Digital Commons Network^™

Tiam1 Coordinates Synaptic Structural And Functional Plasticity Underpinning The Pathophysiology Of Neuropathic Pain, Lingyong Li, Qin Ru, Yungang Lu, Xing Fang, Guanxing Chen, Ali Bin Saifullah, Changqun Yao, Kimberley F Tolias

Faculty, Staff and Students Publications

Neuropathic pain is a common, debilitating chronic pain condition caused by damage or a disease affecting the somatosensory nervous system. Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively. Tiam1 is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendritic and synaptic growth during hippocampal development by inducing actin cytoskeletal remodeling. Here, using multiple neuropathic pain animal models, we show that Tiam1 coordinates synaptic structural and functional plasticity in the spinal dorsal horn via actin cytoskeleton reorganization and synaptic NMDAR stabilization and that these actions are essential for the …

Circadian Disruption And Colorectal Cancer Incidence In Black Women, Lauren E Barber, Trang Vopham, Laura F White, Hemant K Roy, Julie R Palmer, Kimberly A Bertrand

Faculty, Staff and Students Publications

BACKGROUND: Animal and experimental studies suggest circadian disruption increases colorectal cancer risk, but evidence in humans is limited. We examined night shift work, chronotype, and residential position within a time zone, proxies for circadian disruption, in relation to colorectal cancer risk.

METHODS: Participants in the Black Women's Health Study, a prospective cohort of 59,000 Black American women established in 1995, reported history of night shift work and chronotype on follow-up questionnaires. Residential position within a time zone was estimated using participant addresses at each questionnaire cycle. Number of colorectal cancer cases and follow-up duration varied by analysis depending on timing …

Dynamic Functional Thalamocortical Dysconnectivity In Schizophrenia Correlates To Antipsychotics Response, Mi Yang, Liju Liu, Hongmei Cui, Chijun Deng, Weisen Xiong, Guocheng Zhao, Shulin Du, Thomas R Kosten, Huafu Chen, Zezhi Li, Xiangyang Zhang

Faculty, Staff and Students Publications

Although many studies have showed abnormal thalamocortical networks in patients with schizophrenia (SCZ), the dynamic functional thalamocortical connectivity of individuals with SCZ and the effect of antipsychotics on this connectivity have not been investigated. Drug-naïve first-episode individuals with SCZ and healthy controls were recruited. Patients were treated with risperidone for 12 weeks. Resting-state functional magnetic resonance imaging was acquired at baseline and week 12. We identified six functional thalamic subdivisions. The sliding window strategy was used to determine the dynamic functional connectivity (dFC) of each functional thalamic subdivision. Individuals with SCZ displayed decreased or increased dFC variance in different thalamic …

Association Between Historical Neighborhood Redlining And Cardiovascular Outcomes Among Us Veterans With Atherosclerotic Cardiovascular Diseases, Salil V Deo, Issam Motairek, Khurram Nasir, Amgad Mentias, Yakov Elgudin, Salim S Virani, Sanjay Rajagopalan, Sadeer Al-Kindi

Faculty, Staff and Students Publications

Importance: In the 1930s, the government-sponsored Home Owners' Loan Corporation (HOLC) established maps of US neighborhoods that identified mortgage risk (grade A [green] characterizing lowest-risk neighborhoods in the US through mechanisms that transcend traditional risk factors to grade D [red] characterizing highest risk). This practice led to disinvestments and segregation in neighborhoods considered redlined. Very few studies have targeted whether there is an association between redlining and cardiovascular disease.

Objective: To evaluate whether redlining is associated with adverse cardiovascular outcomes in US veterans.

Design, setting, and participants: In this longitudinal cohort study, US veterans were followed up (January 1, 2016, …

Circular Rna As Therapeutic Targets In Atherosclerosis: Are We Running In Circles?, Jeffrey Triska, Christo Mathew, Yang Zhao, Yuqing E Chen, Yochai Birnbaum

Faculty, Staff and Students Publications

Much attention has been paid lately to harnessing the diagnostic and therapeutic potential of non-coding circular ribonucleic acids (circRNAs) and micro-RNAs (miRNAs) for the prevention and treatment of cardiovascular diseases. The genetic environment that contributes to atherosclerosis pathophysiology is immensely complex. Any potential therapeutic application of circRNAs must be assessed for risks, benefits, and off-target effects in both the short and long term. A search of the online PubMed database for publications related to circRNA and atherosclerosis from 2016 to 2022 was conducted. These studies were reviewed for their design, including methods for developing atherosclerosis and the effects of the …

Ywhae Loss Of Function Causes A Rare Neurodevelopmental Disease With Brain Abnormalities In Human And Mouse, Anne-Sophie Denommé-Pichon, Stephan C Collins, Ange-Line Bruel, Anna Mikhaleva, Christel Wagner, Valerie E Vancollie, Quentin Thomas, Martin Chevarin, Mathys Weber, Carlos E Prada, Alexis Overs, María Palomares-Bralo, Fernando Santos-Simarro, Marta Pacio-Míguez, Tiffany Busa, Eric Legius, Carlos A Bacino, Jill A Rosenfeld, Gwenaël Le Guyader, Matthieu Egloff, Xavier Le Guillou, Maria Antonietta Mencarelli, Alessandra Renieri, Salvatore Grosso, Jonathan Levy, Blandine Dozières, Isabelle Desguerre, Antonio Vitobello, Yannis Duffourd, Christopher J Lelliott, Christel Thauvin-Robinet, Christophe Philippe, Laurence Faivre, Binnaz Yalcin

Faculty, Staff and Students Publications

Purpose: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder.

Methods: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae.

Results: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions < 1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans.

Conclusion: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.

Longitudinal Analysis Of The Evolution Of Cellular Immunity To Sars-Cov-2 Induced By Infection And Vaccination, Spyridoula Vasileiou, Manik Kuvalekar, Yovana Velazquez, Ayumi Watanabe, Mansi Narula, Aster G Workineh, Matthew French-Kim, Alejandro Torres Chavez, Sarah Gilmore, Cliona M Rooney, Ann M Leen

Faculty, Staff and Students Publications

No abstract provided.

Systemic Adverse Events Among Patients With Diabetes Treated With Intravitreal Anti-Vascular Endothelial Growth Factor Injections, Sidra Zafar, Annette Walder, Salim Virani, Kristin Biggerstaff, Silvia Orengo-Nania, Jonathan Chang, Roomasa Channa

Faculty, Staff and Students Publications

IMPORTANCE: Anti-vascular endothelial growth factor (VEGF) agents are currently the mainstay of treatment for diabetic retinopathy (DR). Although effective, data on their systemic safety remains inconclusive, particularly in high-risk patient groups.

OBJECTIVE: To explore the systemic safety of intravitreal anti-VEGF agents among patients with diabetes.

DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, longitudinal population-based analysis of the Corporate Data Warehouse, a large-scale database of patients within the US Veteran Health Affairs. All patients 18 years and older with type 2 diabetes who were seen at any Veterans Affairs health care facility in the US between January 1, 2011, and …

Association Of Chronic Pancreatitis Pain Features With Physical, Mental, And Social Health, Dhiraj Yadav, Robert L Askew, Tonya Palermo, Liang Li, Dana K Andersen, Minxing Chen, William E Fisher, Evan L Fogel, Christopher E Forsmark, Phil A Hart, Mohamed O Othman, Stephen J Pandol, Walter G Park, Mark D Topazian, Stephen K Van Den Eeden, Santhi Swaroop Vege, Yunlong Yang, Jose Serrano, Darwin L Conwell, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Pain is a cardinal symptom of chronic pancreatitis (CP). Using Patient-Reported Outcomes Measurement Information System (PROMIS) measures, we characterized physical and mental health and symptom profiles of a well-defined cohort of individuals with CP and compared them with control subjects. Among patients with CP, we also examined associations between pain (intensity, temporal nature) and PROMIS symptom profiles and the prevalence of clinically significant psychological comorbidities.

METHODS: We analyzed baseline data in 488 CP patients and 254 control subjects enrolled in PROCEED (Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies), an ongoing longitudinal cohort study. Participants …

Allogeneic, Off-The-Shelf, Sars-Cov-2-Specific T Cells (Alvr109) For The Treatment Of Covid-19 In High-Risk Patients, Spyridoula Vasileiou, Laquisa Hill, Manik Kuvalekar, Aster G Workineh, Ayumi Watanabe, Yovana Velazquez, Suhasini Lulla, Kimberly Mooney, Natalia Lapteva, Bambi J Grilley, Helen E Heslop, Cliona M Rooney, Malcolm K Brenner, Todd N Eagar, George Carrum, Kevin A Grimes, Ann M Leen, Premal Lulla

Faculty, Staff and Students Publications

Defects in T-cell immunity to SARS-CoV-2 have been linked to an increased risk of severe COVID-19 (even after vaccination), persistent viral shedding and the emergence of more virulent viral variants. To address this T-cell deficit, we sought to prepare and cryopreserve banks of virus-specific T cells, which would be available as a partially HLA-matched, off-the-shelf product for immediate therapeutic use. By interrogating the peripheral blood of healthy convalescent donors, we identified immunodominant and protective T-cell target antigens, and generated and characterized polyclonal virus-specific T-cell lines with activity against multiple clinically important SARS-CoV-2 variants (including 'delta' and 'omicron'). The feasibility of …

Candidemia In Patients With Cardiovascular Implantable Electronic Devices: Uncertainty In Management Based On Current International Guidelines, Supavit Chesdachai, Larry M Baddour, M Rizwan Sohail, Bharath Raj Palraj, Malini Madhavan, Hussam Tabaja, Madiha Fida, Douglas W Challener, Daniel C Desimone

Faculty, Staff and Students Publications

BACKGROUND: In contrast to bloodstream infection due to a variety of bacteria in patients with cardiovascular implantable electronic devices (CIED), there are limited data regarding candidemia and risk of CIED infection.

METHODS: All patients with candidemia and a CIED at Mayo Clinic Rochester between 2012 and 2019 were reviewed. Cardiovascular implantable electronic device infection was defined by (1) clinical signs of pocket site infection or (2) echocardiographic evidence of lead vegetations.

RESULTS: A total of 23 patients with candidemia had underlying CIED; 9 (39.1%) cases were community onset. None of the patients had pocket site infection. The duration between CIED …

Closure Of Refractory Gastrocutaneous Fistula With Endoscopically Guided Percutaneous Suturing With The Use Of Miniature Biopsy Forceps, Rogelio Garcia, Juan D Gomez Cifuentes, Fuad Aloor, Tara Keihanian, Marvin Ryou, Wasif M Abidi

Faculty, Staff and Students Publications

A PEG tube is an ideal option for enteral nutrition in patients with impaired swallowing or for nutrition optimization. After PEG tube removal, the tract usually closes spontaneously. However, persistent gastrocutaneous fistula (GCF) is a rare but well-known adverse event of long-term PEG tube use.¹ Despite the evolution of endoscopic techniques over the last decade, such as over-the-scope clips (OTSCs), endoscopic suturing, and biosynthetic glue plaque, the management of GCF remains challenging.2, 3, 4, 5, 6 Although endoscopic suturing results in full-thickness closure of the gastric wall, persistent leakage from the cutaneous site may …

Pdcl2 Is Essential For Sperm Acrosome Formation And Male Fertility In Mice, Yoshitaka Fujihara, Kiyonori Kobayashi, Ferheen Abbasi, Tsutomu Endo, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. Globozoospermia is an uncommon cause of male factor infertility, characterized by defects in sperm acrosome formation, leading to round-headed spermatozoa.

OBJECTIVE: We generated Pdcl2 knockout mice to investigate the essential roles of PDCL2 in mammalian reproduction.

MATERIALS AND METHODS: We used reverse transcription-polymerase chain reaction to demonstrate that PDCL2 was expressed exclusively in the male reproductive tract in mice and humans. We created Pdcl2 knockout mice using the CRISPR-Cas9 system and analyzed their fertility. Pdcl2 null spermatozoa underwent further evaluation using computer-assisted sperm analysis, …

Remote Neuronal Activity Drives Glioma Progression Through Sema4f, Emmet Huang-Hobbs, Yi-Ting Cheng, Yeunjung Ko, Estefania Luna-Figueroa, Brittney Lozzi, Kathryn R Taylor, Malcolm Mcdonald, Peihao He, Hsiao-Chi Chen, Yuhui Yang, Ehson Maleki, Zhung-Fu Lee, Sanjana Murali, Michael R Williamson, Dongjoo Choi, Rachel Curry, James Bayley, Junsung Woo, Ali Jalali, Michelle Monje, Jeffrey L Noebels, Akdes Serin Harmanci, Ganesh Rao, Benjamin Deneen

Faculty, Staff and Students Publications

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform …

Treatment Of Cervical Dystonia With Botox (Onabotulinumtoxina): Development, Insights, And Impact, Joseph Jankovic, Joseph Tsui, Mitchell F Brin

Faculty, Staff and Students Publications

Cervical dystonia (CD), the most common focal dystonia encountered in neurologic practice, is a chronic disorder in which the muscles of the neck involuntarily contract and cause abnormal postures and movements of the head, neck, and shoulders. Treatment of CD prior to botulinum toxin was unsatisfactory, as existing therapies often did not improve symptoms. The use of botulinum toxin for CD grew out of its success in treating blepharospasm, another type of focal dystonia. On the basis of results from a double-blind, placebo-controlled trial, onabotulinumtoxinA was approved in 2000 in the US for the treatment of CD in adults in …

Barriers To A Successful Healthcare Transition For Individuals With Urea Cycle Disorders, Farah A Ladha, Cynthia Le Mons, William J Craigen, Pilar L Magoulas, Ronit Marom, Andrea M Lewis

Faculty, Staff and Students Publications

The pediatric to adult healthcare transition (HCT) is a process for individuals with chronic health conditions to gradually shift from a pediatric to an adult-oriented care system. Autonomy and self-management skills required for an individual's HCT readiness can be evaluated through the transition readiness assessment questionnaire (TRAQ). Despite general HCT preparation guidelines, little is known about the HCT experience of individuals with a urea cycle disorder (UCD). This is the first study to report the parent or guardian perception of the HCT process in children with a UCD by investigating the stages of transition readiness and transition outcome. We identify …

Genome-Wide Association Analyses Define Pathogenic Signaling Pathways And Prioritize Drug Targets For Iga Nephropathy, Krzysztof Kiryluk, Elena Sanchez-Rodriguez, Xu-Jie Zhou, Francesca Zanoni, Lili Liu, Nikol Mladkova, Atlas Khan, Maddalena Marasa, Jun Y Zhang, Olivia Balderes, Simone Sanna-Cherchi, Andrew S Bomback, Pietro A Canetta, Gerald B Appel, Jai Radhakrishnan, Hernan Trimarchi, Ben Sprangers, Daniel C Cattran, Heather Reich, York Pei, Pietro Ravani, Kresimir Galesic, Dita Maixnerova, Vladimir Tesar, Benedicte Stengel, Marie Metzger, Guillaume Canaud, Nicolas Maillard, Francois Berthoux, Laureline Berthelot, Evangeline Pillebout, Renato Monteiro, Raoul Nelson, Robert J Wyatt, William Smoyer, John Mahan, Al-Akash Samhar, Guillermo Hidalgo, Alejandro Quiroga, Patricia Weng, Raji Sreedharan, David Selewski, Keefe Davis, Mahmoud Kallash, Tetyana L Vasylyeva, Michelle Rheault, Aftab Chishti, Daniel Ranch, Scott E Wenderfer, Dmitry Samsonov, Donna J Claes, Oleh Akchurin, Dimitrios Goumenos, Maria Stangou, Judit Nagy, Tibor Kovacs, Enrico Fiaccadori, Antonio Amoroso, Cristina Barlassina, Daniele Cusi, Lucia Del Vecchio, Giovanni Giorgio Battaglia, Monica Bodria, Emanuela Boer, Luisa Bono, Giuliano Boscutti, Gianluca Caridi, Francesca Lugani, Gianmarco Ghiggeri, Rosanna Coppo, Licia Peruzzi, Vittoria Esposito, Ciro Esposito, Sandro Feriozzi, Rosaria Polci, Giovanni Frasca, Marco Galliani, Maurizio Garozzo, Adele Mitrotti, Loreto Gesualdo, Simona Granata, Gianluigi Zaza, Francesco Londrino, Riccardo Magistroni, Isabella Pisani, Andrea Magnano, Carmelita Marcantoni, Piergiorgio Messa, Renzo Mignani, Antonello Pani, Claudio Ponticelli, Dario Roccatello, Maurizio Salvadori, Erica Salvi, Domenico Santoro, Guido Gembillo, Silvana Savoldi, Donatella Spotti, Pasquale Zamboli, Claudia Izzi, Federico Alberici, Elisa Delbarba, Michał Florczak, Natalia Krata, Krzysztof Mucha, Leszek Pączek, Stanisław Niemczyk, Barbara Moszczuk, Malgorzata Pańczyk-Tomaszewska, Malgorzata Mizerska-Wasiak, Agnieszka Perkowska-Ptasińska, Teresa Bączkowska, Magdalena Durlik, Krzysztof Pawlaczyk, Przemyslaw Sikora, Marcin Zaniew, Dorota Kaminska, Magdalena Krajewska, Izabella Kuzmiuk-Glembin, Zbigniew Heleniak, Barbara Bullo-Piontecka, Tomasz Liberek, Alicja Dębska-Slizien, Tomasz Hryszko, Anna Materna-Kiryluk, Monika Miklaszewska, Maria Szczepańska, Katarzyna Dyga, Edyta Machura, Katarzyna Siniewicz-Luzeńczyk, Monika Pawlak-Bratkowska, Marcin Tkaczyk, Dariusz Runowski, Norbert Kwella, Dorota Drożdż, Ireneusz Habura, Florian Kronenberg, Larisa Prikhodina, David Van Heel, Bertrand Fontaine, Chris Cotsapas, Cisca Wijmenga, Andre Franke, Vito Annese, Peter K Gregersen, Sreeja Parameswaran, Matthew Weirauch, Leah Kottyan, John B Harley, Hitoshi Suzuki, Ichiei Narita, Shin Goto, Hajeong Lee, Dong Ki Kim, Yon Su Kim, Jin-Ho Park, Belong Cho, Murim Choi, Ans Van Wijk, Ana Huerta, Elisabet Ars, Jose Ballarin, Sigrid Lundberg, Bruno Vogt, Laila-Yasmin Mani, Yasar Caliskan, Jonathan Barratt, Thilini Abeygunaratne, Philip A Kalra, Daniel P Gale, Ulf Panzer, Thomas Rauen, Jürgen Floege, Pascal Schlosser, Arif B Ekici, Kai-Uwe Eckardt, Nan Chen, Jingyuan Xie, Richard P Lifton, Ruth J F Loos, Eimear E Kenny, Iuliana Ionita-Laza, Anna Köttgen, Bruce A Julian, Jan Novak, Francesco Scolari, Hong Zhang, Ali G Gharavi

Faculty, Staff and Students Publications

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum …

Prematurity Blunts Protein Synthesis In Skeletal Muscle Independently Of Body Weight In Neonatal Pigs, Marko Rudar, Jane K Naberhuis, Agus Suryawan, Hanh V Nguyen, Marta L Fiorotto, Teresa A Davis

Faculty, Staff and Students Publications

Background

Postnatal growth failure in premature infants is associated with reduced lean mass accretion. Prematurity impairs the feeding-induced stimulation of translation initiation and protein synthesis in the skeletal muscle of neonatal pigs. The objective was to determine whether body weight independently contributes to the blunted postprandial protein synthesis.

Methods

Preterm and term pigs that were either fasted or fed were stratified into quartiles according to birth weight to yield preterm and term groups of similar body weight; first and second quartiles of preterm pigs and third and fourth quartiles of term pigs were compared (preterm-fasted, n = 23; preterm-fed, n …

Association Between Antibiotic Prophylaxis Before Cystectomy Or Stent Removal And Infection Complications: A Systematic Review, Luca Antonelli, Kirby Sebro, Abdelilah Lahmar, Peter C Black, Saum Ghodoussipour, Jill M Hamilton-Reeves, Jay Shah, Jensen Bente Thoft, Seth Paul Lerner, Carlos Llorente, Ilaria Lucca, Mark A Preston, Sarah P Psutka, John P Sfakianos, Susanne Vahr Lauridsen, Stephen B Williams, James Catto, Hooman Djaladat, Wassim Kassouf, Katherine Loftus, Siamak Daneshmand, Christian D Fankhauser

Faculty, Staff and Students Publications

Context: Patients undergoing radical cystectomy frequently suffer from infectious complications, including urinary tract infections (UTIs) and surgical site infections (SSIs) leading to emergency department visits, hospital readmission, and added cost.

Objective: To summarize the literature regarding perioperative antibiotic prophylaxis, ureteric stent usage, and prevalence of infectious complications after cystectomy.

Evidence acquisition: A systematic review of PubMed/Medline, EMBASE, Cochrane Library, and reference lists was conducted.

Evidence synthesis: We identified 20 reports including a total of 55 306 patients. The median rates of any infection, UTIs, SSIs, and bacteremia were 40%, 20%, 11%, and 6%, respectively. Perioperative antibiotic prophylaxis differed substantially between …

Affinity-Based Electrochemical Sensors For Biomolecular Detection In Whole Blood, Elizabeth C Wilkirson, Kavya L Singampalli, Jiran Li, Desh Deepak Dixit, Xue Jiang, Diego H Gonzalez, Peter B Lillehoj

Faculty, Staff and Students Publications

The detection and/or quantification of biomarkers in blood is important for the early detection, diagnosis, and treatment of a variety of diseases and medical conditions. Among the different types of sensors for detecting molecular biomarkers, such as proteins, nucleic acids, and small-molecule drugs, affinity-based electrochemical sensors offer the advantages of high analytical sensitivity and specificity, fast detection times, simple operation, and portability. However, biomolecular detection in whole blood is challenging due to its highly complex matrix, necessitating sample purification (i.e., centrifugation), which involves the use of bulky, expensive equipment and tedious sample-handling procedures. To address these challenges, various strategies have …

Generation Of Humanized Ldhc Knock-In Mice As A Tool To Assess Human Ldhc-Targeting Contraceptive Drugs, Rie Iida-Norita, Haruhiko Miyata, Yuki Kaneda, Chihiro Emori, Taichi Noda, Tatsuya Nakagawa, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Background: Lactate dehydrogenase C (LDHC) is specifically expressed in male germ cells and plays critical roles in glycolysis. Glycolysis is required to supply energy for sperm motility. Previous studies showed that Ldhc knock-out mice exhibit impaired sperm motility.

Objectives: We established human LDHC knock-in (hLDHC KI) mice and examined whether hLDHC KI mice can be used to assess LDHC-targeting drugs.

Material and methods: HLDHC was knocked-in to the mouse Ldhc (mLdhc) allele using the CRISPR/Cas9 system. Mating tests, sperm motility examinations with a computer-assisted sperm analysis (CASA) system, and in vitro fertilization (IVF) were performed. Furthermore, the effect of an …

Exploring The Role Of Vitamin D And The Gut Microbiome: A Cross-Sectional Study Of Individuals With Irritable Bowel Syndrome And Healthy Controls, Sarah W Matthews, Anna Plantinga, Robert Burr, Kevin C Cain, Tor Savidge, Kendra Kamp, Margaret M Heitkemper

Faculty, Staff and Students Publications

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with multifaceted pathophysiology. Prior studies have demonstrated higher rates of vitamin D deficiency in individuals with IBS compared to healthy controls (HC), as well as associations of vitamin D concentration with IBS symptoms. A systematic review of 10 mouse and 14 human studies reported a positive association between vitamin D (serum levels and supplementation) and beta diversity of gut microbiome in a variety of conditions. The present retrospective case-control study aimed to compare vitamin D (25(OH)D) plasma concentrations and gut microbiome composition in adult women with IBS (n=99) and …

Presentation Of External Ear Rosai-Dorfman Disease With Laryngeal Involvement, Kenji R Kobayashi, Yusif Hajiyev, Maren Y Fuller, Gunes Orman, Elton M Lambert

Faculty, Staff and Students Publications

Rosai-Dorfman disease (RDD) is a rare benign systemic histiocytic proliferation characterized by massive lymph node enlargement and sometimes associated with extranodal involvement. Even though it is considered to be benign, death can occur depending on the extent and location. Our case highlights a primary extranodal site of the right pinna with extension through the Eustachian tube to the subglottis. A previously healthy 15-year-old female presented with 1-year right pinna swelling, slowly enlarging and becoming more bothersome. An incisional biopsy was performed on the ear along with S100 staining yielding a diagnosis. After multidisciplinary case discussion, clofarabine monotherapy and systemic therapy …

Vincristine/Irinotecan/Temsirolimus Upfront Window Treatment Of High-Risk Hepatoblastoma: A Report From The Children’S Oncology Group Ahep0731 Study Committee, Patrick A Thompson, Marcio H Malogolowkin, Wayne L Furman, Jin Piao, Mark D Krailo, Nadia Chung, Lindsay Brock, Alexander J Towbin, Elizabeth B Mccarville, Milton J Finegold, Sarangarajan Ranganathan, Stephen P Dunn, Max R Langham, Eugene D Mcgahren, Gregory M Tiao, Christopher B Weldon, Allison F O'Neill, Carlos Rodriguez-Galindo, Rebecka L Meyers, Howard M Katzenstein

Faculty, Staff and Students Publications

Background: Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR)/metastatic HB.

Procedures: Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1-5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline …

Biallelic Variants In Cript Cause A Rothmund-Thomson-Like Syndrome With Increased Cellular Senescence, Luisa Averdunk, Maxim A Huetzen, Daniel Moreno-Andrés, Reinhard Kalb, Shane Mckee, Tzung-Chien Hsieh, Annette Seibt, Marten Schouwink, Seema Lalani, Eissa Ali Faqeih, Theresa Brunet, Peter Boor, Kornelia Neveling, Alexander Hoischen, Barbara Hildebrandt, Elisabeth Graf, Linchao Lu, Weidong Jin, Joerg Schaper, Jamal A Omer, Tanguy Demaret, Nicole Fleischer, Detlev Schindler, Peter Krawitz, Ertan Mayatepek, Dagmar Wieczorek, Lisa L Wang, Wolfram Antonin, Ron D Jachimowicz, Verena Von Felbert, Felix Distelmaier

Faculty, Staff and Students Publications

Purpose: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789).

Methods: Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.

Results: All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental …

De Novo Variants In Cnot9 Cause A Neurodevelopmental Disorder With Or Without Epilepsy, Lydia Von Wintzingerode, Bruria Ben-Zeev, Claudia Cesario, Katie M Chan, Christel Depienne, Orly Elpeleg, Maria Iascone, Whitley V Kelley, Marie-Cécile Nassogne, Marcello Niceta, Lidia Pezzani, Nils Rahner, Nicole Revencu, Mir Reza Bekheirnia, Teresa Santiago-Sim, Marco Tartaglia, Michelle L Thompson, Marina Trivisano, Julia Hentschel, Heinrich Sticht, Rami Abou Jamra, Henry Oppermann

Faculty, Staff and Students Publications

Purpose: The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.

Methods: Individuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics.

Results: We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have …

Prevalence Of Ddc Genotypes In Patients With Aromatic L-Amino Acid Decarboxylase (Aadc) Deficiency And In Silico Prediction Of Structural Protein Changes, Nastassja Himmelreich, Mariarita Bertoldi, Majid Alfadhel, Malak Ali Alghamdi, Yair Anikster, Xinhua Bao, Fahad A Bashiri, Bruria Ben Zeev, Giovanni Bisello, Ahmet Cevdet Ceylan, Yin-Hsiu Chien, Yew Sing Choy, Sarah H Elsea, Lisa Flint, Àngels García-Cazorla, Charul Gijavanekar, Emel Yılmaz Gümüş, Muddathir H Hamad, Burcu Hişmi, Tomas Honzik, Oya Kuseyri Hübschmann, Wuh-Liang Hwu, Salvador Ibáñez-Micó, Kathrin Jeltsch, Natalia Juliá-Palacios, Çiğdem Seher Kasapkara, Manju A Kurian, Katarzyna Kusmierska, Ning Liu, Lock Hock Ngu, John D Odom, Winnie Peitee Ong, Thomas Opladen, Mari Oppeboen, Phillip L Pearl, Belén Pérez, Roser Pons, Agnieszka Magdalena Rygiel, Tan Ee Shien, Robert Spaull, Jolanta Sykut-Cegielska, Brahim Tabarki, Trine Tangeraas, Beat Thöny, Tessa Wassenberg, Yongxin Wen, Yusnita Yakob, Jasmine Goh Chew Yin, Jiri Zeman, Nenad Blau

Faculty, Staff and Students Publications

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, …

Obsessive-Compulsive Disorder In Youth And Young Adults With Depression: Clinical Characteristics Of Comorbid Presentations, David B Riddle, Andrew Guzick, Abu Minhajuddin, Orri Smárason, Gabrielle M Armstrong, Holli Slater, Taryn L Mayes, Lynnel C Goodman, Denise L Baughn, Sarah L Martin, Sarah M Wakefield, Joseph Blader, Ryan Brown, Wayne K Goodman, Madhukar H Trivedi, Eric A Storch

Faculty, Staff and Students Publications

Obsessive-compulsive disorder (OCD), anxiety disorders, and depressive disorders are highly comorbid, and each contribute to significant functional impairment for affected youth. Comorbid anxiety disorders in depressed youth have been associated with greater depressive symptom severity and impairment, but the impact of comorbid OCD in this population remains unclear. Accordingly, the present study examined the differential clinical characteristics of youth with depression and comorbid OCD relative to age/gender matched depressed youth with no such comorbidity and to those with depression and a comorbid (non-OCD) anxiety disorder. A sample of 797 youth and young adults ages 8-20 years who met diagnostic criteria …

Distinct Serum Immune Profiles Define The Spectrum Of Acute And Chronic Pancreatitis From The Multicenter Prospective Evaluation Of Chronic Pancreatitis For Epidemiologic And Translational Studies (Proceed) Study, Bomi Lee, Elaina K Jones, Murli Manohar, Liang Li, Dhiraj Yadav, Darwin L Conwell, Phil A Hart, Santhi Swaroop Vege, Evan L Fogel, Jose Serrano, Dana Andersen, Melena D Bellin, Mark D Topazian, Stephen K Van Den Eeden, Stephen J Pandol, Chris E Forsmark, William E Fisher, Walter G Park, Sohail Z Husain, Aida Habtezion, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis.

METHODS: Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic …

Radiologic-Pathologic Correlation Of Covid-19-Associated Acute Disseminated Encephalomyelitis, Amy Bezold, Huda Hussain, Julum Nwanze, James T Roberts, Kuang-Chun J Hsieh

Faculty, Staff and Students Publications

A 42-year-old woman presented with drooling, slurred speech, inability to walk and talk, and a recent positive COVID-19 test. She had two prior hospital admissions within the past week for similar symptoms with inconclusive evaluation. MRI of the brain demonstrated multifocal white matter hyperintense lesions on fluid-attenuated inversion recovery (FLAIR)/diffusion with variable enhancement. These imaging findings have been described in recent literature and are associated with inflammatory demyelinating disease, such as acute disseminated encephalomyelitis. The patient subsequently underwent a brain biopsy with a final diagnosis of inflammatory demyelinating lesion. To our knowledge, this is the first radiologic-pathologic correlation of COVID-19-associated …