), or a high-sucrose diet …

Catabolic Degradation Of Endothelial Vegfa Via Autophagy, Thomas Neill, Carolyn Chen, Simone Buraschi, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion …

Bispecific Human Il2-Ccr4 Immunotoxin Targets Human Cutaneous T-Cell Lymphoma, Haoyu Wang, Zhaohui Wang, Huiping Zhang, Zeng Qi, Ariel C Johnson, David Mathes, Elizabeth A Pomfret, Erin Rubin, Christene A Huang, Zhirui Wang

Faculty, Staff and Student Publications

The majority of clinically diagnosed cutaneous T‐cell lymphomas (CTCL) highly express the cell‐surface markers CC chemokine receptor 4 (CCR4) and/or CD25. Recently, we have developed diphtheria toxin‐based recombinant Ontak®‐like human IL2 fusion toxin (IL2 fusion toxin) and anti‐human CCR4 immunotoxin (CCR4 IT). In this study, we first compared the efficacy of the CCR4 IT vs IL2 fusion toxin for targeting human CD25+CCR4+ CTCL. We demonstrated that CCR4 IT was more effective than IL2 fusion toxin. We further constructed an IL2‐CCR4 bispecific IT. The bispecific IT was significantly more effective than either IL2 fusion toxin or CCR4 IT alone. The bispecific …

Dietary Fat And Sugar Differentially Affect Β-Adrenergic Stimulation Of Cardiac Erk And Akt Pathways In C57bl/6 Male Mice Subjected To High-Calorie Feeding, Sadia Ashraf, Gizem Yilmaz, Xu Chen, Romain Harmancey

Faculty, Staff and Student Publications

BACKGROUND: High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear.

OBJECTIVE: The goal of this study was to investigate the mechanisms by which high amounts of dietary fat and sugar affect cardiac growth regulatory pathways.

METHODS: Male C57BL/6 mice (9 wk old; n = 20/group) were fed a standard rodent diet (STD; kcal% protein-fat-carbohydrate, 29-17-54), a high-fat diet (HFD; 20-60-20), a high-fat and high-sugar Western diet (WD; 20-45-35), a high-sugar diet with mixed carbohydrates (HCD; 20-10-70), or a high-sucrose diet …

Oral Localization Of Scardovia Wiggsiae, Graydon Ramos Carr

UNLV Theses, Dissertations, Professional Papers, and Capstones

Early childhood caries is one of the most prevalent diseases in the United States among children. The formation of caries is a complex, multifactorial process that is still being studied. Researchers have thought for years that Streptococcus mutans was the primary causative agent of early childhood caries. The recent discovery of a novel cariogenic pathogen, Scardovia wiggsiae and its significant contribution to the etiology of early childhood caries has led oral health researchers to re-evaluate this microorganism and its link to this disease. While there have been several projects undertaken within the University of Nevada, Las Vegas School of Dental …

The Effects Of Total Body Proton Irradiation On Mouse Myometrium, Lillith Bulawa

Undergraduate Honors Theses

The boundaries of human space exploration continue to expand with new technology and discoveries making it even more important to investigate the effects of space on biological systems. Although humans have explored space in small increments, reproductive studies must be conducted to determine if stable short- or long-term residences for humans can exist in space. This study explored the effects of whole-body proton radiation on uterine smooth muscle known as the myometrium. Two types of mice utilized in this study were C57BL/6 and B6.129S6Cybbtm1Din/J NOX2 knockout mice. C57BL/6 mice are standard laboratory mice that were used to represent the wildtype …

The National Burden Of Orthopedic Injury: Cross-Sectional Estimates For Trauma System Planning And Optimization, Molly P. Jarman, Michael J. Weaver, Adil H. Haider, Ali Saleem, Mitchel B. Harris

Department of Surgery Docs

Background: Management of orthopedic injuries is a critical component of comprehensive trauma care. As patterns of injury incidence and recovery change in the face of emerging injury prevention efforts and technologies and an aging US population, assessment of the burden of orthopedic injury is essential to optimize trauma system planning. We sought to estimate the incidence of orthopedic injury requiring emergency orthopedic surgery in the United States.
Methods: Using nationally representative samples from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project, we estimated the incidence of orthopedic injury, polytrauma with orthopedic injury, and emergency operative orthopedic …

Effects Of Alternative Chemotherapeutic Agents On Thyroid Cancer Cell Line Ml-1, Husref Rizvanovic

Graduate Theses/Dissertations

Though differentiated thyroid carcinomas have decent prognosis when detected early, radioactive iodine (RAI) resistant and advanced thyroid cancers are still difficult to treat with existing therapies. Better therapeutic agents are needed. Studies have shown that aggressive thyroid cancers (ML-1) express the extracellular matrix protein, matrix metalloproteinase (MMP-2). MMP-2 has been linked to metastasis and aggressiveness of several cancers and has been shown to play a crucial role in tumor invasion. Chlorotoxin is a selective MMP-2 receptor agonist, and Saporin is a well-known ribosome-inactivating protein used for anti-cancer treatment; however, these two agents have never been studied when conjugated together. I …

Ubiquitination Of The Dna-Damage Checkpoint Kinase Chk1 By Traf4 Is Required For Chk1 Activation, Xinfang Yu, Wei Li, Haidan Liu, Qipan Deng, Xu Wang, Hui Hu, Zijun Y Xu-Monette, Wei Xiong, Zhongxin Lu, Ken H Young, Wei Wang, Yong Li

Faculty, Staff and Students Publications

BACKGROUND: Aberrant activation of DNA damage response (DDR) is a major cause of chemoresistance in colorectal cancer (CRC). CHK1 is upregulated in CRC and contributes to therapeutic resistance. We investigated the upstream signaling pathways governing CHK1 activation in CRC.

METHODS: We identified CHK1-binding proteins by mass spectrometry analysis. We analyzed the biologic consequences of knockout or overexpression of TRAF4 using immunoblotting, immunoprecipitation, and immunofluorescence. CHK1 and TRAF4 ubiquitination was studied in vitro and in vivo. We tested the functions of TRAF4 in CHK1 phosphorylation and CRC chemoresistance by measuring cell viability and proliferation, anchorage-dependent and -independent cell growth, and mouse …

Metabolic-Sensing Of The Skeletal Muscle Clock Coordinates Fuel Oxidation, Hongshan Yin, Weini Li, Somik Chatterjee, Xuekai Xiong, Pradip Saha, Vijay Yechoor, Ke Ma

Faculty, Staff and Students Publications

Circadian clock confers temporal control in metabolism, with its disruption leading to the development of insulin resistance. Metabolic substrate utilization in skeletal muscle is coordinated with diurnal nutrient cycles. However, whether the molecular clock is involved in this coordination is largely unknown. Using a myocyte-selective genetic ablation mouse model of the essential clock activator Bmal1, here we identify muscle-intrinsic clock as a sensor of feeding cues to orchestrate skeletal muscle oxidation required for global nutrient flux. Bmal1 in skeletal muscle responds robustly to feeding in vivo and insulin induces its expression. Muscle Bmal1 deficiency impaired the transcriptional control of glucose …

Transcriptional Upregulation Of Nlrc5 By Radiation Drives Sting- And Interferon-Independent Mhc-I Expression On Cancer Cells And T Cell Cytotoxicity., Lauren Zebertavage, Alejandro F Alice, Marka R Crittenden, Michael J. Gough

Articles, Abstracts, and Reports

Radiation therapy has been shown to enhance the efficacy of various T cell-targeted immunotherapies that improve antigen-specific T cell expansion, T regulatory cell depletion, or effector T cell function. Additionally, radiation therapy has been proposed as a means to recruit T cells to the treatment site and modulate cancer cells as effector T cell targets. The significance of these features remains unclear. We set out to determine, in checkpoint inhibitor resistant models, which components of radiation are primarily responsible for overcoming this resistance. In order to model the vaccination effect of radiation, we used a Listeria monocytogenes based vaccine to …