Neurosciences Commons^™

Monoclonal Antibody For The Prevention Of Respiratory Syncytial Virus In Infants And Children: A Systematic Review And Network Meta-Analysis, Mingyao Sun, Honghao Lai, Feiyang Na, Sheng Li, Xia Qiu, Jinhui Tian, Zhigang Zhang, Long Ge

Faculty, Staff and Student Publications

IMPORTANCE: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection in children younger than 5 years; effective prevention strategies are urgently needed.

OBJECTIVE: To compare the efficacy and safety of monoclonal antibodies for the prevention of RSV infection in infants and children.

DATA SOURCES: In this systematic review and network meta-analysis, PubMed, Embase, CENTRAL, and ClinicalTrials.gov were searched from database inception to March 2022.

STUDY SELECTION: Randomized clinical trials that enrolled infants at high risk of RSV infection to receive a monoclonal antibody or placebo were included. Keywords and extensive vocabulary related to monoclonal antibodies, RSV, …

Psychosocial, Medical, And Demographic Variables Associated With Parent Mealtime Behavior In Young Children Recently Diagnosed With Type 1 Diabetes, Caroline Gonynor, Christine Wang, Carrie Tully, Maureen Monaghan, Randi Streisand, Marisa E Hilliard

Faculty, Staff and Students Publications

OBJECTIVE: Managing young children's mealtime concerns can be challenging after type 1 diabetes (T1D) diagnosis because of developmental factors and diabetes management demands. To identify potential intervention targets, we evaluated medical, psychosocial, and demographic factors in relation to parents' engagement in problem mealtime behaviors (e.g., pressure to eat, restriction).

METHOD: Parents (N = 157) of young children (age 1-6 years) reported on psychosocial variables (parent fear of hypoglycemia, family functioning, parent problem solving, and parents' problem mealtime behavior frequency and perceptions of being problematic) within 2 months after T1D diagnosis. Hierarchical regression analyses examined associations among psychosocial variables, demographics (child …

Comparison Of Percentile Tables And Algorithm-Based Calculators For Classification Of Blood Pressures In Children And Adolescents With Obesity: A Secondary Analysis Of A Clinical Trial, William J Pitts, Tami L Cave, Alana Cavadino, Roman J Shypailo, Sarah E Maessen, Paul L Hofman, William Wong, Yvonne C Anderson

Faculty, Staff and Students Publications

AIM: Obesity as a major risk factor for childhood hypertension necessitates careful blood pressure (BP) monitoring of those affected. This study aimed to compare BP classification in a cohort of children affected by obesity using tables versus digital calculations in two sets of guidelines.

METHODS: This study was a secondary analysis of data collected from a randomised clinical trial of a multidisciplinary life-style assessment and intervention program. Baseline data from 237 children with a body mass index >99th percentile or >91st percentile with weight-related comorbidities and available BP measurements were analysed. We assessed agreement between tables and algorithms in classification …

Mutations In The Transcriptional Regulator Mecp2 Severely Impact Key Cellular And Molecular Signatures Of Human Astrocytes During Maturation, Jialin Sun, Sivan Osenberg, Austin Irwin, Li-Hua Ma, Nigel Lee, Yangfei Xiang, Feng Li, Ying-Wooi Wan, In-Hyun Park, Mirjana Maletic-Savatic, Nurit Ballas

Faculty, Staff and Students Publications

Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether MECP2 mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing MECP2 mutations greatly impact the key role of astrocytes in regulating overall brain bioenergetics and that these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal maturation, astrocytes rely on neurons to induce their complex stellate morphology and transcriptional changes. While MECP2 mutations cause cell-intrinsic aberrations in the astrocyte transcriptional landscape, surprisingly, they do not affect the neuron-induced …

Brain Nuclear Receptors And Cardiovascular Function, Mengjie Wang, Yongjie Yang, Yong Xu

Faculty, Staff and Students Publications

Brain-heart interaction has raised up increasing attentions. Nuclear receptors (NRs) are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of cardiovascular diseases (CVDs), including hypertension, heart failure, atherosclerosis, etc. In this review, we will elaborate recent findings that have established the physiological relevance of brain NRs in the context of cardiovascular function. In addition, we will discuss the currently available evidence regarding the distinct neuronal populations that respond to brain NRs in the cardiovascular control. These findings suggest connections between cardiac control and brain dynamics through NR signaling, which …

Association Of Omega 3 Polyunsaturated Fatty Acids With Incident Chronic Kidney Disease: Pooled Analysis Of 19 Cohorts, Kwok Leung Ong, Matti Marklund, Liping Huang, Kerry-Anne Rye, Nicholas Hui, Xiong-Fei Pan, Casey M Rebholz, Hyunju Kim, Lyn M Steffen, Anniek C Van Westing, Johanna M Geleijnse, Ellen K Hoogeveen, Yun-Yu Chen, Kuo-Liong Chien, Amanda M Fretts, Rozenn N Lemaitre, Fumiaki Imamura, Nita G Forouhi, Nicholas J Wareham, Anna Birukov, Susanne Jäger, Olga Kuxhaus, Matthias B Schulze, Vanessa Derenji De Mello, Jaakko Tuomilehto, Matti Uusitupa, Jaana Lindström, Nathan Tintle, William S Harris, Keisuke Yamasaki, Yoichiro Hirakawa, Toshiharu Ninomiya, Toshiko Tanaka, Luigi Ferrucci, Stefania Bandinelli, Jyrki K Virtanen, Ari Voutilainen, Tharusha Jayasena, Anbupalam Thalamuthu, Anne Poljak, Sonia Bustamante, Perminder S Sachdev, Mackenzie K Senn, Stephen S Rich, Michael Y Tsai, Alexis C Wood, Markku Laakso, Maria Lankinen, Xiaowei Yang, Liang Sun, Huaixing Li, Xu Lin, Christoph Nowak, Johan Ärnlöv, Ulf Risérus, Lars Lind, Mélanie Le Goff, Cécilia Samieri, Catherine Helmer, Frank Qian, Renata Micha, Adrienne Tin, Anna Köttgen, Ian H De Boer, David S Siscovick, Dariush Mozaffarian, Jason Hy Wu

Faculty, Staff and Students Publications

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were …

Single-Cell Multi-Omics Integration For Unpaired Data By A Siamese Network With Graph-Based Contrastive Loss, Chaozhong Liu, Linhua Wang, Zhandong Liu

Faculty, Staff and Students Publications

BACKGROUND: Single-cell omics technology is rapidly developing to measure the epigenome, genome, and transcriptome across a range of cell types. However, it is still challenging to integrate omics data from different modalities. Here, we propose a variation of the Siamese neural network framework called MinNet, which is trained to integrate multi-omics data on the single-cell resolution by using graph-based contrastive loss.

RESULTS: By training the model and testing it on several benchmark datasets, we showed its accuracy and generalizability in integrating scRNA-seq with scATAC-seq, and scRNA-seq with epitope data. Further evaluation demonstrated our model's unique ability to remove the batch …

Increased Camkk2 Expression Is An Adaptive Response That Maintains The Fitness Of Tumor-Infiltrating Natural Killer Cells, Patrick K Juras, Luigi Racioppi, Debarati Mukherjee, Sandeep Artham, Xia Gao, Laura Akullian D'Agostino, Ching-Yi Chang, Donald P Mcdonnell

Faculty, Staff and Students Publications

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) …

A Story Of Hope: How A Community Project Is Transforming The Lives Of Filipino Children With Intellectual And Developmental Disabilities, Lance Vincent C. Sese, Ma Celina L. Guillermo

Ateneo School of Medicine and Public Health Publications

The issue of social inequality became more prevalent during the pandemic and with it, the call for preferential option toward the vulnerable. 1 Not only do we protect them from sickness and death, but we are also called to improve their quality of life. Thus, it is imperative that in this call for inclusivity, we address the gap, one group at a time—for example, children with special needs. The project discussed in this perspective article exemplifies the importance of collaboration in bridging the gap to create a more holistic environment for Filipino children with special needs. This article then serves …

An Individual Data-Driven Virtual Resection Model Based On Epileptic Network Dynamics In Children With Intractable Epilepsy: A Magnetoencephalography Interictal Activity Application, Pablo Cuesta, Ricardo Bruña, Ekta Shah, Christopher Laohathai, Stephanie Garcia-Tarodo, Michael Funke, Gretchen Von Allmen, Fernando Maestú

Faculty, Staff and Student Publications

Epilepsy surgery continues to be a recommended treatment for intractable (medication-resistant) epilepsy; however, 30-70% of epilepsy surgery patients can continue to have seizures. Surgical failures are often associated with incomplete resection or inaccurate localization of the epileptogenic zone. This retrospective study aims to improve surgical outcome through in silico testing of surgical hypotheses through a personalized computational neurosurgery model created from individualized patient's magnetoencephalography recording and MRI. The framework assesses the extent of the epileptic network and evaluates underlying spike dynamics, resulting in identification of one single brain volume as a candidate for resection. Dynamic-locked networks were utilized for virtual …

Mass Spectrometry Imaging As An Emerging Tool For Studying Metabolism In Human Brain Organoids, Gerarda Cappuccio, Saleh M Khalil, Sivan Osenberg, Feng Li, Mirjana Maletic-Savatic

Faculty, Staff and Students Publications

Human brain organoids are emerging models to study human brain development and pathology as they recapitulate the development and characteristics of major neural cell types, and enable manipulation through an in vitro system. Over the past decade, with the advent of spatial technologies, mass spectrometry imaging (MSI) has become a prominent tool for metabolic microscopy, providing label-free, non-targeted molecular and spatial distribution information of the metabolites within tissue, including lipids. This technology has never been used for studies of brain organoids and here, we set out to develop a standardized protocol for preparation and mass spectrometry imaging of human brain …

Forniceal Deep Brain Stimulation In A Mouse Model Of Rett Syndrome Increases Neurogenesis And Hippocampal Memory Beyond The Treatment Period, Qi Wang, Bin Tang, Shuang Hao, Zhenyu Wu, Tingting Yang, Jianrong Tang

Faculty, Staff and Students Publications

BACKGROUND: Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT.

OBJECTIVES: To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice.

METHODS: Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual …

Sex-Specific Associations Between Urinary Bisphenols Concentrations During Pregnancy And Problematic Child Behaviors At Age 2 Years, Sarah Dee Geiger, Salma Musaad, Jennifer Hill, Andréa Aguiar, Susan Schantz

Faculty, Staff and Students Publications

Effects of prenatal bisphenol A (BPA) exposure on child behavior are mixed with some reports suggesting increased problematic behaviors in girls (e.g., aggression and emotional reactivity) and in boys (i.e., externalizing behaviors), while other reports suggest decreased problematic behaviors in girls. Little is known about the potential impact of pregnancy bisphenol S (BPS) exposure on child behavior. In a prospective cohort study (n=68), five maternal spot urine samples collected across pregnancy were pooled and analyzed for BPA and BPS. Child behavior at 2 years was assessed using the Child Behavior Checklist (CBCL). Linear regression models were used to assess associations …

Spatial Analysis Of Nanoparticle Distribution In Human Breast Xenografts Reveals Nanoparticles Targeted To Cancer Cells Localized With Tumor-Associated Stromal Cells, Sean Healy, Elizabeth T Henderson, Suqi Ke, Jacqueline Kelly, Brian W Simons, Chen Hu, Robert Ivkov, Preethi Korangath

Faculty, Staff and Students Publications

The biological influence of physicochemical parameters of “targeted” nanoparticles on their delivery to cancer tumors remains poorly understood. A comparative analysis of nanoparticle distributions in tumors following systemic delivery across several models can provide valuable insights.

Methods: Bionized nanoferrite nanoparticles (iron oxide core coated with starch), either conjugated with a targeted anti-HER2 antibody (BH), or unconjugated (BP), were intravenously injected into athymic nude or NOD-scid gamma (NSG) female mice bearing one of five human breast cancer tumor xenografts growing in a mammary fat pad. Tumors were harvested 24 hours after nanoparticle injection, fixed, mounted, and stained. We performed detailed histopathology …

Protocol For The Promoting Resilience In Stress Management (Prism) Intervention: A Multi-Site Randomized Controlled Trial For Adolescents With Type 1 Diabetes, Maeve B O'Donnell, Samantha R Scott, Britney M Ellisor, Viena T Cao, Chuan Zhou, Miranda C Bradford, Catherine Pihoker, Daniel J Desalvo, Faisal S Malik, Marisa E Hilliard, Abby R Rosenberg, Joyce P Yi-Frazier

Faculty, Staff and Students Publications

BACKGROUND: Adolescents with type 1 diabetes (T1D) are at high risk for elevated diabetes distress, which greatly impacts diabetes management, glycemic outcomes and overall quality of life. Developing protective skills and "resilience resources" to navigate adversity and manage diabetes distress has high potential to help adolescents with T1D achieve optimal behavioral, psychological, and health outcomes. The "Promoting Resilience in Stress Management" (PRISM) program is a manualized, brief, skills-based intervention delivered over 6 months via two 45-60 min one-on-one sessions and a family meeting with a PRISM coach, and supplemented by booster calls and a digital app. This trial (PRISM versus …

The Role Of Supervised School Therapy In Poorly Controlled Asthma In Children, Muppala Raju, Malvika Sagar, Andrew Bush, Eugene Quaye, Shekhar Ghamande, Sonal Malhotra, Mercedes E Arroliga

Faculty, Staff and Students Publications

BACKGROUND: In children, nonadherence to inhaled corticosteroid (ICS) therapy leads to poor asthma control and complications.

METHODS: We evaluated the benefit from initiation of ICS administration once daily at school. We retrospectively chose patients from our pediatric pulmonary clinic who had poorly controlled asthma and prescribed ICS daily. For the study period, we examined the number of corticosteroid courses, emergency room visits, hospital admissions, symptom history, and pulmonary function tests.

RESULTS: Thirty-four patients who satisfied the inclusion criteria began the intervention. Preintervention, there were a mean number of 2.6 oral corticosteroid courses compared to 2 courses in the year following …

Long-Term Neuropsychological Outcomes In Children With Febrile Infection-Related Epilepsy Syndrome (Fires) Treated With Anakinra, Anima Shrestha, E Lynne Wood, Gretchen Berrios-Siervo, Coral M Stredny, Katrina Boyer, Clemente Vega, Srishti Nangia, Eyal Muscal, Krista Eschbach

Faculty, Staff and Students Publications

BACKGROUND: Febrile-infection related epilepsy syndrome (FIRES) is a rare epilepsy syndrome in which a previously healthy individual develops refractory status epilepticus in the setting of a preceding febrile illness. There are limited data regarding detailed long-term outcomes. This study aims to describe the long-term neuropsychological outcomes in a series of pediatric patients with FIRES.

METHODS: This is a retrospective multi-center case series of pediatric patients with a diagnosis of FIRES treated acutely with anakinra who had neuropsychological testing at least 12 months after status epilepticus onset. Each patient underwent comprehensive neuropsychological evaluation as part of routine clinical care. Additional data …

Specialized Intensive Inpatient Rehabilitation Is Crucial And Time-Sensitive For Functional Recovery From Disorders Of Consciousness, Bei Zhang, Katherine O'Brien, Jean Woo, Bradley Chi, Colton Reeh, Sheng Li, Sunil Kothari

Faculty, Staff and Students Publications

BACKGROUND: Disorders of consciousness (DoCs) after severe brain injury are considered to be conditions with dire prognosis. Despite the accumulating evidence, inpatient rehabilitation is often denied by payers referring to the Medicare/Medicaid criteria, under the assumption that such patients will not "

OBJECTIVE: This study aimed to report on the effectiveness and efficiency of a specialized inpatient DoC rehabilitation program based on measurable clinical parameters.

METHODS: A retrospective cohort study was conducted. The cohort comprised 137 patients with DoC admitted to a specialized acute inpatient rehabilitation program between January 2014 and October 2018. Patients were categorized as having been admitted …

Behavioral Improvements Following Lesion Resection For Pediatric Epilepsy: Pediatric Psychosurgery?, Huy Dang, Abdul Basit Khan, Nisha Gadgil, Himanshu Sharma, Cristina Trandafir, Fatema Malbari, Howard L Weiner

Faculty, Staff and Students Publications

Introduction: Resection of brain lesions associated with refractory epilepsy to achieve seizure control is well accepted. However, concurrent behavioral effects of these lesions such as changes in mood, personality, and cognition and the effects of surgery on behavior have not been well characterized. We describe 5 such children with epileptogenic lesions and significant behavioral abnormalities which improved after surgery.

Case descriptions: Five children (ages 3-14 years) with major behavioral abnormalities and lesional epilepsy were identified and treated at our center. Behavioral problems included academic impairment, impulsivity, self-injurious behavior, and decreased social interaction with diagnoses of ADHD, oppositional defiant disorder, and …

Covid-19 Pandemic And Infant Neurodevelopmental Impairment: A Systematic Review And Meta-Analysis, Kamran Hessami, Amir Hossein Norooznezhad, Sonia Monteiro, Enrico R Barrozo, Abolfazl Shirdel Abdolmaleki, Sara E Arian, Nikan Zargarzadeh, Lara S Shekerdemian, Kjersti M Aagaard, Alireza A Shamshirsaz

Faculty, Staff and Students Publications

IMPORTANCE: Primary studies proposed that aberrant maternal antiviral immunity and/or giving birth in quarantine, such as during the ongoing COVID-19 pandemic, may be associated with the risk of neurodevelopmental impairment (NDI) in offspring.

OBJECTIVES: To evaluate the associations of birth and being raised during the COVID-19 pandemic with risk of NDI among infants and to assess the association of gestational exposure to SARS-CoV-2 with risk of NDI.

DATA SOURCES: PubMed, Web of Science, Scopus, Embase, and preprint servers were systematically searched from inception to March 25, 2022.

STUDY SELECTION: Studies evaluating the neurodevelopment of infants born during the SARS-CoV-2 pandemic …

Heterozygous Variants In Myh10 Associated With Neurodevelopmental Disorders And Congenital Anomalies With Evidence For Primary Cilia-Dependent Defects In Hedgehog Signaling, Alexander M Holtz, Rachel Vancoillie, Elizabeth A Vansickle, Deanna Alexis Carere, Kara Withrow, Erin Torti, Jane Juusola, Francisca Millan, Richard Person, Maria J Guillen Sacoto, Yue Si, Ingrid M Wentzensen, Jada Pugh, Georgia Vasileiou, Melissa Rieger, André Reis, Emanuela Argilli, Elliott H Sherr, Kimberly A Aldinger, William B Dobyns, Theresa Brunet, Julia Hoefele, Matias Wagner, Benjamin Haber, Urania Kotzaeridou, Boris Keren, Delphine Heron, Cyril Mignot, Solveig Heide, Thomas Courtin, Julien Buratti, Serini Murugasen, Kirsten A Donald, Emily O'Heir, Shade Moody, Katherine H Kim, Barbara K Burton, Grace Yoon, Miguel Del Campo, Diane Masser-Frye, Mariya Kozenko, Christina Parkinson, Susan L Sell, Patricia L Gordon, Jeremy W Prokop, Amel Karaa, Caleb Bupp, Benjamin A Raby

Faculty, Staff and Student Publications

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.

METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.

RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a …

Cardiovascular Adverse Events In Oncology Trials: Understanding And Appreciating The Differences Between Clinical Trial Data And Real-World Reports, Michael S Ewer, Jay Herson

Duncan NRI Faculty and Staff Publications

Reports of cardiac adverse events from oncology clinical trials often are at variance with reports derived from clinical observations or data-base reviews. These differences may lead to confusion, as different levels of risks abound in the literature, and the true cardiac risk of using some agents is uncertain. Additionally, such discrepancies may lead to the creation of over-cautious surveillance algorithms. Reasons for these reported differences are complex and often reflect subtleties in the criteria for individual patient evaluation. Both clinical trial data and real-world data have potential flaws that make reconciliation problematic. Importantly, however, both provide crucial information regarding the …

Gene-Based Therapeutics For Rare Genetic Neurodevelopmental Psychiatric Disorders, Beverly L Davidson, Guangping Gao, Elizabeth Berry-Kravis, Allison M Bradbury, Carsten Bönnemann, Joseph D Buxbaum, Gavin R Corcoran, Steven J Gray, Heather Gray-Edwards, Robin J Kleiman, Adam J Shaywitz, Dan Wang, Huda Y Zoghbi, Terence R Flotte, Sitra Tauscher-Wisniewski, Cynthia J Tifft, Mustafa Sahin

Duncan NRI Faculty and Staff Publications

We are in an emerging era of gene-based therapeutics with significant promise for rare genetic disorders. The potential is particularly significant for genetic central nervous system disorders that have begun to achieve Food and Drug Administration approval for select patient populations. This review summarizes the discussions and presentations of the National Institute of Mental Health-sponsored workshop "Gene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders," which was held in January 2021. Here, we distill the points raised regarding various precision medicine approaches related to neurodevelopmental and psychiatric disorders that may be amenable to gene-based therapies.

Using Artificial Neural Networks To Predict Intra-Abdominal Abscess Risk Post-Appendectomy, Morouge M Alramadhan, Hassan S Al Khatib, James R Murphy, Kuojen Tsao, Michael L Chang

Faculty, Staff and Student Publications

OBJECTIVE: To determine if artificial neural networks (ANN) could predict the risk of intra-abdominal abscess (IAA) development post-appendectomy.

BACKGROUND: IAA formation occurs in 13.6% to 14.6% of appendicitis cases with "complicated" appendicitis as the most common cause of IAA. There remains inconsistency in describing the severity of appendicitis with variation in treatment with respect to perforated appendicitis.

METHODS: Two "reproducible" ANN with different architectures were developed on demographic, clinical, and surgical information from a retrospective surgical dataset of 1574 patients less than 19 years old classified as either negative (n = 1,328) or positive (n = 246) for IAA post-appendectomy …

Prune1 C933g>A Synonymous Variant Induces Exon 7 Skipping, Disrupts The Dhha2 Domain, And Leads To An Atypical Nmihba Syndrome Presentation: Case Report And Review Of The Literature, Christina L Magyar, David R Murdock, Lindsay C Burrage, Hongzheng Dai, Seema R Lalani, Richard A Lewis, Yuezhen Lin, Marcela F Astudillo, Jill A Rosenfeld, Alyssa A Tran, James B Gibson, Undiagnosed Diseases Network, Carlos A Bacino, Brendan H Lee, Hsiao-Tuan Chao

Faculty, Staff and Students Publications

Prune exopolyphosphatase-1 (PRUNE1) encodes a member of the aspartic acid-histidine-histidine (DHH) phosphodiesterase superfamily that regulates cell migration and proliferation during brain development. In 2015, biallelic PRUNE1 loss-of-function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of PRUNE1-related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous …

Electrographic Seizures In Neonates With A High Risk Of Encephalopathy, Wan-Hsuan Chen, Oi-Wa Chan, Jainn-Jim Lin, Ming-Chou Chiang, Shao-Hsuan Hsia, Huei-Shyong Wang, En-Pei Lee, Yi-Shan Wang, Cheng-Yen Kuo, Kuang-Lin Lin, On The Behalf Of The Icns Group

Faculty, Staff and Student Publications

Background: Neonatal encephalopathy is caused by a wide variety of acute brain insults in newborns and presents with a spectrum of neurologic dysfunction, such as consciousness disturbance, seizures, and coma. The increased excitability in the neonatal brain appears to be highly susceptible to seizures after a variety of insults, and seizures may be the first clinical sign of a serious neurologic disorder. Subtle seizures are common in the neonatal period, and abnormal clinical paroxysmal events may raise the suspicion of neonatal seizures. Continuous video electroencephalographic (EEG) monitoring is the gold standard for the diagnosis of neonatal seizures. The aim of …

Berenice Final Analysis: Cardiac Safety Study Of Neoadjuvant Pertuzumab, Trastuzumab, And Chemotherapy Followed By Adjuvant Pertuzumab And Trastuzumab In Her2-Positive Early Breast Cancer, Chau Dang, Michael S Ewer, Suzette Delaloge, Jean-Marc Ferrero, Ramon Colomer, Luis De La Cruz-Merino, Theresa L Werner, Katherine Dadswell, Mark Verrill, Daniel Eiger, Sriparna Sarkar, Sanne Lysbet De Haas, Eleonora Restuccia, Sandra M Swain

Duncan NRI Faculty and Staff Publications

Simple Summary

A combination of pertuzumab, trastuzumab, and chemotherapy is a standard treatment for patients with a type of breast cancer called HER2-positive. Before the BERENICE study, little was known about the safety and effectiveness of pertuzumab with trastuzumab after surgery. Cardiac safety was a particular concern, especially when the chemotherapy given before surgery included drugs called anthracyclines. BERENICE was designed to assess the cardiac safety of pertuzumab with trastuzumab before surgery in combination with two different types of anthracycline-based chemotherapies. This paper describes additional safety and effectiveness data from BERENICE after patients had undergone surgery and when they had …

A D2 To D1 Shift In Dopaminergic Inputs To Midbrain 5-Ht Neurons Causes Anorexia In Mice, Xing Cai, Hailan Liu, Bing Feng, Meng Yu, Yang He, Hesong Liu, Chen Liang, Yongjie Yang, Longlong Tu, Nan Zhang, Lina Wang, Na Yin, Junying Han, Zili Yan, Chunmei Wang, Pingwen Xu, Qi Wu, Qingchun Tong, Yanlin He, Yong Xu

Faculty, Staff and Students Publications

Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HT

Disruption Of Mecp2-Tcf20 Complex Underlies Distinct Neurodevelopmental Disorders, Jian Zhou, Hamdan Hamdan, Hari Krishna Yalamanchili, Kaifang Pang, Amy E Pohodich, Joanna Lopez, Yingyao Shao, Juan A Oses-Prieto, Lifang Li, Wonho Kim, Mark A Durham, Sameer S Bajikar, Donna J Palmer, Philip Ng, Michelle L Thompson, E Martina Bebin, Amelie J Müller, Alma Kuechler, Antje Kampmeier, Tobias B Haack, Alma L Burlingame, Zhandong Liu, Matthew N Rasband, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

MeCP2 is associated with Rett syndrome (RTT), MECP2 duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Duncan NRI Faculty and Staff Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …