Diseases Commons^™

Prediction Of Survival With Intensive Chemotherapy In Acute Myeloid Leukemia, Koji Sasaki, Farhad Ravandi, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Nicholas Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Joseph Khoury, Sergej Konoplev, Sanam Loghavi, Keyur Patel, Guillermo Montalban-Bravo, Lucia Masarova, Marina Konopleva, Hagop Kantarjian

Faculty, Staff and Student Publications

Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, …

Mice Lacking Wnt9a Or Wnt4 Are Prone To Develop Spontaneous Osteoarthritis With Age And Display Alteration In Either The Trabecular Or Cortical Bone Compartment, Stefan Teufel, Lena Wolff, Ulrich König, Akio Kobayashi, Richard Behringer, Christine Hartmann

Faculty, Staff and Student Publications

Osteoarthritis (OA) is a common degenerative disease of the joint, with a complex multifactorial not yet fully understood etiology. Over the past years, the Wnt signaling pathway has been implicated in osteoarthritis. In a recent genomewide association study (GWAS), the chromosomal location on chromosome 1, linked to the Wnt3a-Wnt9a gene locus, was identified as the most significant locus associated with a thumb osteoarthritis endophenotype. Previously, it was shown that WNT9a is involved in maintaining synovial cell identity in the elbow joint during embryogenesis. Here, we report that the conditional loss of Wnt9a in the Prx1-Cre expressing limb mesenchyme or Prg4-CreER …

Lenalidomide Enhances Cd23car T Cell Therapy In Chronic Lymphocytic Leukemia, Sarah Tettamanti, Maria Caterina Rotiroti, Greta Maria Paola Giordano Attianese, Silvia Arcangeli, Ronghua Zhang, Priyanka Banerjee, Giovanni Galletti, Sheighlah Mcmanus, Massimiliano Mazza, Fabio Nicolini, Giovanni Martinelli, Cristina Ivan, Tania Veliz Rodriguez, Federica Barbaglio, Lydia Scarfò, Maurilio Ponzoni, William Wierda, Varsha Gandhi, Michael Keating, Andrea Biondi, Federico Caligaris-Cappio, Ettore Biagi, Paolo Ghia, Maria Teresa Sabrina Bertilaccio

Faculty, Staff and Student Publications

Chimeric antigen receptors (CAR)-modified T cells are an emerging therapeutic tool for chronic lymphocytic leukemia (CLL). However, in patients with CLL, well-known T-cell defects and the inhibitory properties of the tumor microenvironment (TME) hinder the efficacy of CAR T cells. We explored a novel approach combining CARs with lenalidomide, an immunomodulatory drug that tempers the immunosuppressive activity of the CLL TME. T cells from patients with CLL were engineered to express a CAR specific for CD23, a promising target antigen. Lenalidomide maintained the in vitro effector functions of CD23.CAR+ T cells effector functions in terms of antigen-specific cytotoxicity, cytokine release …

Monkeypox: A Contemporary Review For Healthcare Professionals, Boghuma K Titanji, Bryan Tegomoh, Saman Nematollahi, Michael Konomos, Prathit A Kulkarni

Faculty, Staff and Students Publications

The ongoing 2022 multicountry outbreak of monkeypox is the largest in history to occur outside of Africa. Monkeypox is an emerging zoonotic disease that for decades has been viewed as an infectious disease with significant epidemic potential because of the increasing occurrence of human outbreaks in recent years. As public health entities work to contain the current outbreak, healthcare professionals globally are aiming to become familiar with the various clinical presentations and management of this infection. We present in this review an updated overview of monkeypox for healthcare professionals in the context of the ongoing outbreaks around the world.

Chronic Lung Allograft Dysfunction, Anupam Kumar, Puneet Singh Garcha

Faculty, Staff and Students Publications

Lung transplantation remains the only cure for selected patients with advanced irreversible lung diseases. More than 4000 lung transplants are performed worldwide annually. In the last two decades, significant advances have been made in this arena, the most impactful being a modest but improved survival of the recipients. Unfortunately majority of recipients still succumb to chronic lung allograft dysfunction (CLAD), and it remains the most common cause of death after the first year of transplantation. Below is a concise review of the current definition of CLAD, including the various phenotypes, and a brief discussion of the tools available for its …

United States Healthcare Burden Of Pediatric Functional Gastrointestinal Pain Disorder Hospitalizations From 2002 To 2018, John M Hollier, Jason L Salemi, Robert J Shulman

Faculty, Staff and Students Publications

BACKGROUND: The healthcare burden of pediatric functional gastrointestinal pain disorders (FGIDs) is unclear. Our study aimed to characterize the burden of these hospitalizations in the United States (US).

METHODS: We utilized the US National Inpatient Sample from 2002 to 2018 to capture pediatric hospitalizations (ages 4 to 18 years old) with a primary discharge diagnosis of abdominal pain, constipation, irritable bowel syndrome, dyspepsia, abdominal migraine, cyclic vomiting syndrome, or fecal incontinence. We calculated the FGID hospitalization prevalence rate, length of stay (LOS), and inflation-adjusted costs annually and assessed for statistically significant trend changes using joinpoint analyses.

KEY RESULTS: 22.3 million …

Mediating Effects Of Neighborhood-Level Socioeconomic Deprivation On The Association Between Race/Ethnicity And Advanced Hepatocellular Carcinoma, Abiodun O Oluyomi, Kusha A Mohammadi, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND: Racial/ethnic minorities are more likely than non-Hispanic whites (NHW) to be diagnosed with advanced stage hepatocellular carcinoma (HCC). We examined the role of neighborhood disadvantage as a mediator of the association between race/ethnicity and HCC stage at diagnosis.

METHODS: We used data from HCC cases diagnosed in Texas from 2007 to 2015. HCC cases were classified as local versus regional/advanced stage. A mediation model approach was used to estimate the average direct effect, average mediated (indirect) effect, total effect, and proportion mediated by the Area Deprivation Index (ADI), a composite measure of disadvantage.

RESULTS: 7,622 had local while 6303 …

Regulation Of Pgc1Α Downstream Of The Insulin Signaling Pathway Plays A Role In The Hepatic Proteotoxicity Of Mutant Α1-Antitrypsin Deficiency Variant Z, David A Rudnick, Jiansheng Huang, Tunda Hidvegi, Andrew S Chu, Pamela Hale, Admire Munanairi, Dennis J Dietzen, Paul F Cliften, Eric Tycksen, Andrew J Lutkewitte, Brian N Finck, Stephen C Pak, Gary A Silverman, David H Perlmutter

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Insulin signaling is known to regulate essential proteostasis mechanisms.

METHODS: The analyses here examined effects of insulin signaling in the PiZ mouse model of α1-antitrypsin deficiency in which hepatocellular accumulation and proteotoxicity of the misfolded α1-antitrypsin Z variant (ATZ) causes liver fibrosis and cancer.

RESULTS: We first studied the effects of breeding PiZ mice to liver-insulin-receptor knockout (LIRKO) mice (with hepatocyte-specific insulin-receptor gene disruption). The results showed decreased hepatic ATZ accumulation and liver fibrosis in PiZ x LIRKO vs PiZ mice, with reversal of those effects when we bred PiZ x LIRKO mice onto a FOXO1-deficient background. …

Postprandial Symptoms In Patients With Symptoms Of Gastroparesis: Roles Of Gastric Emptying And Accommodation, Henry P Parkman, Mark L Van Natta, Alan H Maurer, Kenneth L Koch, Madhusudan Grover, Zubair Malik, Irene Sarosiek, Thomas L Abell, Robert Bulat, Braden Kuo, Robert J Shulman, Gianrico Farrugia, Laura Miriel, James Tonascia, Frank Hamilton, Pankaj J Pasricha, Richard W Mccallum

Faculty, Staff and Students Publications

Patients often are evaluated for gastroparesis because of symptoms occurring with meals. Gastric emptying scintigraphy (GES) is used for gastroparesis diagnosis, although results are not well correlated with gastroparesis symptoms. The aim of this study is to assess relationships between gastroparesis symptoms, gastric emptying (GE), and gastric accommodation (GA). Patients with symptoms of gastroparesis completed the Patient Assessment of Upper GI Symptoms (PAGI-SYM) and recorded symptoms during GES and water load satiety test (WLST), an indirect assessment for GA. A total of 109 patients with gastroparesis symptoms were assessed. Symptom severity increased after GES meal for stomach fullness, belching, nausea, …

Cholestasis Alters Brain Lipid And Bile Acid Composition And Compromises Motor Function In Neonatal Piglets, Nicole Lind Henriksen, Svend Høime Hansen, Matthew Domenic Lycas, Xiaoyu Pan, Thomas Eriksen, Lars Søndergaard Johansen, Richard R Sprenger, Christer Stenby Ejsing, Douglas G Burrin, Kerstin Skovgaard, Vibeke Brix Christensen, Thomas Thymann, Stanislava Pankratova

Faculty, Staff and Students Publications

Infants with neonatal cholestasis are prone to neurodevelopmental deficits, however, the underlying pathogenesis is unclear. Lipid malabsorption and accumulation of potentially neurotoxic molecules in the blood such as bile acids are important yet relatively unexplored pathways. Here, we developed a translational piglet model to understand how the molecular bile acid and lipid composition of the brain is affected by this disease and relates to motor function. Piglets (8-days old) had bile duct ligation or sham surgery and were fed a formula diet for 3 weeks. Alongside sensory-motor deficits observed in bile duct-ligated animals, we found a shift toward a more …

Crispr Detection Of Circulating Cell-Free Mycobacterium Tuberculosis Dna In Adults And Children, Including Children With Hiv: A Molecular Diagnostics Study, Zhen Huang, Sylvia M Lacourse, Alexander W Kay, Joshua Stern, Jaclyn N Escudero, Brady M Youngquist, Wenshu Zheng, Debrah Vambe, Muyalo Dlamini, Godwin Mtetwa, Lisa M Cranmer, Irene Njuguna, Dalton C Wamalwa, Elizabeth Maleche-Obimbo, Donald G Catanzaro, Christopher J Lyon, Grace John-Stewart, Andrew Dinardo, Anna M Mandalakas, Bo Ning, Tony Y Hu

Faculty, Staff and Students Publications

BACKGROUND: Tuberculosis remains a leading cause of global mortality, especially for adults and children living with HIV (CLHIV) underdiagnosed by sputum-based assays. Non-sputum-based assays are needed to improve tuberculosis diagnosis and tuberculosis treatment monitoring. Our aim in this study was to determine whether ultrasensitive detection of Mycobacterium tuberculosis cell-free DNA (Mtb-cfDNA) in blood can diagnose tuberculosis and evaluate tuberculosis treatment responses.

METHODS: In this molecular diagnostics study we analysed archived serum from two patient populations evaluated for tuberculosis in Eswatini and Kenya to detect Mtb-cfDNA, analysing serum from all individuals who had both sufficient serum volumes and clear diagnostic results. …

Pilot Phase Results Of A Prospective, Randomized Controlled Trial Of Narrowband Ultraviolet B Phototherapy In Hospitalized Covid-19 Patients, Frank H Lau, Catherine E Powell, Giacomo Adonecchi, Denise M Danos, Andrew R Dinardo, Robert J Chugden, Peter Wolf, Carmen F Castilla

Faculty, Staff and Students Publications

COVID-19 morbidity and mortality are driven by poor immune regulation. Narrowband ultraviolet B (NB-UVB) phototherapy is standard of care in a number of immune-dysregulated diseases. To assess the efficacy of NB-UVB phototherapy for improving COVID-19 outcomes in high-risk, hospitalized, we developed the Adaptive Photo-Protection Trial. This is a multi-center, prospective, double-blinded, randomized, placebo-controlled trial. The pilot phase results are reported here. Consecutive patients admitted with a positive COVID-19 PCR were screened for eligibility. Enrolled subjects were computer randomized 1:1 to NB-UVB or placebo phototherapy. Subjects were treated daily with escalating doses on 27% of their body surface area for up …

Detection Accuracy Of The Cobas Hpv Assay For High-Risk Hpv In Head And Neck Fna Biopsy Specimens, Ming Guo, Abha Khanna, Agata A Tinnirello, Jessica Hwang, Ping Zhang, Li Xu, Guojun Li, Kristina R Dahlstrom, Erich M Sturgis, John Stewart

Faculty, Staff and Students Publications

BACKGROUND: This study evaluated the detection accuracy of the Cobas human papillomavirus (HPV) assay for high-risk human papillomavirus (hrHPV) and HPV-16 in head and neck fine-needle aspiration (FNA) specimens with squamous cell carcinoma.

METHODS: Head and neck FNA biopsy specimens from 2012 to 2020 were retrospectively collected. Cobas HPV testing was performed on 90 FNA specimens with valid Cervista HPV testing results. Results of Cobas HPV and Cervista HPV assays were compared. A Linear Array or SPF10-LiPA25 HPV genotyping assay resolved cases with discrepant results. The κ value and accuracy of Cobas HPV testing were calculated. The accuracy of the …

Activating Connexin43 Gap Junctions Primes Adipose Tissue For Therapeutic Intervention, Yi Zhu, Na Li, Mingyang Huang, Xi Chen, Yu A An, Jianping Li, Shangang Zhao, Jan-Bernd Funcke, Jianhong Cao, Zhenyan He, Qingzhang Zhu, Zhuzhen Zhang, Zhao V Wang, Lin Xu, Kevin W Williams, Chien Li, Kevin Grove, Philipp E Scherer

Faculty, Staff and Students Publications

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic …

Deletion Of The Lmna Gene In Fibroblasts Causes Senescence-Associated Dilated Cardiomyopathy By Activating The Double-Stranded Dna Damage Response And Induction Of Senescence-Associated Secretory Phenotype, Leila Rouhi, Gaelle Auguste, Qiong Zhou, Raffaella Lombardi, Melis Olcum, Kimia Pourebrahim, Sirisha M Cheedipudi, Saman Asghar, Kui Hong, Matthew J Robertson, Cristian Coarfa, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Students Publications

INTRODUCTION: Mutations in the LMNA gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed in other cardiac cell types, including fibroblasts.

AIM: The purpose of the study was to determine the contribution of the fibroblasts to DCM caused by LMNA deficiency.

METHODS AND RESULTS: The Lmna gene was deleted by crossing the platelet-derived growth factor receptor α-Cre recombinase (Pdgfra-Cre) and floxed Lmna (LmnaF/F) …

The 5th Edition Of The World Health Organization Classification Of Haematolymphoid Tumours: Myeloid And Histiocytic/Dendritic Neoplasms, Joseph D Khoury, Eric Solary, Oussama Abla, Yassmine Akkari, Rita Alaggio, Jane F Apperley, Rafael Bejar, Emilio Berti, Lambert Busque, John K C Chan, Weina Chen, Xueyan Chen, Wee-Joo Chng, John K Choi, Isabel Colmenero, Sarah E Coupland, Nicholas C P Cross, Daphne De Jong, M Tarek Elghetany, Emiko Takahashi, Jean-Francois Emile, Judith Ferry, Linda Fogelstrand, Michaela Fontenay, Ulrich Germing, Sumeet Gujral, Torsten Haferlach, Claire Harrison, Jennelle C Hodge, Shimin Hu, Joop H Jansen, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Christian P Kratz, Xiao-Qiu Li, Megan S Lim, Keith Loeb, Sanam Loghavi, Andrea Marcogliese, Soheil Meshinchi, Phillip Michaels, Kikkeri N Naresh, Yasodha Natkunam, Reza Nejati, German Ott, Eric Padron, Keyur P Patel, Nikhil Patkar, Jennifer Picarsic, Uwe Platzbecker, Irene Roberts, Anna Schuh, William Sewell, Reiner Siebert, Prashant Tembhare, Jeffrey Tyner, Srdan Verstovsek, Wei Wang, Brent Wood, Wenbin Xiao, Cecilia Yeung, Andreas Hochhaus

Faculty, Staff and Students Publications

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought …

Association Of Rare Apoe Missense Variants V236e And R251g With Risk Of Alzheimer Disease, Yann Le Guen, Michael E Belloy, Benjamin Grenier-Boley, Itziar De Rojas, Atahualpa Castillo-Morales, Iris Jansen, Aude Nicolas, Céline Bellenguez, Carolina Dalmasso, Fahri Küçükali, Sarah J Eger, Katrine Laura Rasmussen, Jesper Qvist Thomassen, Jean-François Deleuze, Zihuai He, Valerio Napolioni, Philippe Amouyel, Frank Jessen, Patrick G Kehoe, Cornelia Van Duijn, Magda Tsolaki, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Giacomina Rossi, Mikko Hiltunen, Rebecca Sims, Wiesje M Van Der Flier, Alfredo Ramirez, Ole A Andreassen, Ruth Frikke-Schmidt, Julie Williams, Agustín Ruiz, Jean-Charles Lambert, Michael D Greicius, Members Of The Eadb, Gr@Ace, Degesco, Demgene, Gerad, And Eadi Groups, Beatrice Arosio, Luisa Benussi, Anne Boland, Barbara Borroni, Paolo Caffarra, Delphine Daian, Antonio Daniele, Stéphanie Debette, Carole Dufouil, Emrah Düzel, Daniela Galimberti, Vilmantas Giedraitis, Timo Grimmer, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Henne Holstege, Jakub Hort, Deckert Jürgen, Teemu Kuulasmaa, Aad Van Der Lugt, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre De Mendonça, Susanne Moebus, Benedetta Nacmias, Gael Nicolas, Robert Olaso, Goran Papenberg, Lucilla Parnetti, Florence Pasquier, Oliver Peters, Yolande A L Pijnenburg, Julius Popp, Innocenzo Rainero, Inez Ramakers, Steffi Riedel-Heller, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Hilkka Soininen, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John Van Swieten, Thomas J Tegos, Lucio Tremolizzo, Frans Verhey, Martin Vyhnalek, Jens Wiltfang, Mercè Boada, Pablo García-González, Raquel Puerta, Luis M Real, Victoria Álvarez, María J Bullido, Jordi Clarimon, José María García-Alberca, Pablo Mir, Fermin Moreno, Pau Pastor, Gerard Piñol-Ripoll, Laura Molina-Porcel, Jordi Pérez-Tur, Eloy Rodríguez-Rodríguez, Jose Luís Royo, Raquel Sánchez-Valle, Martin Dichgans, Dan Rujescu

Faculty, Staff and Students Publications

IMPORTANCE: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly.

OBJECTIVE: To determine whether rare missense variants on APOE are associated with AD risk.

DESIGN, SETTING, …

Changes In Measures Of Vestibular And Balance Function And Hippocampus Volume In Alzheimer's Disease And Mild Cognitive Impairment, Helen S Cohen, Christie M Lincoln, Valory N Pavlik, Haleh Sangi-Haghpeykar

Faculty, Staff and Students Publications

OBJECTIVE: To test the hypotheses that people with Alzheimer's disease and mild cognitive impairment have increased frequency of vestibular impairments and decreased hippocampal volume compared with healthy age-matched controls.

STUDY DESIGN: Retrospective, with some historical controls.

SETTING: Out-patient, tertiary care center.

SUBJECTS: People with mild to moderate dementia diagnosed with Alzheimer's disease and with mild cognitive impairment. Main Outcome Measures: A standard clinical battery of objective tests of the vestibular system, and screening for balance; available clinical diagnostic magnetic resonance imaging (MRIs) were reviewed and postprocessed to quantify the left and right hippocampal volumes utilizing both manual segmentation and computer …

Emicizumab-Kxwh: A Critical Review, Kiera O'Leary

International Undergraduate Journal of Health Sciences

The first descriptions of haemophilia A were reported in the second century AD, with the first modern description by John Conrad Otto in 1803. Historically, the natural history of haemophilia A was associated with very high rates morbidity and mortality, often following trivial accidents. Although treatment options for haemophilia A have been revolutionised in recent decades, haemophilia A remains a hereditary disease of concern and factor replacement products remain the mainstay of treatment.

As such, patients with haemophilia can carry huge burdens, particularly when a complication such as a FVIII inhibitor is present. A recently approved novel therapeutic, Emicizumab-kxwh, has …

Pathogenesis Of Tuberculosis: The 1930 Lübeck Disaster Revisited, Peter Donald, Stefan Kaufmann, Stephanie Thee, Anna Maria Mandalakas, Christoph Lange

Faculty, Staff and Students Publications

During the 1930 Lübeck Mycobacterium bovis bacille Calmette–Guérin (BCG) disaster, 251 neonates received three oral BCG doses accidentally contaminated by virulent Mycobacterium tuberculosis; 67 (26.7%) infants died of tuberculosis. BCG reversion to pathogenicity did not occur. Detailed post mortem examinations clarified contested aspects of tuberculosis pathogenesis. Gastrointestinal infection was seldom “silent” and did not cause typical primary pulmonary lesions. In 15 infants, primary pulmonary foci were found but these resulted from vaccine ingestion and aspiration and were not caused by gastrointestinal infection spreading to the lungs without trace of its journey, as claimed by prominent researchers such as Calmette …

Dual-Mode Tumor Imaging Using Probes That Are Responsive To Hypoxia-Induced Pathological Conditions, S A Amali S Subasinghe, Robia G Pautler, Md Abul Hassan Samee, Jason T Yustein, Matthew J Allen

Faculty, Staff and Students Publications

Hypoxia in solid tumors is associated with poor prognosis, increased aggressiveness, and strong resistance to therapeutics, making accurate monitoring of hypoxia important. Several imaging modalities have been used to study hypoxia, but each modality has inherent limitations. The use of a second modality can compensate for the limitations and validate the results of any single imaging modality. In this review, we describe dual-mode imaging systems for the detection of hypoxia that have been reported since the start of the 21st century. First, we provide a brief overview of the hallmarks of hypoxia used for imaging and the imaging modalities used …

Regulation Of Age-Associated Insulin Resistance By Mt1-Mmp-Mediated Cleavage Of Insulin Receptor, Xuanming Guo, Pallavi Asthana, Susma Gurung, Shuo Zhang, Sheung Kin Ken Wong, Samane Fallah, Chi Fung Willis Chow, Sijia Che, Lixiang Zhai, Zening Wang, Xin Ge, Zhixin Jiang, Jiayan Wu, Yijing Zhang, Xiaoyu Wu, Keyang Xu, Cheng Yuan Lin, Hiu Yee Kwan, Aiping Lyu, Zhongjun Zhou, Zhao-Xiang Bian, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin …

Expanding Anti-Cd38 Immunotherapy For Lymphoid Malignancies, Xu Wang, Xinfang Yu, Wei Li, Praveen Neeli, Ming Liu, Ling Li, Mingzhi Zhang, Xiaosheng Fang, Ken H Young, Yong Li

Faculty, Staff and Students Publications

BACKGROUND: Lymphoid neoplasms, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and NK/T cell neoplasms, are a major cause of blood cancer morbidity and mortality. CD38 (cyclic ADP ribose hydrolase) is a transmembrane glycoprotein expressed on the surface of plasma cells and MM cells. The high expression of CD38 across MM and other lymphoid malignancies and its restricted expression in normal tissues make CD38 an attractive target for immunotherapy. CD38-targeting antibodies, like daratumumab, have been approved for the treatment of MM and tested against lymphoma and leukemia in multiple clinical trials.

METHODS: We generated chimeric antigen receptor (CAR) T cells targeting …

Gain-Of-Signal Assays For Probing Inhibition Of Sars-Cov-2 Mpro/3clpro In Living Cells, Seyed Arad Moghadasi, Morgan A Esler, Yuka Otsuka, Jordan T Becker, Sofia N Moraes, Constance B Anderson, Srinivas Chamakuri, Christopher Belica, Chloe Wick, Daniel A Harki, Damian W Young, Louis Scampavia, Timothy P Spicer, Ke Shi, Hideki Aihara, William L Brown, Reuben S Harris

Faculty, Staff and Students Publications

The main protease, Mpro, of SARS-CoV-2 is required to cleave the viral polyprotein into precise functional units for virus replication and pathogenesis. Here, we report quantitative reporters for Mpro function in living cells in which protease inhibition by genetic or chemical methods results in robust signal readouts by fluorescence (enhanced green fluorescent protein [eGFP]) or bioluminescence (firefly luciferase). These gain-of-signal systems are scalable to high-throughput platforms for quantitative discrimination between Mpro mutants and/or inhibitor potencies as evidenced by validation of several reported inhibitors. Additional utility is shown by single Mpro amino acid variants and structural information combining to demonstrate that …

Efficacy And Outcomes Of Faecal Microbiota Transplantation For Recurrent Clostridioides Difficile Infection In Children With Inflammatory Bowel Disease, Maribeth R Nicholson, Erin Alexander, Sonia Ballal, Zev Davidovics, Michael Docktor, Michael Dole, Jonathan M Gisser, Alka Goyal, Suchitra K Hourigan, M Kyle Jensen, Jess L Kaplan, Richard Kellermayer, Judith R Kelsen, Melissa A Kennedy, Sahil Khanna, Elizabeth D Knackstedt, Jennifer Lentine, Jeffery D Lewis, Sonia Michail, Paul D Mitchell, Maria Oliva-Hemker, Tiffany Patton, Karen Queliza, Sarah Sidhu, Aliza B Solomon, David L Suskind, Madison Weatherly, Steven Werlin, Edwin F De Zoeten, Stacy A Kahn, North American Society Of Pediatric Gastroenterology And Nutrition Faecal Microbiota Transplantation Special Interest Group

Faculty, Staff and Students Publications

BACKGROUND: Children with inflammatory bowel disease [IBD] are disproportionally affected by recurrent Clostridioides difficile infection [rCDI]. Although faecal microbiota transplantation [FMT] has been used with good efficacy in adults with IBD, little is known about outcomes associated with FMT in paediatric IBD.

METHODS: We performed a retrospective review of FMT at 20 paediatric centres in the USA from March 2012 to March 2020. Children with and without IBD were compared with determined differences in the efficacy of FMT for rCDI. In addition, children with IBD with and without a successful outcome were compared with determined predictors of success. Safety data …

Evaluation Of Long-Chain Fatty Acid Respiration In Neonatal Mouse Cardiomyocytes Using Seahorse Instrument, Aude Angelini, Xinchun Pi, Liang Xie

Faculty, Staff and Students Publications

Metabolic switches play a critical role in the pathophysiology of cardiac diseases, including heart failure. Here, we describe an assay for long-chain fatty acid oxidation in neonatal mouse cardiomyocytes by using a SeaHorse Flux Analyzer (Agilent). This protocol is a simplified but robust adaptation of the standard protocol that enables metabolic measurements in cells isolated from transgenic mouse models, which can be timesaving and informative. Cell isolation and culture represent a critical point that may require bench optimization.

For complete details on the use and execution of this protocol, please refer to Angelini et al. (2021).

Effect Of Sub-Inhibitory Concentrations Of Nitrofurantoin, Ciprofloxacin And Trimethoprim On In-Vitro Biofilm Formation In Uropathogenic Escherichia Coli, Shane Whelan

ORBioM (Open Research BioSciences Meeting)

The purpose of the current study was to determine the effect of sublethal concentrations of nitrofurantoin, ciprofloxacin and trimethoprim on biofilm formation in 57 uropathogenic Escherichia coli strains (UPEC).

The MIC of nitrofurantoin, ciprofloxacin and trimethoprim was determined for 57 UPEC isolates. Biofilm formation for each isolate with and without sub-lethal concentrations of each antibiotic was then quantified, and the statistical significance of changes in biofilm formation was ascertained by way of a Dunnett's test.

The effects of sub-MIC antibiotics on biofilm formation of UPEC were variable. A total of 22.8% of strains were induced to form biofilm by nitrofurantoin, …

Genetically Encoded Atp Biosensors For Direct Monitoring Of Cellular Atp Dynamics, Donnell White, Qinglin Yang

School of Medicine Faculty Publications

Adenosine 5′-triphosphate, or ATP, is the primary molecule for storing and transferring energy in cells. ATP is mainly produced via oxidative phosphorylation in mitochondria, and to a lesser extent, via glycolysis in the cytosol. In general, cytosolic glycolysis is the primary ATP producer in proliferative cells or cells subjected to hypoxia. On the other hand, mitochondria produce over 90% of cellular ATP in differentiated cells under normoxic conditions. Under pathological conditions, ATP demand rises to meet the needs of biosynthesis for cellular repair, signaling transduction for stress responses, and biochemical processes. These changes affect how mitochondria and cytosolic glycolysis function …

Meta-Analysis Of 175 Patients With Covid-19 And Seizures, Status Epilepticus, Or Cortical Myoclonus: An Individual Patient Data Analysis, Aditi Kappagantu Bs, Helena A. Brantz Ms, Amman Bhasin Ba, Cristina Jageka Bs, Rooqash Ali Md, Izzy Saef Md, Brittany M. Stopa Mph, Ayaz Khawaja Md

Medical Student Research Symposium

Objective

To characterize management and outcomes of seizures, status epilepticus, and cortical myoclonus in COVID-19, with individual patient data analysis of published literature.

Methods

Systematic literature review was conducted in accordance with PRISMA guidelines. Criteria included new-onset seizures, status epilepticus, and/or cortical myoclonus with concomitant COVID-19. COVID-19 severity was dichotomized into mild and severe cases. Good outcome was defined as discharge without severe deficits, and/or return to baseline.

Results

A total of 105 studies reporting 176 patients (male 56.3%;mean age 47.8,SD 25.6) were included. Status epilepticus occurred in 47 patients (26.7%) and myoclonus in 41 (23.3%). Severe COVID-19 occurred in …

Lysosomal Zn 2+ Release Triggers Rapid, Mitochondria-Mediated, Non-Apoptotic Cell Death In Metastatic Melanoma, Wanlu Du, Mingxue Gu, Meiqin Hu, Timothy Nold, Prateeksunder Pinchi, Wei Chen, Michael Ryan, Ahmed Bannaga, Haoxing Xu

Medical Student Research Symposium

During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca2+ and Zn2+ release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn2+-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells. ML-SA-caused mitochondria swelling and dysfunction lead to cellular ATP depletion. While pharmacological inhibition or genetic silencing of TRPML1 in …