Digital Commons Network^™

Individual Dynamic Prediction For Cure And Survival Based On Longitudinal Biomarkers, Can Xie, Xuelin Huang, Ruosha Li, Alexander Tsodikov, Kapil Bhalla

Faculty, Staff and Student Publications

To optimize personalized treatment strategies and extend patients' survival times, it is critical to accurately predict patients' prognoses at all stages, from disease diagnosis to follow-up visits. The longitudinal biomarker measurements during visits are essential for this prediction purpose. Patients' ultimate concerns are cure and survival. However, in many situations, there is no clear biomarker indicator for cure. We propose a comprehensive joint model of longitudinal and survival data and a landmark cure model, incorporating proportions of potentially cured patients. The survival distributions in the joint and landmark models are specified through flexible hazard functions with the proportional hazards as …

Normal Breast Tissues Harbour Rare Populations Of Aneuploid Epithelial Cells, Yiyun Lin, Junke Wang, Kaile Wang, Shanshan Bai, Aatish Thennavan, Runmin Wei, Yun Yan, Jianzhuo Li, Heba Elgamal, Emi Sei, Anna Casasent, Mitchell Rao, Chenling Tang, Asha S Multani, Jin Ma, Jessica Montalvan, Chandandeep Nagi, Sebastian Winocour, Bora Lim, Alastair Thompson, Nicholas Navin

Faculty, Staff and Student Publications

Aneuploid epithelial cells are common in breast cancer

Association Between Microsatellite Instability Status, Clinicopathological Features And Mitochondrial Dna Amplification In Patients With Colorectal Cancer, Junmi Lu, Hong Tan, Tao Guo, Xi Chen, Zhongyi Tong

Faculty, Staff and Students Publications

The relationship between BRAF-V600E mutations, mitochondrial DNA amplification and microsatellite instability-high (MSI-H) in colorectal cancer (CRC) has yet to be fully elucidated. The aim of the present study was to assess the association between the MSI status and BRAF-V600E gene mutations/clinicopathological features/mitochondrial DNA amplification in CRC. A non-interventional study analysis was performed using the clinicopathological features of 455 patients with CRC. Immunohistochemistry was used to evaluate four mismatch repair proteins (MutS homolog 2, MutS homolog 6, MutL homolog 1 and postmeiotic segregation increased 2), Ki-67 index, and programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) expression. …

A Proteome-Wide Association Study Identifies Putative Causal Proteins For Breast Cancer Risk, Tianying Zhao, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Jill E Henry, Bing Zhang, Xingyi Guo, Michele L Cote, Qiuyin Cai, Xiao-Ou Shu, Wei Zheng, Jirong Long

Faculty, Staff and Students Publications

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 breast cancer risk-associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue related to breast cancer risk.

METHODS: We profiled the proteome in fresh frozen breast tissue samples from 120 cancer-free European-ancestry women from the Susan G. Komen Tissue Bank (KTB). Protein expression levels were log2-transformed then normalized via quantile and inverse-rank transformations. GWAS data were also generated for …

Chronic Β3-Ar Stimulation Activates Distinct Thermogenic Mechanisms In Brown And White Adipose Tissue And Improves Systemic Metabolism In Aged Mice, Duraipandy Natarajan, Bhuvana Plakkot, Kritika Tiwari, Shoba Ekambaram, Weidong Wang, Michael Rudolph, Mahmoud A Mohammad, Shaji K Chacko, Madhan Subramanian, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar, Priya Balasubramanian

Faculty, Staff and Students Publications

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a …

Randomized, Observer-Blind, Controlled Phase 1 Study Of The Safety And Immunogenicity Of The Na-Gst-1/Alhydrogel Hookworm Vaccine With Or Without A Cpg Odn Adjuvant In Hookworm-Naïve Adults, David J Diemert, Maria Zumer, Mark Bova, Christina Gibbs-Tewary, Elissa M Malkin, Doreen Campbell, Lara Hoeweler, Guangzhao Li, Maria Elena Bottazzi, Peter J Hotez, Jeffrey M Bethony

Faculty, Staff and Students Publications

BACKGROUND: Recombinant Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) formulated on Alhydrogel (Na-GST-1/Alhydrogel) is being developed to prevent anemia and other complications of N. americanus infection. Antibodies induced by vaccination with recombinant Na-GST-1 are hypothesized to interfere with the blood digestion pathway of adult hookworms in the host. Phase 1 trials have demonstrated the safety of Na-GST-1 formulated on Alhydrogel, but further optimization of the vaccine adjuvant formulation may improve humoral immune responses, thereby increasing the likelihood of vaccine efficacy.

METHODS: A randomized, observer-blind, dose escalation Phase 1 trial was conducted in 24 healthy, hookworm-naïve adults. In each cohort of 12 participants, 4 …

Immunopeptidomic Mhc-I Profiling And Immunogenicity Testing Identifies Tcj2 As A New Chagas Disease Mrna Vaccine Candidate, Leroy Versteeg, Rakesh Adhikari, Gonteria Robinson, Jungsoon Lee, Junfei Wei, Nelufa Islam, Brian Keegan, William K Russell, Cristina Poveda, Maria Jose Villar, Kathryn Jones, Maria Elena Bottazzi, Peter Hotez, Edwin Tijhaar, Jeroen Pollet

Faculty, Staff and Students Publications

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease. Globally 6 to 7 million people are infected by this parasite of which 20-30% will progress to develop Chronic Chagasic Cardiomyopathy (CCC). Despite its high disease burden, no clinically approved vaccine exists for the prevention or treatment of CCC. Developing vaccines that can stimulate T. cruzi-specific CD8+ cytotoxic T cells and eliminate infected cells requires targeting parasitic antigens presented on major histocompatibility complex-I (MHC-I) molecules. We utilized mass spectrometry-based immunopeptidomics to investigate which parasitic peptides are displayed on MHC-I of T. cruzi infected cells. Through duplicate experiments, we identified an …

The Long Road Of Drug Development For Endometriosis – Pains, Gains, And Hopes, Zian Liao, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Endometriosis, defined by the growth of endometrial tissues outside of the uterine cavity, is a global health burden for ∼200 million women. Patients with endometriosis usually present with chronic pain and are often diagnosed with infertility. The pathogenesis of endometriosis is still an open question; however, tissue stemness and immunological and genetic factors have been extensively discussed in the establishment of endometriotic lesions. Current treatments for endometriosis can be categorized into pharmacological management of hormone levels and surgical removal of the lesions. Both approaches have limited efficacy, with recurrences often encountered; thus, there is no complete cure for the disease …

Diabetter Together: Clinical Trial Protocol For A Strengths-Based Peer Mentor Intervention For Young Adults With Type 1 Diabetes Transitioning To Adult Care, Samantha A Carreon, Charles G Minard, Sarah K Lyons, Wendy Levy, Stephanie Camey, Kishan Desai, Brenda Duran, Randi Streisand, Barbara J Anderson, Siripoom V Mckay, Tricia S Tang, Sridevi Devaraj, Ryan Ramphul, Marisa E Hilliard

Faculty, Staff and Students Publications

Background: Type 1 diabetes (T1D) management is challenging for young adults, who are expected to transfer from the pediatric to adult T1D healthcare system while also managing typical developmental demands (e.g., social, financial, work/school, residential). Many young adults have extended gaps in care before following up in adult care, increasing risk for poor health outcomes. There are few evidence-based programs to support young adults with T1D to promote a timelier transition during this period. This paper reports on the design of DiaBetter Together, a randomized controlled trial to evaluate a 12-month Peer Mentor-delivered intervention compared to usual care among young …

Bst2 Facilitates Activation Of Hematopoietic Stem Cells Through Erk Signaling, Marcus A Florez, Apoorva Thatavarty, Duy T Le, Holly A Hill, Youngjae Jeong, Brian M Ho, Pawel Kus, Trisha K Wathan, Bailee N Kain, Shixia Huang, Dongsu Park, Katherine Y King

Faculty, Staff and Students Publications

The proinflammatory cytokine interferon-gamma (IFNγ) is upregulated in a variety of infections and contributes to bone marrow failure through hematopoietic stem cell (HSC) activation and subsequent exhaustion. The cell surface protein, bone marrow stromal antigen 2 (BST2), is a key mediator of this process, as it is induced upon interferon stimulation and required for interferon-dependent HSC activation. To identify the mechanism by which BST2 promotes interferon-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling. Our studies indicated that knock out (KO) of BST2 in a murine model does not disrupt …

Osteogenesis Imperfecta: Skeletal And Non-Skeletal Challenges In Adulthood, Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C S Nagamani, Cathleen Raggio, Stuart H Ralston, Oliver Semler, Laura Tosi, Eric Orwoll

Faculty, Staff and Students Publications

Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which …

Persistent Growth-Promoting Effects Of Vosoritide In Children With Achondroplasia Are Accompanied By Improvements In Physical And Social Aspects Of Health-Related Quality Of Life, Ravi Savarirayan, Melita Irving, William R Wilcox, Carlos A Bacino, Julie E Hoover-Fong, Paul Harmatz, Lynda E Polgreen, Klaus Mohnike, Carlos E Prada, Takuo Kubota, Paul Arundel, Antonio Leiva-Gea, Richard Rowell, Andrea Low, Ian Sabir, Alice Huntsman-Labed, Jonathan Day

Faculty, Staff and Students Publications

Purpose: Evaluate the impact of vosoritide on health-related quality of life in children with achondroplasia.

Methods: Participants received vosoritide (15 μg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766).

Results: The population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the Quality of Life of Short Stature Youth physical score (5.99 [19.41], caregiver reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 [22.64], respectively). Changes were greatest in participants with …

Comparison Of Predicted And Actual Dermatitis Generated From Computed Tomography Images And Dose Distribution Maps, Yasuhide Miyabe, Saori Oshiro, Hiroto Seki, Yusuke Muroi, Eriko Kawashima, Megumi Hosoda, Kento Ohashi, Hiromu Yamanaka, Mingliang Shao, Hiromi Sugawara, Jyunetsu Mizoe, Ritsuko Komaki

Faculty, Staff and Students Publications

Anticipating the onset, location and severity of radiation dermatitis before radiotherapy can aid in dermatological care. This study developed a method for creation of a prediction diagram for dermatitis and conducted a comparative verification between the prediction diagram and actual patient condition. The prediction diagram involved converting skin doses into 2 Gy fractionated equivalent doses using α/β of 10.0, defining regions of interest (ROIs) from 20-50 Gy at 10 Gy intervals. Overlaps between these ROIs at each dose level and the skin (external) was sequentially color-coded as blue, yellow, red, and purple. The study included four patients: two underwent head …

Genome-Derived Ampullary Adenocarcinoma Classifier And Postresection Prognostication, Brett L Ecker, Kenneth Seier, Austin M Eckhoff, Gabriella N Tortorello, Peter J Allen, Vinod P Balachandran, Nicola Blackburn, Michael I D'Angelica, Ronald P Dematteo, Daniel G Blazer, Jeffrey A Drebin, William E Fisher, Danielle Fortuna, Anthony J Gill, Marie-Claude Gingras, T Peter Kingham, Major K Lee, Michael E Lidsky, Daniel P Nussbaum, Michael J Overman, Jaswinder S Samra, Ronglai Shen, Carlie S Sigel, Kevin C Soares, Charles M Vollmer, Alice C Wei, Sabino Zani, Robert E Roses, Mithat Gonen, William R Jarnagin

Faculty, Staff and Students Publications

Importance: Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use.

Objective: To test external validity of the prognostic value of the hidden genome classifier of AA.

Design, setting, and participants: This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020.

Exposures: The multilevel meta-feature regression model previously trained on …

Template-Assisted Covalent Modification Underlies Activity Of Covalent Molecular Glues, Yen-Der Li, Michelle W Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine C Rutter, Ryan J Lumpkin, Brittany Sandoval, Cyrus Y Jin, Anna M Schmoker, Scott B Ficarro, Hakyung Cheong, Rebecca J Metivier, Michelle Y Wang, Shawn Xu, Woong Sub Byun, Brian J Groendyke, Inchul You, Logan H Sigua, Isidoro Tavares, Charles Zou, Jonathan M Tsai, Paul M C Park, Hojong Yoon, Felix C Majewski, Haniya T Sperling, Jarrod A Marto, Jun Qi, Radosław P Nowak, Katherine A Donovan, Mikołaj Słabicki, Nathanael S Gray, Eric S Fischer, Benjamin L Ebert

Faculty, Staff and Students Publications

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes …

Aging-Associated Mechanisms Of Atrial Fibrillation Progression And Their Therapeutic Potential, Shuai Zhao, Aaron M Johnston, Chi Him Kendrick Yiu, Lucia M Moreira, Svetlana Reilly, Xander H T Wehrens

Faculty, Staff and Students Publications

Atrial fibrillation (AF) is the most common sustained arrhythmia, with a particularly high prevalence in the elderly. As the global aging population rapidly expands, it is increasingly important to examine how alterations to the aging heart contribute to an increased AF susceptibility. This work critically reviews the key molecular mechanisms that may underpin the complex association between aging and AF. Moreover, we identify emerging novel opportunities for therapeutic intervention that may be able to prevent and/or improve the current treatment paradigms for age-related AF. This review contributes to a holistic understanding of the intricate relationship between aging and AF.

Lack Of Association Of First And Second-Line Medication Dosing And Progression To Refractory Status Epilepticus In Children, Cristina Barcia Aguilar, Marta Amengual-Gual, J Nicholas Brenton, Kevin E Chapman, Justice Clark, William D Gaillard, Joshua L Goldstein, Howard P Goodkin, Robert Kahoud, Yi-Chen Lai, Mohamad A Mikati, Lindsey A Morgan, Eric T Payne, Craig A Press, Latania Reece, Tristan T Sands, Kumar Sannagowdara, Theodore Sheehan, Renée A Shellhaas, Robert C Tasker, Mark S Wainwright, Bo Zhang, Tobias Loddenkemper

Faculty, Staff and Students Publications

Purpose: Evaluate the relationship between first and second-line medication dosing and progression to refractory status epilepticus (RSE) in children.

Methods: This is a retrospective analysis of prospectively collected data from September 2014 to February 2020 of children with status epilepticus (SE) who received at least two antiseizure medications (ASMs). We evaluated the risk of developing RSE after receiving a low total benzodiazepine dose (lower than 100 % of the minimum recommended dose for each benzodiazepine dose administered within 10 min) and a low first non-benzodiazepine ASM dose (lower than 100 % of the minimum recommended dose of non-benzodiazepine ASM given …

Pathophysiology And Treatment Of Prediabetes And Type 2 Diabetes In Youth, Fida Bacha, Tamara S Hannon, Mustafa Tosur, Julie M Pike, Ashley Butler, Kalie L Tommerdahl, Philip S Zeitler

Faculty, Staff and Students Publications

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, …

Proteomic Analysis Uncovers Multiprotein Signatures Associated With Early Diabetic Kidney Disease In Youth With Type 2 Diabetes Mellitus, Laura Pyle, Ye Ji Choi, Phoom Narongkiatikhun, Kumar Sharma, Sushrut Waikar, Anita Layton, Kalie L Tommerdahl, Ian De Boer, Timothy Vigers, Robert G Nelson, Jane Lynch, Frank Brosius, Pierre J Saulnier, Jesse A Goodrich, Jeanie B Tryggestad, Elvira Isganaitis, Fida Bacha, Kristen J Nadeau, Daniel Van Raalte, Matthias Kretzler, Hiddo Heerspink, Petter Bjornstad

Faculty, Staff and Students Publications

Background: The onset of diabetic kidney disease (DKD) in youth with type 2 diabetes (T2D) mellitus often occurs early, leading to complications in young adulthood. Risk biomarkers associated with the early onset of DKD are urgently needed in youth with T2D.

Methods: We conducted an in-depth analysis of 6596 proteins (SomaScan 7K) in 374 baseline plasma samples from the Treatment Options for Type 2 Diabetes in Adolescents and Youth study to identify multiprotein signatures associated with the onset of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), a rapid decline in eGFR (annual eGFR decline >3 ml/min per 1.73 m2 and/or ≥3.3% …

Are Prediction Models Moving Closer To Clinical Application In The Diagnosis Of Type Of Diabetes In Youth?, Fida Bacha

Faculty, Staff and Students Publications

No abstract provided.

Shared Genetic Architecture Of Non-Viral Cirrhosis With Several Pleiotropic Traits: A Nested Case-Control Study In The Uk Biobank, Jinyoung Byun, Hyun-Seok Kim, Younghun Han, Aaron P Thrift, Sabrina M Lin, Xiangjun Xiao, Hyeyeun Lim, Goo Jun, Stacia M Desantis, Hashem B El-Serag, Fasiha Kanwal, Christopher I Amos

Faculty, Staff and Students Publications

Background & aims: Cirrhosis is a leading cause of liver-related mortality and a multifactorial disease. To date, the complex genetic architecture of non-viral cirrhosis has not been fully explored. Cross-trait genetic correlations can elucidate the common genetic etiology of genetically correlated phenotypes. This study aims to identify polygenic and pleiotropic traits associated with cirrhosis using the linkage disequilibrium score regression analysis.

Methods: We conducted genome-wide association analysis of 9,622,842 imputed SNPs on 3,368 non-viral cirrhosis cases and 258,258 controls, and cross-trait analysis between non-viral cirrhosis and various polygenic and pleiotropic traits using the UK Biobank cohort study. We further performed …

Retinal Ganglion Cell Circuits And Glial Interactions In Humans And Mice, Kang-Chieh Huang, Mohamed Tawfik, Melanie A Samuel

Faculty, Staff and Students Publications

Retinal ganglion cells (RGCs) are the brain's gateway for vision, and their degeneration underlies several blinding diseases. RGCs interact with other neuronal cell types, microglia, and astrocytes in the retina and in the brain. Much knowledge has been gained about RGCs and glia from mice and other model organisms, often with the assumption that certain aspects of their biology may be conserved in humans. However, RGCs vary considerably between species, which could affect how they interact with their neuronal and glial partners. This review details which RGC and glial features are conserved between mice, humans, and primates, and which differ. …

Exploring Fibroblast Interactions On Nanocrystalline Surfaces In Physiological Environments Through A Phenomenological Lens, R D K Misra, Aladin M Boriek

Faculty, Staff and Students Publications

The cytological behaviour and functional dynamics (adhesion, spreading, synthesis of proteins) of fibroblasts when interacting with biomedical surfaces are intricately influenced by the inherent nature of surface (nanocrystalline or microcrystalline), where the nanocrystalline (NC) surface is preferred in relation to the microcrystalline (MC) surface. This preference is a direct consequence of the distinct differences in physical and chemical characteristics between NC and MC surfaces, which include crystal boundary bio-physical attributes, electron work function, surface energy, and charge carrier density. The observed variances in cytological behaviour at the interfaces of NC and MC bio-surfaces can be attributed to these fundamental differences, …

Association Of Left Atrial Function With Frailty: The Atherosclerosis Risk In Communities (Aric) Study, Daokun Sun, Romil R Parikh, Wendy Wang, Anne Eaton, Pamela L Lutsey, B Gwen Windham, Riccardo M Inciardi, Scott D Solomon, Christie M Ballantyne, Amil M Shah, Lin Yee Chen

Faculty, Staff and Students Publications

Background: Frailty is common in people with cardiovascular disease. Worse left atrial (LA) function is an independent risk factor for cardiovascular disease. However, whether worse LA function is associated with frailty is unclear.

Methods: We included 3292 older adults from the Atherosclerosis Risk in Communities study who were non-frail at baseline (visit 5, 2011-2013) and had LA function (reservoir, conduit, and contractile strain) measured from two-dimensional speckle-tracking echocardiography. LA stiffness index was calculated as a ratio of E/e' to LA reservoir strain. Frailty was defined using the validated Fried frailty phenotype. Incident frailty was assessed between 2016 and 2019 during …

Π-Hub: The Proteomic Navigator Of The Human Body, Fuchu He, Ruedi Aebersold, Mark S Baker, Xiuwu Bian, Xiaochen Bo, Daniel W Chan, Cheng Chang, Luonan Chen, Xiangmei Chen, Yu-Ju Chen, Heping Cheng, Ben C Collins, Fernando Corrales, Jürgen Cox, Weinan E, Jennifer E Van Eyk, Jia Fan, Pouya Faridi, Daniel Figeys, George Fu Gao, Wen Gao, Zu-Hua Gao, Keisuke Goda, Wilson Wen Bin Goh, Dongfeng Gu, Changjiang Guo, Tiannan Guo, Yuezhong He, Albert J R Heck, Henning Hermjakob, Tony Hunter, Narayanan Gopalakrishna Iyer, Ying Jiang, Connie R Jimenez, Lokesh Joshi, Neil L Kelleher, Ming Li, Yang Li, Qingsong Lin, Cui Hua Liu, Fan Liu, Guang-Hui Liu, Yansheng Liu, Zhihua Liu, Teck Yew Low, Ben Lu, Matthias Mann, Anming Meng, Robert L Moritz, Edouard Nice, Guang Ning, Gilbert S Omenn, Christopher M Overall, Giuseppe Palmisano, Yaojin Peng, Charles Pineau, Terence Chuen Wai Poon, Anthony W Purcell, Jie Qiao, Roger R Reddel, Phillip J Robinson, Paola Roncada, Chris Sander, Jiahao Sha, Erwei Song, Sanjeeva Srivastava, Aihua Sun, Siu Kwan Sze, Chao Tang, Liujun Tang, Ruijun Tian, Juan Antonio Vizcaíno, Chanjuan Wang, Chen Wang, Xiaowen Wang, Xinxing Wang, Yan Wang, Tobias Weiss, Mathias Wilhelm, Robert Winkler, Bernd Wollscheid, Limsoon Wong, Linhai Xie, Wei Xie, Tao Xu, Tianhao Xu, Liying Yan, Jing Yang, Xiao Yang, John Yates, Tao Yun, Qiwei Zhai, Bing Zhang, Hui Zhang, Lihua Zhang, Lingqiang Zhang, Pingwen Zhang, Yukui Zhang, Yu Zi Zheng, Qing Zhong, Yunping Zhu, Π-Hub Consortium

Faculty, Staff and Students Publications

The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies. Recent advances in proteomic technology and computational sciences now provide opportunities to investigate the intricate biology of the human body …

Tyk2 Regulates Tau Levels, Phosphorylation And Aggregation In A Tauopathy Mouse Model, Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-Eun Chloe Chung, Bradley Hyman, David M Holtzman, Huda Yahya Zoghbi

Faculty, Staff and Students Publications

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau …

Hemodynamic And Clinical Outcomes With Balloon-Expandable Valves Versus Self-Expanding Valves In Patients With Small Aortic Annulus Undergoing Transcatheter Aortic Valve Replacement: A Meta-Analysis Of Randomized Controlled Trials And Propensity Score Matched Studies, Mushood Ahmed, Areeba Ahsan, Shehroze Tabassum, Irra Tariq, Eeshal Zulfiqar, Mahnoor Farooq Raja, Asma Mahmood, Raheel Ahmed, Farhan Shahid, Syed Khurram M Gardezi, Mahboob Alam, Rodrigo Bagur, Mamas A Mamas

Faculty, Staff and Students Publications

Transcatheter aortic valve replacement (TAVR) is considered more effective than surgical aortic valve implantation for patients with a small aortic annulus (SAA), however, the comparative efficacy of different transcatheter heart valves (THVs) remains uncertain. A literature search was performed across databases from their inception until June 2024 to identify eligible randomized controlled trials (RCTs) and propensity-score matched (PSM) studies. Clinical outcomes were evaluated using a random-effects model to pool risk ratios (RRs) with 95 % confidence intervals (CIs). The analysis included 10 studies with 2,960 patients. BEVs were associated with a significantly smaller indexed effective orifice area (MD: -0.18, 95 …

Steering Research On Mrna Splicing In Cancer Towards Clinical Translation, Olga Anczukow, Frédéric H-T Allain, Brittany L Angarola, Douglas L Black, Angela N Brooks, Chonghui Cheng, Ana Conesa, Edie I Crosse, Eduardo Eyras, Ernesto Guccione, Sydney X Lu, Karla M Neugebauer, Priyanka Sehgal, Xiao Song, Zuzana Tothova, Juan Valcárcel, Kevin M Weeks, Gene W Yeo, Andrei Thomas-Tikhonenko

Faculty, Staff and Students Publications

Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. …

Rfc2 May Contribute To The Pathogenicity Of Williams Syndrome Revealed In A Zebrafish Model, Ji-Won Park, Tae-Ik Choi, Tae-Yoon Kim, Yu-Ri Lee, Dilan Wellalage Don, Jaya K George-Abraham, Laurie A Robak, Cristina C Trandafir, Pengfei Liu, Jill A Rosenfeld, Tae Hyeong Kim, Florence Petit, Yoo-Mi Kim, Chong Kun Cheon, Yoonsung Lee, Cheol-Hee Kim

Faculty, Staff and Students Publications

Williams syndrome (WS) is a rare multisystemic disorder caused by recurrent microdeletions on 7q11.23, characterized by intellectual disability, distinctive craniofacial and dental features, and cardiovascular problems. Previous studies have explored the roles of individual genes within these microdeletions in contributing to WS phenotypes. Here, we report five patients with WS with 1.4 Mb-1.5 Mb microdeletions that include RFC2, as well as one patient with a 167-kb microdeletion involving RFC2 and six patients with intragenic variants within RFC2. To investigate the potential involvement of RFC2 in WS pathogenicity, we generate a rfc2 knockout (KO) zebrafish using CRISPR-Cas9 technology. Additionally, we generate …

Modification Of A Parent-Report Sleep Scale For Individuals With Cdkl5 Deficiency Disorder: A Psychometric Study, Jacinta M Saldaris, Scott Demarest, Peter Jacoby, Heather E Olson, Kiran Maski, Elia Pestana-Knight, Dana Price, Rajsekar Rajaraman, Bernhard Suter, Judith Weisenberg, Helen Leonard, Eric D Marsh, Tim A Benke, Jenny Downs

Faculty, Staff and Students Publications

Study objectives: Sleep difficulties are common in CDKL5 deficiency disorder, a developmental and epileptic encephalopathy. This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Somnolence (DOES), and Sleep Breathing Disorders domains of the Sleep Disturbance Scale for Children for CDKL5 deficiency disorder.

Methods: A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a United States Centers of Excellence clinic or registered with the International CDKL5 Disorder Database.

Results: The median age was 10.3 years (range 3.2-40.7 years) and 105 (84%) …