Medical Specialties Commons^™

High Response Rate With Extended Dosing Of Cemiplimab In Advanced Cutaneous Squamous Cell Carcinoma, Danny Rischin, Brett G M Hughes, Nicole Basset-Séguin, Dirk Schadendorf, Samantha Bowyer, Sabiha Trabelsi Messai, Friedegund Meier, Thomas K Eigentler, Victoria Casado Echarren, Brian Stein, Marie Beylot-Barry, Sophie Dalac, Brigitte Dréno, Michael R Migden, Axel Hauschild, Chrysalyne D Schmults, Annette M Lim, Suk-Young Yoo, Anne J Paccaly, Apostolos Papachristos, Jenny-Hoa Nguyen, Emmanuel Okoye, Frank Seebach, Jocelyn Booth, Israel Lowy, Matthew G Fury, Alexander Guminski

Faculty, Staff and Student Publications

BACKGROUND: Cemiplimab (Libtayo

METHODS: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review.

RESULTS: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n

CONCLUSIONS: Extended dosing of cemiplimab 600 mg intravenously Q4W …

Ape-Gen20: Expanding Rapid Class I Peptide-Major Histocompatibility Complex Modeling To Post-Translational Modifications And Noncanonical Peptide Geometries, Romanos Fasoulis, Mauricio M Rigo, Gregory Lizée, Dinler A Antunes, Lydia E Kavraki

Faculty, Staff and Student Publications

The recognition of peptides bound to class I major histocompatibility complex (MHC-I) receptors by T-cell receptors (TCRs) is a determinant of triggering the adaptive immune response. While the exact molecular features that drive the TCR recognition are still unknown, studies have suggested that the geometry of the joint peptide–MHC (pMHC) structure plays an important role. As such, there is a definite need for methods and tools that accurately predict the structure of the peptide bound to the MHC-I receptor. In the past few years, many pMHC structural modeling tools have emerged that provide high-quality modeled structures in the general case. …

Toward Generalizable Machine Learning Models In Speech, Language, And Hearing Sciences: Estimating Sample Size And Reducing Overfitting, Hamzeh Ghasemzadeh, Robert E Hillman, Daryush D Mehta

Faculty, Staff and Student Publications

PURPOSE: Many studies using machine learning (ML) in speech, language, and hearing sciences rely upon cross-validations with single data splitting. This study's first purpose is to provide quantitative evidence that would incentivize researchers to instead use the more robust data splitting method of nested

METHOD: First, the significant impact of different cross-validations on ML outcomes was demonstrated using real-world clinical data. Then, Monte Carlo simulations were used to quantify the interactions among the employed cross-validation method, the discriminative power of features, the dimensionality of the feature space, the dimensionality of the model, and the sample size. Four different cross-validation methods …

Contemporary Approach To Narrow Angles, Wesam Shamseldin Shalaby, Rohit Reddy, Reza Razeghinejad, L. Jay Katz

Wills Eye Hospital Papers

Glaucoma is the leading cause of irreversible blindness worldwide. Among all glaucoma types, primary angle closure glaucoma (PACG) affects approximately 23 million people worldwide, and is responsible for 50% of glaucoma-related blindness, highlighting the devastating consequences of this disease. The main mechanism of PACG is relative pupillary block. High-risk populations are female gender, Asian ethnicity, high hyperopia, short axial length, and a thick/anteriorly positioned lens. This review discusses the clinical diagnosis, classification, and management of patients with a narrow angle with and without intraocular pressure (IOP) elevation and glaucomatous optic nerve damage, including laser peripheral iridotomy (LPI), endocycloplasty (ECPL), lens …

Microvascular Vasoregulatory Dysfunction In African Americans - An Enhanced Opportunity For Early Prevention And Treatment Of Atherosclerotic Cardiovascular Disease, Renee Bullock-Palmer, Panithaya Chareonthaitawee, Ervin Fox, Garth Beache

Division of Cardiology Faculty Papers

Atherosclerotic cardiovascular disease and its risk factors and precursors are a major driver of disparities in cardiovascular health. This review examines reported evidence that vascular endothelial dysfunction, and its manifestation as coronary microvascular dysfunction, underlies observed excess morbidity and mortality in African Americans. Advanced imaging insights that reveal patho-mechanisms, along with population evidence from the Jackson Heart Study, and the growing evidence emanating from national and international clinical trials and registries are presented. We examine a physiological framework that recognizes insulin-resistant cardiometabolic underpinnings of the conditions of the American Heart Associations' Life's Essential Eight construct of cardiovascular health as a …

Operative Versus Nonoperative Management For Diverticulitis Complicated By Abscess, Alix Bernholtz, Abbie R. Bauer

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

You K, Bendl R, Taut C, et al. Randomized clinical trial of elective resection versus observation in diverticulitis with extraluminal air or abscess initially managed conservatively. Br J Surg. 2018;105(8):971-979. https://doi.org/10.1002/bjs.10868

for a patient with a recurrent diverticulitis complicated by abscess formation.

Integration Of Pan-Omics Technologies And Three-Dimensional In Vitro Tumor Models: An Approach Toward Drug Discovery And Precision Medicine., Anmi Jose, Pallavi Kulkarni, Jaya Thilakan, Murali Munisamy, Anvita Gupta Malhotra, Jitendra Singh, Ashok Kumar, Vivek M. Rangnekar, Neha Arya, Mahadev Rao

Markey Cancer Center Faculty Publications

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to …

Simplifying Treatment From Double-Inhaler To Single-Inhaler Triple Therapy In Patients With Chronic Obstructive Pulmonary Disease, Kelly Yang, Leah Warren

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using

Ferguson GT, Brown N, Compton C, et al. Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials. Respir Res. 2020;21(1):131. https://doi.org/10.1186/s12931-020-01360-w

for a patient requesting a simplified therapeutic regimen with equal efficacy for chronic obstructive pulmonary disease (COPD) management.

Balancing The Medical, Psychiatric, And Ethical Considerations In The Inpatient Treatment Of Extreme Anorexia Nervosa: A Case Report, Carter A. Schulz, Carolyn A. Kennedy

Aesculapius Journal (Health Sciences & Medicine)

Introduction: Anorexia nervosa (AN) is a psychiatric illness characterized by restricted energy intake, intense fear of gaining weight, and a disturbance in body image. A 2011 meta-analysis estimated the mortality rate for anorexia nervosa to be over 5 times that of the general population, with one-fifth of deaths in AN patients being due to suicide. Treating this disease is notoriously difficult, and treatment is complicated by these patients’ characteristically poor insight.

Case summary: Here we present the case of a 37 year old woman who visited the ED with complaints of nausea and weakness; she was admitted due to hypoglycemia, …

Effects Of Chaplain Care On Coping With Cancer, Sarah Battiston, Scott L. Baughan

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical case decision report using:

Piderman KM, Radecki CR, Jenkins SM, et al. Hearing and heeding the voices of those with advanced illnesses. Journal of Palliative Care. 2020;35(4):248-255. https://doi.org/10.1177/0825859720928623

for a patient having difficulty coping with cancer

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

Faculty, Staff and Student Publications

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

Isoform Alterations In The Ubiquitination Machinery Impacting Gastrointestinal Malignancies, Srimathi Kasturirangan, Derek Nancarrow, Ayush Shah, Kiran Lagisetty, Theodore Lawrence, David Beer, Dipankar Ray

Department of Medicine Faculty Papers

The advancement of RNAseq and isoform-specific expression platforms has led to the understanding that isoform changes can alter molecular signaling to promote tumorigenesis. An active area in cancer research is uncovering the roles of ubiquitination on spliceosome assembly contributing to transcript diversity and expression of alternative isoforms. However, the effects of isoform changes on functionality of ubiquitination machineries (E1, E2, E3, E4, and deubiquitinating (DUB) enzymes) influencing onco- and tumor suppressor protein stabilities is currently understudied. Characterizing these changes could be instrumental in improving cancer outcomes via the identification of novel biomarkers and targetable signaling pathways. In this review, we …

Treatment Of Gastrointestinal Bleeding In The Biliopancreatic Limb With Embolization In A Patient With Duodenal Switch Anatomy, Alice S. Pang, Robert Adamo, Robert Coben

Division of Gastroenterology and Hepatology Faculty Papers

INTRODUCTION: Biliopancreatic diversion with duodenal switch (BPD/DS) is an uncommon type of bariatric surgery that can rarely lead to bleeding in the biliopancreatic limb. The altered anatomy poses significant diagnostic and therapeutic challenges.

CASE PRESENTATION: We present an unusual case of a woman status post-BPD/DS nearly a decade ago who presented with gastrointestinal bleeding in the duodenum of the biliopancreatic limb, a rare phenomenon given the unique surgery.

CONCLUSION: We illustrate a promising minimally invasive option of successfully treating the bleeding by interventional radiology (IR) embolization as an alternative to more invasive and challenging options of balloon-assisted enteroscopy, lumen-apposing metal …

A Structured, Journal-Led Peer-Review Mentoring Program Enhances Peer Review Training, Ariel Maia Lyons-Warren, Whitley W Aamodt, Kathleen M Pieper, Roy E Strowd

Faculty, Staff and Students Publications

BACKGROUND: Peer review is essential to the advancement of knowledge. However, training on how to conduct peer review is limited, unorganized, and not well studied. Thus, we sought to determine if a structured mentored peer-review program improved peer review training as measured by multiple quantitative and qualitative assessments.

METHODS: This pre-post intervention study enrolled 55 mentees across 5 cohorts from 2020 to 2023. Each cohort completed pre-program evaluations, participated in 2 mentored reviews, and completed post-program evaluations over 6 months. Mentors and mentees completed pre-program demographic and review experience questionnaires. Outcome measures included (1) total and sub-scores on the modified …

Antioxidant Responses And Phytochemical Accumulation In Raphanus Species Sprouts Through Elicitors And Predictive Models Under High Temperature Stress, María-Trinidad Toro, Roberto Fustos-Toribio, Jaime Ortiz, José Becerra, Nelson Zapata, María Dolores López-Belchí

Faculty, Staff and Students Publications

Crop production is being impacted by higher temperatures, which can decrease food yield and pose a threat to human nutrition. In the current study, edible and wild radish sprouts were exposed to elevated growth temperatures along with the exogenous application of various elicitors to activate defense mechanisms. Developmental traits, oxidative damage, glucosinolate and anthocyanin content, and antioxidant capacity were evaluated alongside the development of a predictive model. A combination of four elicitors (citric acid, methyl jasmonate—MeJa, chitosan, and K2SO4) and high temperatures were applied. The accumulation of bioactives was significantly enhanced through the application of two elicitors, K2SO4 and methyl …

Evaluation Of Perioperative Care And Drivers Of Cost In Geriatric Thoracolumbar Trauma, Omar Tarawneh, Rajkishen Narayanan, Michael Mccurdy, Tariq Issa, Yunsoo Lee, Olivia Opara, Nicholas Pohl, Alexa Tomlak, Matthew Sherman, Jose Canseco, Alan Hilibrand, Alex Vaccaro, Gregory Schroeder, Christopher Kepler

Department of Orthopaedic Surgery Faculty Papers

INTRODUCTION: As the population of elderly patients continues to rise, the number of these individuals presenting with thoracolumbar trauma is expected to increase.

RESEARCH QUESTION: To investigate thoracolumbar fusion outcomes for patients with vertebral fractures as stratified by decade. Secondarily, we examined the variability of cost across age groups by identifying drivers of cost of care.

MATERIALS AND METHODS: We queried the United States Nationwide Inpatient Sample(NIS) for adult patients undergoing spinal fusion for thoracolumbar fractures between 2012 and 2017. Patients were stratified by decade 60-69(sexagenarians), 70-79(septuagenarians) and 80-89(octogenarians). Bivariable analysis followed by multivariable regression was performed to assess independent …

The Acceptance And Use Of Digital Technologies For Self-Reporting Medication Safety Events After Care Transitions To Home In Patients With Cancer: Survey Study, Yun Jiang, Misun Hwang, Youmin Cho, Christopher R Friese, Sarah T Hawley, Milisa Manojlovich, John C Krauss, Yang Gong

Faculty, Staff and Student Publications

BACKGROUND: Actively engaging patients with cancer and their families in monitoring and reporting medication safety events during care transitions is indispensable for achieving optimal patient safety outcomes. However, existing patient self-reporting systems often cannot address patients' various experiences and concerns regarding medication safety over time. In addition, these systems are usually not designed for patients' just-in-time reporting. There is a significant knowledge gap in understanding the nature, scope, and causes of medication safety events after patients' transition back home because of a lack of patient engagement in self-monitoring and reporting of safety events. The challenges for patients with cancer in …

A Case Report : Rosai-Dorfman Disease Of The Breast, Jenjeera Prueksadee

Chulalongkorn Medical Journal

Abstract

A case report of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) of the breast is one of the rare diseases, characterized by benign proliferative disorder of histiocyte. Most occur within lymph nodes whereas the rest involve extranodal sites. Breast involvement is considered extremely rare but considerable because of radiological findings simulating breast cancer. We report the case of a 59-year-old Thai woman who underwent screening mammography. Her biopsy resulted in abnormal histiocytes with S-100 protein expression, some of them with emperipolesis (lymphophagocytosis). Recognition of Rosai-Dorfman disease leads to correct diagnosis and further appropriate proper treatment strategy.

Primary Lung And Pleural Malignancies In Children: Imaging Of A Case Series, Teerasak Phewplung, Tanitha Phruksahirun

Chulalongkorn Medical Journal

Early diagnosis of primary lung and pleural malignancies is a challenge because it is extremely rare in children. The patient often presents with metastatic disease and non-neoplastic lesions. Clinical detection and imaging studies are nonspecific findings and may be indistinguishable from other lung malformations, resulting in a delay in diagnosis and treatment and an increase in tumor morbidity and mortality.

We present four cases of children whose clinical presentation and initial imaging had suspicious abnormalities and were eventually revealed to be primary lung and pleural malignancies. The literature on primary lung and pleural malignancies is also reviewed.

Pediatric Appendicitis Or Not? A Retrospective Cohort Study From A Single Institution - Our Management And Factors Determining The Disease, Nimmita Srisan, Teerasak Phewplung, Katawaetee Decharun, Prapapan Rajatapiti, Paisarn Vejchapipat

Chulalongkorn Medical Journal

Purpose: The aims were to assess our treatment guidelines and to determine factors in differentiating children with acute appendicitis from other diseases.

Methods: Pediatric surgery consultations for suspected appendicitis from October 2019 to October 2021 was retrospectively studied. The treatment guidelines of children with suspected appendicitis were elucidated. Moreover, factors identifying the diagnosis of appendicitis were analyzed using multi-variate logistic regression.

Results: Ninety-one children were consulted for suspected appendicitis. Forty-one children (45.1%) were promptly successfully treated without observation or ultrasonography, except one negative appendectomy (2.4%). The other 50 children (54.9%), showed equivocal clinical symptoms and signs, requiring further management either …

Analysis Of Breast Mri Performed On Patients With Axillary Nodal Metastasis And Negative Mammogram And Ultrasound, Pakpawee Pichayakul, Palita Hansakul

Chulalongkorn Medical Journal

Background: Occult breast cancer is a rare type of breast cancer which magnetic resonance imaging (MRI) has an immense role to confirm diagnosis and disclose non-demonstrable finding on initial modality.

Objective: To analysis breast MRI findings in patients with axillary nodal metastasis and negative mammogram and ultrasound, and retrospective review of the initial mammography and second-look ultrasound.

Methods: From January 2010 to January 2023, women who diagnosed occult breast cancer by presenting metastatic axillary lymph node on pathological report with negative mammography and ultrasonography, underwent breast MRI to identify occult breast carcinoma. Their breast MRI were retrospectively reviewed …

Target: A Randomized, Noninferiority Trial Of A Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling For Prostate Cancer Germline Testing, Stacy Loeb, Scott Keith, Heather Cheng, Amy Leader, Laura Gross, Tatiana Sanchez Nolasco, Nataliya Byrne, Rebecca Hartman, Lauren Brown, Christopher Pieczonka, Leonard Gomella, William Kevin Kelly, Costas Lallas, Nathan Handley, Patrick Mille, James Mark, Gordon Brown, Sameer Chopra, Alexandra Mcclellan, David Wise, Lucas Hollifield, Veda Giri

Department of Urology Faculty Papers

PURPOSE: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services.

METHODS: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at …

Editorial: Reviews And Advances In The Molecular Mechanisms Of Breast Cancer, A. Redfern, V. Agarwal, Suresh Alahari

School of Medicine Faculty Publications

No abstract provided.

Commentary On 2022 Guidelines On Clinical Trial Design In Cluster Headache And Further Suggestions, Ioana Medrea, Stewart J Tepper, Donliang Wang, Paul G Mathew, Mark Burish

Faculty, Staff and Student Publications

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies.

MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment.

CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Final Results Of Urelumab, An Anti-Cd137 Agonist Monoclonal Antibody, In Combination With Cetuximab Or Nivolumab In Patients With Advanced Solid Tumors, Nikhil I Khushalani, Patrick A Ott, Robert L Ferris, Tina Cascone, Dirk Schadendorf, Dung T Le, Manish R Sharma, Fabrice Barlesi, William Sharfman, Jason J Luke, Ignacio Melero, Deanne Lathers, Jaclyn Neely, Satyendra Suryawanshi, Abanti Sanyal, James L Holloway, Rasika Suryawanshi, Scott Ely, Neil H Segal

Faculty, Staff and Student Publications

BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.

METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m

RESULTS: CA186-018: 66 patients received study treatment. The most frequent …

Rehabilitation Treatment Specification System For Voice Therapy: Application To Everyday Clinical Care, Jeremy Wolfberg, John Whyte, Patricia Doyle, Shirley Gherson, Jason Muise, Brian Petty, Carol Jorgensen Tolejano, Robert E Hillman, Tara Stadelman-Cohen, Jarrad H Van Stan

Faculty, Staff and Student Publications

PURPOSE: Rehabilitation intervention descriptions often do not explicitly identify active ingredients or how those ingredients lead to changes in patient functioning. The Rehabilitation Treatment Specification System (RTSS) provides guidance to identify the critical aspects of any rehabilitation therapy and supported the development of standardly named ingredients and targets in voice therapy (Rehabilitation Treatment Specification System for Voice Therapy [RTSS-Voice]). This study sought to test the content validity of the RTSS-Voice and determine if the RTSS-Voice can be used to identify commonalities and differences in treatment (criterion validity) across clinicians in everyday clinical practice.

METHOD: Five speech-language pathologists from different institutions …

Correction To: Using Phosphoproteomics Data To Understand Cellular Signaling: A Comprehensive Guide To Bioinformatics Resources, Sara R Savage, Bing Zhang

Faculty, Staff and Students Publications

No abstract provided.

Heterogeneity And Overlap In The Continuum Of Linguistic Profile Of Logopenic And Semantic Variants Of Primary Progressive Aphasia: A Profile Analysis Based On Multidimensional Scaling Study, Gaia Chiara Santi, Francesca Conca, Valentina Esposito, Cristina Polito, Silvia Paola Caminiti, Cecilia Boccalini, Carmen Morinelli, Valentina Berti, Salvatore Mazzeo, Valentina Bessi, Alessandra Marcone, Sandro Iannaccone, Se-Kang Kim, Sandro Sorbi, Daniela Perani, Stefano F Cappa, Eleonora Catricalà

Faculty, Staff and Students Publications

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce.

METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [

RESULTS: Patients' profiles were distributed across a …

De Novo Variants In Dennd5b Cause A Neurodevelopmental Disorder, Marcello Scala, Valeria Tomati, Matteo Ferla, Mariateresa Lena, Julie S Cohen, Ali Fatemi, Elly Brokamp, Anna Bican, John A Phillips, Mary E Koziura, Michael Nicouleau, Marlene Rio, Karine Siquier, Nathalie Boddaert, Ilaria Musante, Serena Tamburro, Simona Baldassari, Michele Iacomino, Paolo Scudieri, Undiagnosed Diseases Network, Jill A Rosenfeld, Gary Bellus, Sara Reed, Hind Al Saif, Rossana Sanchez Russo, Matthew B Walsh, Vincent Cantagrel, Amy Crunk, Stefano Gustincich, Sarah M Ruggiero, Mark P Fitzgerald, Ingo Helbig, Pasquale Striano, Mariasavina Severino, Vincenzo Salpietro, Nicoletta Pedemonte, Federico Zara

Faculty, Staff and Students Publications

The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal …

Haploinsufficiency Of Zfhx3, Encoding A Key Player In Neuronal Development, Causes Syndromic Intellectual Disability, María Del Rocío Pérez Baca, Eva Z Jacobs, Lies Vantomme, Pontus Leblanc, Elke Bogaert, Annelies Dheedene, Laurenz De Cock, Sadegheh Haghshenas, Aidin Foroutan, Michael A Levy, Jennifer Kerkhof, Haley Mcconkey, Chun-An Chen, Nurit Assia Batzir, Xia Wang, María Palomares, Marieke Carels, Zfhx3 Consortium, Bart Dermaut, Bekim Sadikovic, Björn Menten, Bo Yuan, Sarah Vergult, Bert Callewaert

Faculty, Staff and Students Publications

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability (ID). ZFHX3 is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tumorigenesis. We describe 42 individuals with protein-truncating variants (PTVs) or (partial) deletions of ZFHX3, exhibiting variable intellectual disability and autism spectrum disorder, recurrent facial features, relative short stature, brachydactyly, and, rarely, cleft palate. ZFHX3 LoF associates with a specific methylation profile in whole blood extracted DNA. Nuclear abundance of ZFHX3 increases during human brain development and …