Medical Specialties Commons^™

Reducing Pulmonary Function Testing Procedure Times In Pediatric Patients, Kathleen Richards Rrt, Shontae Hill Rrt, Kaylynn Bernardo-Stagg Rrt, Heather Miller Rrt, Daniel Barker Rrt, Kailee Perkins Rrt, Michael Richards Mba, Mha

Journal of Nursing & Interprofessional Leadership in Quality & Safety

Problem. The Pulmonary Function Test Time Project (PFT Project) is a quality improvement (QI) initiative designed to decrease PFT testing time and PFT total time in pediatric patients and improve the overall process for both providers and patients. Patients scheduled to see a pulmonary provider were also scheduled for a PFT prior to the provider’s visit. Data showed that the length of time to perform a pulmonary function test (PFT) was causing: (1) a delay in the pulmonary provider seeing patients at the intended appointment time, (2) a disruption to clinic workflow, resulting in scheduling difficulties, and (3) a decreased …

Safety And Activity Of Pembrolizumab In Combination With Rituximab In Relapsed Or Refractory Follicular Lymphoma, Loretta J Nastoupil, Collin K Chin, Jason R Westin, Nathan H Fowler, Felipe Samaniego, Xiaoyun Cheng, Man Chun John Ma, Zhiqiang Wang, Fuliang Chu, Ly Dsouza, Chizobam Obi, Jennifer Mims, Lei Feng, Shouhao Zhou, Michael Green, Richard Eric Davis, Sattva S Neelapu

Faculty, Staff and Student Publications

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were …

'Analogy-Based Comprehensive Diabetes Education' (Abcde) Improves Glycemic Control Of Diabetic Patients In An Underserved Population: Results Of A Retrospective Chart Analysis, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Diabetes is the leading global cause for blindness, kidney failure and amputations. Preventing these complications requires optimal glycemic control, and it is imperative that diabetic patients understand the fundamental concepts of diabetes care. Although patients attend formal diabetes education classes, many do not comprehend basic concepts of diabetes, and are often noncompliant with diet, exercise and medications. A novel approach termed 'analogy-based comprehensive diabetes education' (ABCDE) was developed to educate HIV-patients with diabetes about basic concepts of diabetes care. The object of this manuscript is to report the results of a retrospective chart review on the impact of ABCDE on …

Activation Of Ras/Mapk Pathway Confers Mcl-1 Mediated Acquired Resistance To Bcl-2 Inhibitor Venetoclax In Acute Myeloid Leukemia, Qi Zhang, Bridget Riley-Gillis, Lina Han, Yannan Jia, Alessia Lodi, Haijiao Zhang, Saravanan Ganesan, Rongqing Pan, Sergej N Konoplev, Shannon R Sweeney, Jeremy A Ryan, Yulia Jitkova, Kenneth Dunner, Shaun E Grosskurth, Priyanka Vijay, Sujana Ghosh, Charles Lu, Wencai Ma, Stephen Kurtz, Vivian R Ruvolo, Helen Ma, Connie C Weng, Cassandra L Ramage, Natalia Baran, Ce Shi, Tianyu Cai, Richard Eric Davis, Venkata L Battula, Yingchang Mi, Jing Wang, Courtney D Dinardo, Michael Andreeff, Jeffery W Tyner, Aaron Schimmer, Anthony Letai, Rose Ann Padua, Carlos E Bueso-Ramos, Stefano Tiziani, Joel Leverson, Relja Popovic, Marina Konopleva

Faculty, Staff and Student Publications

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance …

The Influence Of Preoperative Dialysis On Survival After Continuous-Flow Left Ventricular Assist Device Implantation, Harveen K Lamba, Fadi I Musfee, Subhasis Chatterjee, Ajith P Nair, Andrew B Civitello, Leo Simpson, O H Frazier, George V Letsou

Faculty, Staff and Students Publications

OBJECTIVES: Dialysis is considered a contraindication to continuous-flow left ventricular assist device (CF-LVAD) implantation. We evaluated clinical outcomes and survival in carefully selected, low-risk patients with renal failure who required dialysis before CF-LVAD implantation.

METHODS: We extracted medical record data of patients who underwent CF-LVAD placement at our centre between 1 January 2006 and 31 August 2017, with 2 clinical scenarios: those who required long-term (>14 days) dialysis and those who required short-term (≤14 days) dialysis immediately before implantation. Demographic, clinical and intraoperative characteristics and survival outcomes were assessed.

RESULTS: Of 621 patients who underwent CF-LVAD implantation during the …

Mild Encephalitis/Encephalopathy With A Reversible Splenial Lesion Associated With Systemic Mycoplasma Pneumoniae Infection In North America: A Case Report, Nafee T Talukder, Ashlea Feezel, Jeremy E Lankford

Faculty, Staff and Student Publications

BACKGROUND: Mild encephalitis/encephalopathy with reversible splenial lesion is a clinical-radiological entity found to occur in the setting of an acute systemic inflammatory state with isolated lesions of the splenium of the corpus callosum and mild encephalopathy. Mild encephalitis/encephalopathy with reversible splenial lesion is commonly found to occur in children in the setting of viral infections. It has rarely been associated with Mycoplasma pneumoniae in the United States, unlike in Eastern and Southern Asia where this is much more prominent.

CASE PRESENTATIONS: A 5-year-old African-American boy with autism spectrum disorder presented to our emergency department with acute onset intractable vomiting, diarrhea, …

Blood–Brain Barrier Disruption Mediated By Ffa1 Receptor—Evidence Using Miniscope, Kristen L Lindenau, Jeffrey L Barr, Christopher R Higgins, Kevin T Sporici, Eugen Brailoiu, Gabriela C Brailoiu

Faculty, Staff and Student Publications

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), obtained from diet and dietary supplements, have been tested in clinical trials for the prevention or treatment of several diseases. n-3 PUFAs exert their effects by activation of free fatty acid (FFA) receptors. FFA1 receptor, expressed in the pancreas and brain, is activated by medium- to long-chain fatty acids. Despite some beneficial effects on cognition, the effects of n-3 PUFAs on the blood-brain barrier (BBB) are not clearly understood. We examined the effects of FFA1 activation on BBB permeability in vitro, using rat brain microvascular endothelial cells (RBMVEC), and in vivo, by assessing Evans …

Syndecan-2 Regulates Pad2 To Exert Antifibrotic Effects On Ra-Ild Fibroblasts, Konstantin Tsoyi, Anthony J Esposito, Bo Sun, Ryan G Bowen, Kevin Xiong, Fernando Poli, Rafael Cardenas, Sarah G Chu, Xiaoliang Liang, Stefan W Ryter, Christine Beeton, Tracy J Doyle, Matthew J Robertson, Lindsay J Celada, Freddy Romero, Souheil Y El-Chemaly, Mark A Perrella, I-Cheng Ho, Ivan O Rosas

Faculty, Staff and Students Publications

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix …

Repair-Assisted Damage Detection Reveals Biological Disparities In Prostate Cancer Between African Americans And European Americans, Kimiko L Krieger, Jie H Gohlke, Kevin J Lee, Danthasinghe Waduge Badrajee Piyarathna, Patricia D Castro, Jeffrey A Jones, Michael M Ittmann, Natalie R Gassman, Arun Sreekumar

Faculty, Staff and Students Publications

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues. Tissue microarrays with matched tumor-benign adjacent pairs from 77 AA and EA PCa patients were analyzed for abasic sites, oxidative lesions, crosslinks, and uracil content using the Repair Assisted Damage Detection (RADD) assay. Our analysis revealed that AA PCa, overall, have more DNA damage than …

Novel Role Of Ghrelin Receptor In Gut Dysbiosis And Experimental Colitis In Aging, Ji Yeon Noh, Chia-Shan Wu, Jennifer A A Deluca, Sridevi Devaraj, Arul Jayaraman, Robert C Alaniz, Xiao-Di Tan, Clinton D Allred, Yuxiang Sun

Faculty, Staff and Students Publications

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout …

Applying Evidence-Based Intervention (Ebi) Mapping To Identify The Components And Logic Of Colorectal Cancer Screening Interventions, Jacob Szeszulski, Derek W Craig, Timothy J Walker, Maya Foster, Patricia Dolan Mullen, Maria E Fernandez

Faculty, Staff and Student Publications

Implementation of evidence-based interventions (EBIs) can help to increase colorectal cancer screening (CRCS). Potential users of CRCS EBIs are often unclear about the specific features, logic, and core elements of existing EBIs, making it challenging to use or adapt them. We used EBI Mapping, a systematic process developed from Intervention Mapping that identifies an EBI's components and logic, to characterize existing CRCS EBIs from the National Cancer Institute's Evidence-Based Cancer Control Programs website. The resulting information can facilitate intervention adoption, adaptation, and/or implementation. Two trained coders independently coded intervention materials to describe intervention components and logic (n = 20). We …

Differences In Psychosocial Constructs Among Elementary School Staff That Implement Physical Activity Programs: A Step In Designing Implementation Strategies, Jacob Szeszulski, Timothy J Walker, Michael C Robertson, Maria E Fernandez

Faculty, Staff and Student Publications

Multiple types of school staff members (e.g., classroom teachers, principals) are involved in implementing physical activity programs (e.g., classroom-based, gym), but factors specific to their job responsibilities may inhibit their ability to implement programming effectively. Thus, implementation strategies tailored by job type may be needed. We compare perceptions of behavioral constructs related to implementation of school-based physical activity programs, by job type, among school staff. School staff (n = 139), including principals/assistant principals (n = 21), physical education teachers (n = 41), and classroom teachers (n = 77), from elementary schools (n = 25), completed a cross-sectional survey measuring perceptions …

Virtual Simulated Implantation Of An Adult-Sized Left Ventricular Assist Device In A Pediatric Patient, Dilachew A Adebo, Santosh C Uppu, Avichal Aggarwal, Jorge D Salazar, Damien J Lapar

Faculty, Staff and Student Publications

There is very limited experience with simulated virtual implantation of left ventricular assist devices (LVADs) to assess device fitness in pediatric patients. In this clinical vignette, we report the case of a 9-year-old male patient with dilated cardiomyopathy who underwent successful placement of an LVAD after virtual simulated implantation was performed. (Level of Difficulty: Advanced.)

Spatial Transcriptomics Of Dorsal Root Ganglia Identifies Molecular Signatures Of Human Nociceptors, Diana Tavares-Ferreira, Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Vivekanand Jeevakumar, Ishwarya Sankaranarayanan, Anna M Cervantes, Jeffrey C Reese, Alexander Chamessian, Bryan A Copits, Patrick M Dougherty, Robert W Gereau, Michael D Burton, Gregory Dussor, Theodore J Price

Faculty, Staff and Student Publications

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG …

Pharmacological Modulation Of Kv13 Potassium Channel Selectively Triggers Pathological B Lymphocyte Apoptosis In Vivo In A Genetic Cll Model, Filippo Severin, Andrea Urbani, Tatiana Varanita, Magdalena Bachmann, Michele Azzolini, Veronica Martini, Marco Pizzi, Angelo Paolo Dei Tos, Federica Frezzato, Andrea Mattarei, Paolo Ghia, Maria Teresa Sabrina Bertilaccio, Erich Gulbins, Cristina Paradisi, Mario Zoratti, Gianpietro Carlo Semenzato, Luigi Leanza, Livio Trentin, Ildiko Szabò

Faculty, Staff and Student Publications

Background: Ion channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. In vitro, inhibition of mitoKv1.3 by PAPTP was shown to kill ex vivo primary human CLL cells, while targeting IKCa with TRAM-34 decreased CLL cell proliferation.

Methods: Here we evaluated the effect of the above drugs in CLL cells from ibrutinib-resistant patients and in combination with Venetoclax, two drugs used in the clinical practice. The effects of the drugs were tested also in the Eμ-TCL1 …

Feasibility Of Administering Human Pancreatic Cancer Chemotherapy In A Spontaneous Pancreatic Cancer Mouse Model, Abagail M Delahoussaye, Joseph Abi Jaoude, Morgan Green, Tara N Fujimoto, Jessica Molkentine, Carolina J Garcia Garcia, Jason P Gay, Ningping Feng, Joseph Marszalek, Natalie Fowlkes, Cullen M Taniguchi

Faculty, Staff and Student Publications

Background: Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel chemotherapy regimens have been shown to improve clinical outcomes in patients with pancreatic cancer, and are often used interchangeably as the standard of care. Preclinical studies often do not use these regimens, since administering these multiagent approaches can be difficult. In this study, we assessed the feasibility of administering these two chemotherapy regimens in spontaneous pancreatic tumors using KPC mice with the ultimate goal of advancing preclinical studies.

Methods: KPC mice were created by breeding KrasLSL-G12D/+ to Trp53fl/fl;Ptf1αCre/+, resulting in KrasLSL-G12D/+;p53fl/+;Ptf1αCre/+ mice. At 14 weeks of age, mice were palpated for spontaneous tumor …

Fully Resolved Assembly Of Cryptosporidium Parvum, Vipin K Menon, Pablo C Okhuysen, Cynthia L Chappell, Medhat Mahmoud, Medhat Mahmoud, Qingchang Meng, Harsha Doddapaneni, Vanesa Vee, Yi Han, Sejal Salvi, Sravya Bhamidipati, Kavya Kottapalli, George Weissenberger, Hua Shen, Matthew C Ross, Kristi L Hoffman, Sara Javornik Cregeen, Donna M Muzny, Ginger A Metcalf, Richard A Gibbs, Joseph F Petrosino, Fritz J Sedlazeck

Faculty, Staff and Students Publications

BACKGROUND: Cryptosporidium parvum is an apicomplexan parasite commonly found across many host species with a global infection prevalence in human populations of 7.6%. Understanding its diversity and genomic makeup can help in fighting established infections and prohibiting further transmission. The basis of every genomic study is a high-quality reference genome that has continuity and completeness, thus enabling comprehensive comparative studies.

FINDINGS: Here, we provide a highly accurate and complete reference genome of Cryptosporidium parvum. The assembly is based on Oxford Nanopore reads and was improved using Illumina reads for error correction. We also outline how to evaluate and choose from …

Developing Microbial Co-Culture System For Enhanced Polyhydroxyalkanoates (Pha) Production Using Acid Pretreated Lignocellulosic Biomass, Rijuta Ganesh Saratale, Si-Kyung Cho, Avinash Ashok Kadam, Gajanan Sampatrao Ghodake, Manu Kumar, Ram Naresh Bharagava, Sunita Varjani, Supriya Nair, Dong-Su Kim, Han-Seung Shin, Ganesh Dattatraya Saratale

Faculty, Staff and Student Publications

In the growing polymer industry, the interest of researchers is captivated by bioplastics production with biodegradable and biocompatible properties. This study examines the polyhydroxyalkanoates (PHA) production performance of individual Lysinibacillus sp. RGS and Ralstonia eutropha ATCC 17699 and their co-culture by utilizing sugarcane bagasse (SCB) hydrolysates. Initially, acidic (H2SO4) and acidified sodium chlorite pretreatment was employed for the hydrolysis of SCB. The effects of chemical pretreatment on the SCB biomass assembly and its chemical constituents were studied by employing numerous analytical methods. Acidic pretreatment under optimal conditions showed effective delignification (60%) of the SCB biomass, leading to a maximum hydrolysis …

Fungal Mycobiome Drives Il-33 Secretion And Type 2 Immunity In Pancreatic Cancer, Aftab Alam, Eric Levanduski, Parker Denz, Helena Solleiro Villavicencio, Maulasri Bhatta, Lamees Alhorebi, Yali Zhang, Eduardo Cortes Gomez, Brian Morreale, Sharon Senchanthisai, Jun Li, Steven G Turowski, Sandra Sexton, Sheila Jani Sait, Prashant K Singh, Jianmin Wang, Anirban Maitra, Pawel Kalinski, Ronald A Depinho, Huamin Wang, Wenting Liao, Scott I Abrams, Brahm H Segal, Prasenjit Dey

Faculty, Staff and Student Publications

TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment are unknown. Here, we show that oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretion is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases …

Food Parenting Practices And Feeding Styles And Their Relations With Weight Status In Children In Latin America And The Caribbean, Luisa Pérez, Marcela Vizcarra, Sheryl O Hughes, Maria A Papaioannou

Children’s Nutrition Research Center Staff Publications

While a growing body of literature looks at the associations between food parenting practices, and feeding styles, and child's weight status in developed countries, little is known for less developed countries, in general, and the Latin America and the Caribbean (LAC) region, in particular. This study systemically reviews and synthesizes existing evidence on the associations between child caregivers' food parenting practices and feeding styles and 2 to 12-year-old child weight status. Keywords were used to search in PubMed, Web of Science, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature. Among the ten eligible articles, all of them reported …

Gap Junction-Dependent And -Independent Functions Of Connexin43 In Biology, Yi Zhu

Children’s Nutrition Research Center Staff Publications

Simple Summary

Connexin43 is one of the 21 members of a large protein family that forms intercellular gap junction complexes. It plays a critical role in development by allowing two adjacent cells to exchange cellular content. Mouse deletion studies have demonstrated its critical roles in many organs, including cardiac muscle, blood vessels, bone, adipose tissue and more. However, as the most expressed and most studied connexin in the family, Connexin43 surprisingly shows many gap-junction-independent roles, spanning from the forming of hemichannels, to regulating membrane trafficking, to regulating mitochondrial function. Connexin43 is also unique in the family by forming many smaller …

The Frequency Of Pathogenic Variation In The All Of Us Cohort Reveals Ancestry-Driven Disparities, Oi-Wa Chan, Wan-Hsuan Chen, Jainn-Jim Lin, Ming-Chou Chiang, Shao-Hsuan Hsia, Huei-Shyong Wang, En-Pei Lee, Yi-Shan Wang, Cheng-Yen Kuo, Kuang-Lin Lin, Icns Group

Faculty, Staff and Student Publications

BACKGROUND: In general clinical practice, neonatal seizures are identified visually by direct clinical observation. The study aimed to examine the frequency of clinical seizures in paroxysmal events in a neonatal intensive care unit.

METHODS: We conducted a prospective study of continuous video-EEG monitoring in a neonatal intensive care unit between January 2017 and December 2020. The demographic data were also reviewed.

RESULTS: Sixty-four neonates were enrolled. The median total video-EEG monitoring duration was 24.1 h (IQR 17.5-44.8 h). There were 309 clinically suspected seizure episodes, of which 181 (58.6%) were the motor type and 128 (41.4%) were the non-motor type. …

Sensitivity Enhancement Of An Experimental Benchtop X-Ray Fluorescence Imaging System By Deploying A Single Crystal Cadmium Telluride Detector System Optimized For High Flux X-Ray Operations, Hem Moktan, Sandun Jayarathna, Sang Hyun Cho

Faculty, Staff and Student Publications

In this work, an energy-resolving thermoelectrically cooled single crystal cadmium telluride (CdTe) detector system upgraded with the latest firmware was optimized for high x-ray flux operations using high bias voltage and fast peaking time. This detector system was deployed into an experimental benchtop x-ray fluorescence (XRF) imaging/computed tomography (XFCT) system developed for quantitative imaging of metal nanoprobes such as gold nanoparticles (GNPs). Using the firmware-upgraded and existing/old CdTe detector systems, the Compton/XRF spectra from small (8 mm diameter) GNP-containing phantoms were acquired. The phantoms were irradiated with 1.8 mm Sn-filtered 125 kVp cone beam x-rays at 24 mA. The firmware-upgraded …

Reducing Influenza Virus Transmission: The Potential Value Of Antiviral Treatment, Frederick G Hayden, Jason Asher, Benjamin J Cowling, Aeron C Hurt, Hideyuki Ikematsu, Klaus Kuhlbusch, Annabelle Lemenuel-Diot, Zhanwei Du, Lauren Ancel Meyers, Pedro A Piedra, Takahiro Takazono, Hui-Ling Yen, Arnold S Monto

Faculty, Staff and Students Publications

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication after antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients seems to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of …

Sars-Cov-2 Infection Increases Risk Of Acute Kidney Injury In A Bimodal Age Distribution, Erica C Bjornstad, Gary Cutter, Pramod Guru, Shina Menon, Isabella Aldana, Scott House, Nancy M Tofil, Catherine A St Hill, Yasir Tarabichi, Valerie M Banner-Goodspeed, Amy B Christie, Surapaneni Krishna Mohan, Devang Sanghavi, Jarrod M Mosier, Girish Vadgaonkar, Allan J Walkey, Rahul Kashyap, Vishakha K Kumar, Vikas Bansal, Karen Boman, Mayank Sharma, Marija Bogojevic, Neha Deo, Lynn Retford, Ognjen Gajic, Katja M Gist, Sccm Discovery Virus Investigators Group

Faculty, Staff and Students Publications

BACKGROUND: Hospitalized patients with SARS-CoV2 develop acute kidney injury (AKI) frequently, yet gaps remain in understanding why adults seem to have higher rates compared to children. Our objectives were to evaluate the epidemiology of SARS-CoV2-related AKI across the age spectrum and determine if known risk factors such as illness severity contribute to its pattern.

METHODS: Secondary analysis of ongoing prospective international cohort registry. AKI was defined by KDIGO-creatinine only criteria. Log-linear, logistic and generalized estimating equations assessed odds ratios (OR), risk differences (RD), and 95% confidence intervals (CIs) for AKI and mortality adjusting for sex, pre-existing comorbidities, race/ethnicity, illness severity, …

Effective Therapy For Aml With Runx1 Mutation By Cotreatment With Inhibitors Of Protein Translation And Bcl2, Christopher P Mill, Warren Fiskus, Courtney D Dinardo, Christine Birdwell, John A Davis, Tapan M Kadia, Koichi Takahashi, Nicholas Short, Naval Daver, Maro Ohanian, Gautam Borthakur, Steven M Kornblau, Michael R Green, Yuan Qi, Xiaoping Su, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed …

Depletion Of The Apical Endosome In Response To Viruses And Bacterial Toxins Provides Cell-Autonomous Host Defense At Mucosal Surfaces, Keiko Maeda, Nicholas C Zachos, Megan H Orzalli, Stefanie S Schmieder, Denis Chang, Katlynn Bugda Gwilt, Michele Doucet, Nicholas W Baetz, Sun Lee, Sue E Crawford, Mary K Estes, Jonathan C Kagan, Jerrold R Turner, Wayne I Lencer

Faculty, Staff and Students Publications

Polarized epithelial cells form an essential barrier against infection at mucosal surfaces. Many pathogens breach this barrier to cause disease, often by co-opting cellular endocytosis mechanisms to enter the cell through the lumenal (apical) cell surface. We recently discovered that the loss of the cell polarity gene PARD6B selectively diminishes apical endosome function. Here, we find that in response to the entry of certain viruses and bacterial toxins into the epithelial cells via the apical membrane, PARD6B and aPKC, two components of the PARD6B-aPKC-Cdc42 apical polarity complex, undergo rapid proteasome-dependent degradation. The perturbation of apical membrane glycosphingolipids by toxin- or …

Cryo-Et Of Toxoplasma Parasites Gives Subnanometer Insight Into Tubulin-Based Structures, Stella Y Sun, Li-Av Segev-Zarko, Muyuan Chen, Grigore D Pintilie, Michael F Schmid, Steven J Ludtke, John C Boothroyd, Wah Chiu

Faculty, Staff and Students Publications

Tubulin is a conserved protein that polymerizes into different forms of filamentous structures in Toxoplasma gondii, an obligate intracellular parasite in the phylum Apicomplexa. Two key tubulin-containing cytoskeletal components are subpellicular microtubules (SPMTs) and conoid fibrils (CFs). The SPMTs help maintain shape and gliding motility, while the CFs are implicated in invasion. Here, we use cryogenic electron tomography to determine the molecular structures of the SPMTs and CFs in vitrified intact and detergent-extracted parasites. Subvolume densities from detergent-extracted parasites yielded averaged density maps at subnanometer resolutions, and these were related back to their architecture in situ. An intralumenal spiral …

Regulation Of The Double-Stranded Rna Response Through Adar1 Licenses Metaplastic Reprogramming In Gastric Epithelium, José B Sáenz, Nancy Vargas, Charles J Cho, Jason C Mills

Faculty, Staff and Students Publications

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of …

Myocardial Rev-Erb-Mediated Diurnal Metabolic Rhythm And Obesity Paradox, Shiyang Song, Chih-Liang Tien, Hao Cui, Paul Basil, Ningxia Zhu, Yingyun Gong, Wenbo Li, Hui Li, Qiying Fan, Jong Min Choi, Weijia Luo, Yanfeng Xue, Rui Cao, Wenjun Zhou, Andrea R Ortiz, Brittany Stork, Vatsala Mundra, Nagireddy Putluri, Brian York, Maoping Chu, Jiang Chang, Sung Yun Jung, Liang Xie, Jiangping Song, Lilei Zhang, Zheng Sun

Faculty, Staff and Students Publications

BACKGROUND: The nuclear receptor Rev-erbα/β, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear.

METHODS: We generated mouse lines with cardiac-specific Rev-erbα/β knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) …