Digital Commons Network^™

Impact Of Frontline Treatment Approach On Outcomes In Patients With Secondary Aml With Prior Hypomethylating Agent Exposure, Nicholas J Short, Sangeetha Venugopal, Wei Qiao, Tapan M Kadia, Farhad Ravandi, Courtney D Dinardo, Marina Konopleva, Gautam Borthakur, Elizabeth J Shpall, Uday Popat, Richard E Champlin, Rohtesh Mehta, Gheath Al-Atrash, Betul Oran, Elias Jabbour, Guillermo Garcia-Manero, Ghayas C Issa, Guillermo Montalban-Bravo, Musa Yilmaz, Abhishek Maiti, Hagop Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain.

METHODS: We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).

RESULTS: Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted …

Importance Of Csf-Based Aβ Clearance With Age In Humans Increases With Declining Efficacy Of Blood-Brain Barrier/Proteolytic Pathways, Donald L Elbert, Bruce W Patterson, Brendan P Lucey, Tammie L S Benzinger, Randall J Bateman

Open Access Publications

The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processes. Kinetic parameters were estimated using: (1) MRI-derived brain volumes, (2) stable isotope labeling kinetics (SILK) of amyloid-β peptide (Aβ), and (3) lumbar CSF Aβ concentration …

Comprehensive Evaluation Of Left Ventricular Deformation Using Speckle Tracking Echocardiography In Normal Children: Comparison Of Three-Dimensional And Two-Dimensional Approaches., Doaa Aly, Nitin Madan, Laura Kuzava, Alison Samrany, Anitha Parthiban

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Three-dimensional (3D) speckle tracking echocardiography (STE) can overcome some of the inherent limitations of two-dimensional (2D) STE; however, clinical experience is lacking. We aimed to assess and compare the feasibility, agreement, and reproducibility of left ventricular (LV) global longitudinal (GLS), and regional strain by 3D vs 2D STE in normal children.

METHODS: Healthy pediatric subjects (n = 105, age mean = 11.2 ± 5.5 years) were prospectively enrolled. Three-dimensional and 2D LV GLS, as well as regional strain in 16 myocardial segments were quantified. Bland Altman analysis, intra- class correlation coefficients (ICC), percent error and linear regression were used …

Organoid Models For Infectious Disease

Faculty, Staff and Students Publications

Infectious diseases affect individual health and have widespread societal impacts. New ex vivo models are critical to understand pathogenesis, host response, and features necessary to develop preventive and therapeutic treatments. Pluripotent and tissue stem cell-derived organoids provide new tools for the study of human infections. Organoid models recapitulate many characteristics of in vivo disease and are providing new insights into human respiratory, gastrointestinal, and neuronal host-microbe interactions. Increasing culture complexity by adding the stroma, interorgan communication, and the microbiome will improve the use of organoids as models for infection. Organoid cultures provide a platform with the capability to improve human …

Enteroviruses And Type 1 Diabetes: Multiple Mechanisms And Factors?

Faculty, Staff and Students Publications

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by insulin deficiency and resultant hyperglycemia. Complex interactions of genetic and environmental factors trigger the onset of autoimmune mechanisms responsible for development of autoimmunity to β cell antigens and subsequent development of T1D. A potential role of virus infections has long been hypothesized, and growing evidence continues to implicate enteroviruses as the most probable triggering viruses. Recent studies have strengthened the association between enteroviruses and development of autoimmunity in T1D patients, potentially through persistent infections. Enterovirus infections may contribute to different stages of disease development. We review data from both …

Comprehensive Evaluation Of Left Ventricular Deformation Using Speckle Tracking Echocardiography In Normal Children: Comparison Of Three-Dimensional And Two-Dimensional Approaches, Alison Samrany, Anitha Parthiban

Faculty, Staff and Students Publications

BACKGROUND: Three-dimensional (3D) speckle tracking echocardiography (STE) can overcome some of the inherent limitations of two-dimensional (2D) STE; however, clinical experience is lacking. We aimed to assess and compare the feasibility, agreement, and reproducibility of left ventricular (LV) global longitudinal (GLS), and regional strain by 3D vs 2D STE in normal children.

METHODS: Healthy pediatric subjects (n = 105, age mean = 11.2 ± 5.5 years) were prospectively enrolled. Three-dimensional and 2D LV GLS, as well as regional strain in 16 myocardial segments were quantified. Bland Altman analysis, intra- class correlation coefficients (ICC), percent error and linear regression were used …

Progressive, Long-Term Hearing Loss In Congenital Cmv Disease After Ganciclovir Therapy, Gail Demmler-Harrison

Faculty, Staff and Students Publications

BACKGROUND: Long-term hearing outcomes among children with symptomatic congenital cytomegalovirus (CMV) disease who received 6-week ganciclovir therapy early in life are unknown.

METHODS: Longitudinal study of 76 children with symptomatic congenital CMV disease, born 1983-2005, who were categorized into three groups: group A treated with ganciclovir; group B untreated who had microcephaly, chorioretinitis, or sensorineural hearing loss (SNHL; ≥25 dB) diagnosed in the first month of life (congenital); and group C untreated who did not meet criteria for group B.

RESULTS: Patients in groups A (n = 17), B (n = 27), and C (n = 32) were followed to …

Clinical Influenza Testing Practices In Hospitalized Children At United States Medical Centers, 2015-2018., Mark W. Tenforde, Angela P. Campbell, Marian G. Michaels, Christopher J. Harrison, Eileen J. Klein, Janet A. Englund, Rangaraj Selvarangan, Natasha B. Halasa, Laura S. Stewart, Geoffrey A. Weinberg, John V. Williams, Peter G. Szilagyi, Mary A. Staat, Julie A. Boom, Leila C. Sahni, Monica N. Singer, Parvin H. Azimi, Richard K. Zimmerman, Monica M. Mcneal, H Keipp Talbot, Arnold S. Monto, Emily T. Martin, Manjusha Gaglani, Fernanda P. Silveira, Donald B. Middleton, Jill M. Ferdinands, Melissa A. Rolfes

Manuscripts, Articles, Book Chapters and Other Papers

At nine US hospitals that enrolled children hospitalized with acute respiratory illness (ARI) during 2015-2016 through 2017-2018 influenza seasons, 50% of children with ARI received clinician-initiated testing for influenza and 35% of cases went undiagnosed due to lack of clinician-initiated testing. Marked heterogeneity in testing practice was observed across sites.

Recent Progress In Biopolymer-Based Hydrogel Materials For Biomedical Applications., Ayaz Mahmood, Dev Patel, Brandon Hickson, John Desrochers, Xiao Hu

College of Science & Mathematics Departmental Research

Hydrogels from biopolymers are readily synthesized, can possess various characteristics for different applications, and have been widely used in biomedicine to help with patient treatments and outcomes. Polysaccharides, polypeptides, and nucleic acids can be produced into hydrogels, each for unique purposes depending on their qualities. Examples of polypeptide hydrogels include collagen, gelatin, and elastin, and polysaccharide hydrogels include alginate, cellulose, and glycosaminoglycan. Many different theories have been formulated to research hydrogels, which include Flory-Rehner theory, Rubber Elasticity Theory, and the calculation of porosity and pore size. All these theories take into consideration enthalpy, entropy, and other thermodynamic variables so that …

Transcribed Ultraconserved Regions Are Associated With Clinicopathological Features In Breast Cancer, Erika Pereira Zambalde, Douglas Adamoski, Daniela Fiori Gradia, Iris Rabinovich, Ana Carolina Rodrigues, Enilze M S F Ribeiro, Jaqueline Carvalho De Oliveira

Faculty, Staff and Student Publications

Ultraconserved regions (UCRs) are 481 genome segments, with length longer than 200 bp, that are 100% conserved among humans, mice, and rats. The majority of UCRs are transcriptionally active (T-UCRs) as many of them produce non-coding RNAs. In a previous study, we evaluated the expression level of T-UCRs in breast cancer (BC) patients and found that 63% of transcripts correlated with some clinical and/or molecular parameter of BC. In this study, we delved into the expression levels of 12 T-UCRs and correlated them with clinicopathological parameters, immunohistochemical markers, and overall survival in two breast cancer cohorts: TCGA and Brazilian patients. …

Sequencing Of A Chinese Tetralogy Of Fallot Cohort Reveals Clustering Mutations In Myogenic Heart Progenitors, Clara Sze Man Tang, Mimmi Mononen, Wai-Yee Lam, Sheng Chih Jin, Xuehan Zhuang, Maria-Mercè Garcia-Barcelo, Qiongfen Lin, Yujia Yang, Makoto Sahara, Elif Eroglu, Kenneth R. Chien, Haifa Hong, Paul Kwong Hang Tam, Peter J. Gruber

Open Access Publications

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression …

Utility Of Blood As The Clinical Specimen For The Diagnosis Of Ocular Toxoplasmosis Using Uracil Dna Glycosylase-Supplemented Loop-Mediated Isothermal Amplification And Real-Time Polymerase Chain Reaction Assays Based On Rep-529 Sequence And B1 Gene, Bahman Rahimi Esboei, Shirzad Fallahi, Mohammad Zarei, Bahram Kazemi, Mehdi Mohebali, Saeedeh Shojaee, Parisa Mousavi, Aref Teimouri, Raziyeh Mahmoudzadeh, Mirataollah Salabati, Hossein Keshavarz Valian

Wills Eye Hospital Papers

Background: Ocular infection with Toxoplasma gondii is a major preventable cause of blindness, especially in young people. The aim of the present study was to assess detection rate of T. gondii DNA in blood samples of clinically diagnosed of ocular toxoplasmosis using uracil DNA glycosylase-supplemented loop-mediated isothermal amplification (UDG-LAMP) and real-time quantitative PCR (qPCR) based on REP-529 and B1.

Methods: One hundred and seventeen patients with clinically diagnosed ocular toxoplasmosis (OT) were participated in the study as well as 200 control patients. Peripheral blood samples were assessed using UDG-LAMP and qPCR techniques targeting REP-529 and B1.

Results: Detection limits of …

Allogeneic Transplant And Car-T Therapy After Autologous Transplant Failure In Dlbcl: A Noncomparative Cohort Analysis, Soyoung Kim, Xianmiao Qiu, Sairah Ahmed, Aleksandr Lazaryan, Vijaya Raj Bhatt, Andrew Daly, Premal Lulla, Stefan Ciurea, Jordan Gauthier, Vaibhav Agrawal, Natalie S Grover, Lazaros Lekakis, Dipenkumar Modi, Parastoo B Dahi, Megan M Herr, P Connor Johnson, Hamza Hashmi, Peiman Hematti, Frederick L Locke

Faculty, Staff and Students Publications

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic …

Characterization Of The Copd Alveolar Niche Using Single-Cell Rna Sequencing, Neeharika Kothapalli, Thomas Barnthaler, Rhiannon B Werder, Jonas C Schupp, Jessica Nouws, Matthew J Robertson, Cristian Coarfa, Tao Yang, Maurizio Chioccioli, Norihito Omote, Carlos Cosme, Sergio Poli, Ehab A Ayaub, Sarah G Chu, Klaus H Jensen, Jose L Gomez, Clemente J Britto, Micha Sam B Raredon, Laura E Niklason, Andrew A Wilson, Pascal N Timshel, Naftali Kaminski, Ivan O Rosas

Faculty, Staff and Students Publications

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant …

Steroid-Sensitive Nephrotic Syndrome Candidate Gene Clvs1 Regulates Podocyte Oxidative Stress And Endocytosis, Brandon M. Lane, Andrew F. Malone, Et Al.

2020-Current year OA Pubs

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking …

Efficacy And Safety Of Enasidenib And Azacitidine Combination In Patients With Idh2 Mutated Acute Myeloid Leukemia And Not Eligible For Intensive Chemotherapy, Sangeetha Venugopal, Koichi Takahashi, Naval Daver, Abhishek Maiti, Gautam Borthakur, Nicholas J Short, Lucia Masarova, Ghayas Issa, Xuemei Wang, Bueso-Ramos Carlos, Musa Yilmaz, Tapan Kadia, Michael Andreeff, Farhad Ravandi, Marina Konopleva, Hagop M Kantarjian, Courtney D Dinardo

Faculty, Staff and Student Publications

Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24-88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The …

Systematic Decomposition Of Sequence Determinants Governing Crispr/Cas9 Specificity, Rongjie Fu, Wei He, Jinzhuang Dou, Oscar D Villarreal, Ella Bedford, Connie Hou, Yalong Wang, Dacheng Ma, Yiwen Chen, Xue Gao, Martin Depken, Han Xu

Faculty, Staff and Student Publications

The specificity of CRISPR/Cas9 genome editing is largely determined by the sequences of guide RNA (gRNA) and the targeted DNA, yet the sequence-dependent rules underlying off-target effects are not fully understood. To systematically explore the sequence determinants governing CRISPR/Cas9 specificity, here we describe a dual-target system to measure the relative cleavage rate between off- and on-target sequences (off-on ratios) of 1902 gRNAs on 13,314 synthetic target sequences, and reveal a set of sequence rules involving 2 factors in off-targeting: 1) a guide-intrinsic mismatch tolerance (GMT) independent of the mismatch context; 2) an "epistasis-like" combinatorial effect of multiple mismatches, which are …

Bicyclic Azetidines Target Acute And Chronic Stages Of Toxoplasma Gondii By Inhibiting Parasite Phenylalanyl T-Rna Synthetase, Joshua B Radke, Bruno Melillo, Payal Mittal, Manmohan Sharma, Amit Sharma, Yong Fu, Taher Uddin, Arthur Gonse, Eamon Comer, Stuart L Schreiber, Anil K Gupta, Arnab K Chatterjee, L David Sibley

Open Access Publications

Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world's human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a …

Neural Signatures Of Data-Driven Psychopathology Dimensions At The Transition To Adolescence, Amirhossein Modabbernia, Giorgia Michelini, Abraham Reichenberg, Roman Kotov, Deanna Barch, Sophia Frangou

Open Access Publications

BACKGROUND: One of the challenges in human neuroscience is to uncover associations between brain organization and psychopathology in order to better understand the biological underpinnings of mental disorders. Here, we aimed to characterize the neural correlates of psychopathology dimensions obtained using two conceptually different data-driven approaches.

METHODS: Dimensions of psychopathology that were either maximally dissociable or correlated were respectively extracted by independent component analysis (ICA) and exploratory factor analysis (EFA) applied to the Childhood Behavior Checklist items from 9- to 10-year-olds (n = 9983; 47.8% female, 50.8% white) participating in the Adolescent Brain Cognitive Development study. The patterns of brain …

Antibody Responses Of Healthy Adults To The P27 Peptide Of Respiratory Syncytial Virus Fusion Protein, Vasanthi Avadhanula, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

The respiratory syncytial virus (RSV) fusion (F) protein undergoes two furin-cleavage events to become fusion competent, resulting in the release of a twenty-seven amino acid peptide (p27). Recent studies indicate that the p27 region of the F protein was an immunodominant antigen in young children. In this study, we evaluated the kinetics of the serum antibody response to the p27 peptide following natural RSV reinfection in adults. Nineteen healthy adults under sixty-five years of age were enrolled during the 2018-2019 RSV season in Houston, TX. Blood was collected at three study visits and RSV infection status was defined by changes …

Iam Hiq-A Novel Pair Of Accuracy Indices For Imputed Genotypes, Albert Rosenberger, Viola Tozzi, Heike Bickeböller, Integral-Ilcco Consortium

Faculty, Staff and Student Publications

BACKGROUND: Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in …

Association Of A Longitudinal, Preclinical Ultrasound Curriculum With Medical Student Performance, David A. Haidar, Ross Kessler, Neil K. Khanna, Michael T. Cover, John C. Burkhardt, Nik Theyyunni, Ryan V. Tucker, Rob D. Huang, Elizabeth Holman, Patrick D. Bridge, Katherine A. Klein, Christopher M. Fung

Emergency Medicine Articles

INTRODUCTION: Point-of-care ultrasound (US) is used in clinical practice across many specialties. Ultrasound (US) curricula for medical students are increasingly common. Optimal timing, structure, and effect of ultrasound education during medical school remains poorly understood. This study aims to retrospectively determine the association between participation in a preclinical, longitudinal US curriculum and medical student academic performance.

METHODS: All first-year medical students at a medical school in the Midwest region of the United States were offered a voluntary longitudinal US curriculum. Participants were selected by random lottery. The curriculum consisted of five three-hour hands on-sessions with matching asynchronous content covering anatomy …

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries., Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty Research 2022

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients …

Single-Cell Multi-Omics Reveals Dyssynchrony Of The Innate And Adaptive Immune System In Progressive Covid-19., Avraham Unterman, Tomokazu S Sumida, Nima Nouri, Xiting Yan, Amy Y Zhao, Victor Gasque, Jonas C Schupp, Hiromitsu Asashima, Yunqing Liu, Carlos Cosme, Wenxuan Deng, Ming Chen, Micha Sam Brickman Raredon, Kenneth B Hoehn, Guilin Wang, Zuoheng Wang, Giuseppe Deiuliis, Neal G Ravindra, Ningshan Li, Christopher Castaldi, Patrick Wong, John Fournier, Santos Bermejo, Lokesh Sharma, Arnau Casanovas-Massana, Chantal B F Vogels, Anne L Wyllie, Nathan D Grubaugh, Anthony Melillo, Hailong Meng, Yan Stein, Maksym Minasyan, Subhasis Mohanty, William E Ruff, Inessa Cohen, Khadir Raddassi, Laura E Niklason, Albert I Ko, Ruth R Montgomery, Shelli F Farhadian, Akiko Iwasaki, Albert C Shaw, David Van Dijk, Hongyu Zhao, Steven H Kleinstein, David A Hafler, Naftali Kaminski, Charles S Dela Cruz

Faculty Research 2022

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100A

Grandi Byen-Supporting Child Growth And Development Through Integrated, Responsive Parenting, Nutrition And Hygiene: Study Protocol For A Randomized Controlled Trial, Patricia L Kohl, Emmanuel A Gyimah, Jenna Diaz, F Matthew Kuhlmann, Sherlie Jean-Louis Dulience, Fithi Embaye, Derek S Brown, Shenyang Guo, Joan L Luby, Jennifer L Nicholas, Jay Turner, Melissa Chapnick, Joseline Marhone Pierre, Jacques Boncy, Rony St Fleur, Maureen M Black, Lora L Iannotti

2020-Current year OA Pubs

BACKGROUND: Poor child growth and development outcomes stem from complex relationships encompassing biological, behavioral, social, and environmental conditions. However, there is a dearth of research on integrated approaches targeting these interwoven factors. The Grandi Byen study seeks to fill this research gap through a three-arm longitudinal randomized controlled trial which will evaluate the impact of an integrated nutrition, responsive parenting, and WASH (water, sanitation and hygiene) intervention on holistic child growth and development.

METHODS: We will recruit 600 mother-infant dyads living in Cap-Haitien, Haiti and randomize them equally into one of the following groups: 1) standard well-baby care; 2) nutritional …

Loss Of Irf2bpl Impairs Neuronal Maintenance Through Excess Wnt Signaling, Paul C Marcogliese, Debdeep Dutta, Shrestha Sinha Ray, Nghi D P Dang, Zhongyuan Zuo, Yuchun Wang, Di Lu, Fatima Fazal, Thomas A Ravenscroft, Hyunglok Chung, Oguz Kanca, Jijun Wan, Emilie D Douine, Undiagnosed Diseases Network, Loren D M Pena, Shinya Yamamoto, Stanley F Nelson, Matthew Might, Kathrin C Meyer, Nan Cher Yeo, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction …

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries, Jan Hendrik Van Weerd, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty, Staff and Student Publications

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients …

Transition To Invasive Breast Cancer Is Associated With Progressive Changes In The Structure And Composition Of Tumor Stroma, Tyler Risom, Deborah J Veis, Katherine Deschryver, Graham A Colditz, Michael Angelo, Et Al.

2020-Current year OA Pubs

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune …

The Power And Challenge Of Lipid (A)Symmetry Across The Membrane And Cell

Faculty, Staff and Student Publications

Current treatments for substance use disorders (SUDs) are far from ideal, with no U.S. Food and Drug Administration-approved pharmacotherapies to treat stimulant and other use disorders. New approaches are urgently needed to combat the increasing prevalence of SUDs and overdose deaths. It is widely accepted that addiction is a chronic disease of the brain involving changes in neural circuitry associated with cognitive and reward functioning. Brain stimulation techniques are novel methods that can modulate these circuits directly and thus hold considerable promise for treating SUDs.

Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

Faculty, Staff and Students Publications

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. …