Medical Specialties Commons^™

Exosomes, Microvesicles, And Other Extracellular Vesicles-A Keystone Symposia Report, Jennifer Cable, Kenneth W Witwer, Robert J Coffey, Aleksandar Milosavljevic, Ariana K Von Lersner, Lizandra Jimenez, Ferdinando Pucci, Maureen M Barr, Niek Dekker, Bahnisikha Barman, Daniel Humphrys, Justin Williams, Michele De Palma, Wei Guo, Nuno Bastos, Andrew F Hill, Efrat Levy, Michael P Hantak, Clair Crewe, Elena Aikawa, Alan M Adamczyk, Tamires M Zanotto, Matias Ostrowski, Tanina Arab, Daniel C Rabe, Aadil Sheikh, Danilo Rodrigues Da Silva, Jennifer C Jones, Chioma Okeoma, Thomas Gaborski, Qin Zhang, Olesia Gololobova

Faculty, Staff and Students Publications

Extracellular vesicles (EVs) are small, lipid-bilayer-bound particles released by cells that can contain important bioactive molecules, including lipids, RNAs, and proteins. Once released in the extracellular environment, EVs can act as messengers locally as well as to distant tissues to coordinate tissue homeostasis and systemic responses. There is a growing interest in not only understanding the physiology of EVs as signaling particles but also leveraging them as minimally invasive diagnostic and prognostic biomarkers (e.g., they can be found in biofluids) and drug-delivery vehicles. On October 30-November 2, 2022, researchers in the EV field convened for the Keystone symposium "Exosomes, Microvesicles, …

Genome-Wide Analysis Of Structural Variants In Parkinson Disease, Kimberley J Billingsley, Jinhui Ding, Pilar Alvarez Jerez, Anastasia Illarionova, Kristin Levine, Francis P Grenn, Mary B Makarious, Anni Moore, Daniel Vitale, Xylena Reed, Dena Hernandez, Ali Torkamani, Mina Ryten, John Hardy, Uk Brain Expression Consortium (Ukbec), Ruth Chia, Sonja W Scholz, Bryan J Traynor, Clifton L Dalgard, Debra J Ehrlich, Toshiko Tanaka, Luigi Ferrucci, Thomas G Beach, Geidy E Serrano, John P Quinn, Vivien J Bubb, Ryan L Collins, Xuefang Zhao, Mark Walker, Emma Pierce-Hoffman, Harrison Brand, Michael E Talkowski, Bradford Casey, Mark R Cookson, Androo Markham, Mike A Nalls, Medhat Mahmoud, Fritz J Sedlazeck, Cornelis Blauwendraat, J Raphael Gibbs, Andrew B Singleton

Faculty, Staff and Students Publications

OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.

METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 …

Evaluation Of Retinal Nerve Fibre Layer Thickness As A Possible Measure Of Diabetic Retinal Neurodegeneration In The Epic-Norfolk Eye Study, Sidra Zafar, Kristen A Staggers, Jie Gao, Yao Liu, Praveen J Patel, Paul J Foster, Benjamin J Frankfort, Michael Abramoff, Charles G Minard, Alasdair Warwick, Anthony P Khawaja, Roomasa Channa

Faculty, Staff and Students Publications

BACKGROUND/AIMS: Markers to clinically evaluate structural changes from diabetic retinal neurodegeneration (DRN) have not yet been established. To study the potential role of peripapillary retinal nerve fibre layer (pRNFL) thickness as a marker for DRN, we evaluated the relationship between diabetes, as well as glycaemic control irrespective of diabetes status and pRNFL thickness.

METHODS: Leveraging data from a population-based cohort, we used general linear mixed models (GLMMs) with a random intercept for patient and eye to assess the association between pRNFL thickness (measured using GDx) and demographic, systemic and ocular parameters after adjusting for typical scan score. GLMMs were also …

Comparison Of Neurocognitive And Quality-Of-Life Outcomes In Pediatric Craniopharyngioma Patients Treated With Partial Resection And Radiotherapy Versus Gross-Total Resection Only, Guillermo Aldave, M Fatih Okcu, Murali Chintagumpala, Lucia Ruggieri, Charles G Minard, Fatema Malbari, Lisa E Mash, Arnold C Paulino, Susan Mcgovern, Uma Ramaswamy, William Whitehead, Lisa S Kahalley

Faculty, Staff and Students Publications

OBJECTIVE: The optimal management of pediatric craniopharyngioma patients remains controversial, shifting from radical resection (gross-total resection [GTR]) to a more conservative approach with partial resection/biopsy followed by radiotherapy (PR+RT). To the authors' knowledge, no previous studies have compared neurocognitive and quality-of-life (QOL) outcomes between the two main treatments. In this study, the authors compared changes in intellectual, adaptive, and QOL scores in children treated for craniopharyngioma with GTR and those treated with PR+RT.

METHODS: Patients underwent annual neurocognitive and QOL evaluations for up to 10 years posttreatment, including the Full-Scale IQ, Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working …

Cascade Testing After Exome Sequencing: Retrospective Analysis Of Linked Family Data At 2 Us Laboratories, Julie Stefka, Haley Streff, Pengfei Liu, Meghan Towne, Hadley Stevens Smith

Faculty, Staff and Students Publications

Purpose: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications.

Methods: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and …

Epigenetic Age Acceleration Among Survivors Of Pediatric Medulloblastoma And Primitive Neuroectodermal Tumor, Rachel D Harris, Melissa A Richard, Maria Monica J Gramatges, Kevin Wilhelm, Michael E Scheurer, Philip J Lupo, Austin L Brown

Faculty, Staff and Students Publications

Survivors of childhood central nervous system (CNS) tumors experience early-onset aging-related phenotypes. DNA methylation (DNAm) age is an emerging epigenetic biomarker of physiologic age and may be predictive of chronic health conditions in long-term survivors. This report describes the course of epigenetic age acceleration using post-diagnosis blood samples (median: 3.9 years post-diagnosis; range: 0.04–15.96) from 83 survivors of pediatric CNS tumors. Epigenetic age acceleration was detected in 72% of patients, with an average difference between chronologic and dnam age of 2.58 years (95% Ci: 1.75–3.41, p < 0.001). Time from diagnosis to sample collection correlated with the magnitude of epigenetic age acceleration.

Alveolar Rhabdomyosarcoma Has Superior Response Rates To Vinorelbine Compared To Embryonal Rhabdomyosarcoma In Patients With Relapsed/Refractory Disease: A Meta-Analysis, Wendy Allen-Rhoades, Philip J Lupo, Michael E Scheurer, Yueh-Yun Chi, John F Kuttesch, Rajkumar Venkatramani, William H Meyer, Leo Mascarenhas

Faculty, Staff and Students Publications

BACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.

AIMS: The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.

MATERIALS & METHODS: Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose …

N-Terminal Egfp-Tagging Of Rabbit Apolipoprotein A-I Decreases Expression And Impairs Cholesterol-Efflux Activity, Bradley K Wacker, Lianxiang Bi, Li Liu, Mary G Sorci-Thomas, Philip Ng, Donna J Palmer, Chongren Tang, David A Dichek

Faculty, Staff and Students Publications

No abstract provided.

A Weakly Structured Stem For Human Origins In Africa, Aaron P Ragsdale, Timothy D Weaver, Elizabeth G Atkinson, Eileen G Hoal, Marlo Möller, Brenna M Henn, Simon Gravel

Faculty, Staff and Students Publications

Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent1. Progress is hampered by a shortage of fossil and genomic data, as well as variability in previous estimates of divergence times1. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference2. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated …

Specific Causes Of Excess Late Mortality And Association With Modifiable Risk Factors Among Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study Cohort, Stephanie B Dixon, Qi Liu, Eric J Chow, Kevin C Oeffinger, Paul C Nathan, Rebecca M Howell, Wendy M Leisenring, Matthew J Ehrhardt, Kirsten K Ness, Kevin R Krull, Ann C Mertens, Melissa M Hudson, Leslie L Robison, Yutaka Yasui, Gregory T Armstrong

Faculty, Staff and Student Publications

Background: 5-year survival after childhood cancer does not fully describe life-years lost due to childhood cancer because there are a large number of deaths occurring beyond 5-years (late mortality) related to cancer and cancer treatment. Specific causes of health-related (non-recurrence, non-external) late mortality and risk reduction through modifiable lifestyle and cardiovascular risk factors are not well described. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk.

Methods: In this multi-institutional, hospital-based, …

A Precision Environmental Health Approach To Prevention Of Human Disease, Andrea Baccarelli, Dana C Dolinoy, Cheryl Lyn Walker

Faculty, Staff and Students Publications

Human health is determined by the interaction of our environment with the genome, epigenome, and microbiome, which shape the transcriptomic, proteomic, and metabolomic landscape of cells and tissues. Precision environmental health is an emerging field leveraging environmental and system-level ('omic) data to understand underlying environmental causes of disease, identify biomarkers of exposure and response, and develop new prevention and intervention strategies. In this article we provide real-life illustrations of the utility of precision environmental health approaches, identify current challenges in the field, and outline new opportunities to promote health through a precision environmental health framework.

Consensus Proposal For Revised International Working Group 2023 Response Criteria For Higher-Risk Myelodysplastic Syndromes, Amer M Zeidan, Uwe Platzbecker, Jan Philipp Bewersdorf, Maximilian Stahl, Lionel Adès, Uma Borate, David Bowen, Rena Buckstein, Andrew Brunner, Hetty E Carraway, Naval Daver, Maria Díez-Campelo, Theo De Witte, Amy E Dezern, Fabio Efficace, Guillermo Garcia-Manero, Jacqueline S Garcia, Ulrich Germing, Aristoteles Giagounidis, Elizabeth A Griffiths, Robert P Hasserjian, Eva Hellström-Lindberg, Marcelo Iastrebner, Rami Komrokji, Austin G Kulasekararaj, Luca Malcovati, Yasushi Miyazaki, Olatoyosi Odenike, Valeria Santini, Guillermo Sanz, Phillip Scheinberg, Reinhard Stauder, Arjan A Van De Loosdrecht, Andrew H Wei, Mikkael A Sekeres, Pierre Fenaux

Faculty, Staff and Student Publications

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria …

Positive Selection Of Somatically Mutated Clones Identifies Adaptive Pathways In Metabolic Liver Disease, Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes …

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Mice, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Faculty, Staff and Student Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …

Bridging Clinic And Wildlife Care With Ai-Powered Pan-Species Computational Pathology, Khalid Abduljabbar, Simon P Castillo, Katherine Hughes, Hannah Davidson, Amy M Boddy, Lisa M Abegglen, Lucia Minoli, Selina Iussich, Elizabeth P Murchison, Trevor A Graham, Simon Spiro, Carlo C Maley, Luca Aresu, Chiara Palmieri, Yinyin Yuan

Faculty, Staff and Student Publications

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves …

Framing The Family: A Qualitative Exploration Of Factors That Shape Family-Level Experience Of Pediatric Genomic Sequencing, Hadley Stevens Smith, Emily S Bonkowski, Madison R Hickingbotham, Raymond Belanger Deloge, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Families of children with rare and undiagnosed conditions face many psychosocial and logistical challenges that may affect their approach to decisions about their child’s care and their family’s well-being. As genomic sequencing (GS) is increasingly incorporated into pediatric diagnostic workups, assessing the family-level characteristics that shape the experience of pediatric GS is crucial to understanding how families approach decision-making about the test and how they incorporate the results into their family life. We conducted semi-structured interviews with parents and other primary caregivers of pediatric patients who were evaluated for a suspected genetic condition and who were recommended to have GS …

Armo: Automated And Reliable Multi-Objective Model For Lymph Node Metastasis Prediction In Head And Neck Cancer, Zhiguo Zhou, Liyuan Chen, Michael Dohopolski, David Sher, Jing Wang

Faculty, Staff and Student Publications

Objective:

Accurate diagnosis of lymph node metastasis (LNM) is critical in treatment management for patients with head & neck cancer. Positron emission tomography (PET) and computed tomography (CT) are routinely used for identifying LNM status. However, for small or less fluorodeoxyglucose (FDG) avid nodes, there are always uncertainties in LNM diagnosis. We are aiming to develop a reliable prediction model is for identifying LNM.

Approach:

In this study, a new automated and reliable multi-objective learning model (ARMO) is proposed. In ARMO, a multi-objective model is introduced to obtain balanced sensitivity and specificity. Meanwhile, confidence is calibrated by introducing individual reliability, …

Machine Learning Models For The Identification Of Prognostic And Predictive Cancer Biomarkers: A Systematic Review, Qasem Al-Tashi, Maliazurina B Saad, Amgad Muneer, Rizwan Qureshi, Seyedali Mirjalili, Ajay Sheshadri, Xiuning Le, Natalie I Vokes, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

The identification of biomarkers plays a crucial role in personalized medicine, both in the clinical and research settings. However, the contrast between predictive and prognostic biomarkers can be challenging due to the overlap between the two. A prognostic biomarker predicts the future outcome of cancer, regardless of treatment, and a predictive biomarker predicts the effectiveness of a therapeutic intervention. Misclassifying a prognostic biomarker as predictive (or vice versa) can have serious financial and personal consequences for patients. To address this issue, various statistical and machine learning approaches have been developed. The aim of this study is to present an in-depth …

A Small Secreted Protein Nicol Regulates Lumicrine-Mediated Sperm Maturation And Male Fertility, Daiji Kiyozumi, Kentaro Shimada, Michael Chalick, Chihiro Emori, Mayo Kodani, Seiya Oura, Taichi Noda, Tsutomu Endo, Martin M Matzuk, Daniel H Wreschner, Masahito Ikawa

Faculty, Staff and Students Publications

The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the …

Identifying Signatures Of Ev Secretion In Metastatic Breast Cancer Through Functional Single-Cell Profiling, Mohsen Fathi, Melisa Martinez-Paniagua, Ali Rezvan, Melisa J Montalvo, Vakul Mohanty, Ken Chen, Sendurai A Mani, Navin Varadarajan

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) regulate the tumor microenvironment by facilitating transport of biomolecules. Despite extensive investigation, heterogeneity in EV secretion among cancer cells and the mechanisms that support EV secretion are not well characterized. We developed an integrated method to identify individual cells with differences in EV secretion and performed linked single-cell RNA-sequencing on cloned single cells from the metastatic breast cancer cells. Differential gene expression analyses identified a four-gene signature of breast cancer EV secretion: HSP90AA1, HSPH1, EIF5, and DIAPH3. We functionally validated this gene signature by testing it across cell lines with different metastatic potential …

Synaptic Scaling Of Corticostriatal Circuits Underlies Hyperactivity In Gaba Transporter-1 Deficient Mice, Yan-Jiao Wu, Xin Yi, Xue Gu, Qi Wang, Qin Jiang, Ying Li, Michael X Zhu, Jianqing Ding, Wei-Guang Li, Tian-Le Xu

Faculty, Staff and Student Publications

Homeostatic synaptic scaling entails adjustment of synaptic strength on a cell to prolonged changes of neuronal activity, which is postulated to participate in neuropsychiatric disorders in vivo. Here, we find that sustained elevation in ambient GABA levels, by either genetic deletion or pharmacological blockade of GABA transporter-1 (GAT1), leads to synaptic scaling up of corticostriatal pathways, which underlies locomotor hyperactivity. Meanwhile, medium spiny neurons of the dorsal striatum exhibit an aberrant increase in excitatory synaptic transmission and corresponding structural changes in dendritic spines. Mechanistically, GAT1 deficiency dampens the expression and function of metabotropic glutamate receptors (mGluRs) and endocannabinoid (eCB)-dependent …

Cross-Dataset Single-Cell Analysis Identifies Temporal Alterations In Cell Populations Of Primary Pancreatic Tumor And Liver Metastasis, Daowei Yang, Rohan Moniruzzaman, Hua Wang, Huamin Wang, Yang Chen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) has a unique tumor microenvironment composed of various cell populations such as cancer cells, cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. Recently, single-cell RNA-sequencing analysis (scRNA-seq) has systemically revealed the genomic profiles of these cell populations in PDAC. However, the direct comparison of cell population composition and genomic profile between primary tumors (at both early- and late-stage) and metastatic tumors of PDAC is still lacking. In this study, we combined and analyzed recent scRNA-seq datasets of transgenic KPC mouse models with autochthonous PDAC and matched liver metastasis, revealing the unique tumor ecosystem and cell composition …

Synthetic Errα/Β/Γ Agonist Induces An Errα-Dependent Acute Aerobic Exercise Response And Enhances Exercise Capacity, Cyrielle Billon, Sadichha Sitaula, Subhashis Banerjee, Ryan Welch, Bahaa Elgendy, Lamees Hegazy, Tae Gyu Oh, Melissa Kazantzis, Arindam Chatterjee, John Chrivia, Matthew E Hayes, Weiyi Xu, Angelica Hamilton, Janice M Huss, Lilei Zhang, John K Walker, Michael Downes, Ronald M Evans, Thomas P Burris

Faculty, Staff and Students Publications

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo. Here, we report the …

Development And Validation Of A Prediction Model For Kidney Failure In Long-Term Survivors Of Childhood Cancer, Natalie L Wu, Yan Chen, Bryan V Dieffenbach, Matthew J Ehrhardt, Sangeeta Hingorani, Rebecca M Howell, John L Jefferies, Daniel A Mulrooney, Kevin C Oeffinger, Leslie L Robison, Brent R Weil, Yan Yuan, Yutaka Yasui, Melissa M Hudson, Wendy M Leisenring, Gregory T Armstrong, Eric J Chow

Faculty, Staff and Student Publications

Purpose: Kidney failure is a rare but serious late effect following treatment for childhood cancer. We developed a model using demographic and treatment characteristics to predict individual risk of kidney failure among 5-year survivors of childhood cancer.

Methods: Five-year survivors from the Childhood Cancer Survivor Study (CCSS) without history of kidney failure (n = 25,483) were assessed for subsequent kidney failure (ie, dialysis, kidney transplantation, or kidney-related death) by age 40 years. Outcomes were identified by self-report and linkage with the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5,045) served as a …

An Altered Extracellular Matrix-Integrin Interface Contributes To Huntington’S Disease-Associated Cns Dysfunction In Glial And Vascular Cells, Sarah J Hernandez, Ryan G Lim, Tarik Onur, Mark A Dane, Rebecca Smith, Keona Wang, Grace En-Hway Jean, Andrea Reyes-Ortiz, Kaylyn Devlin, Ricardo Miramontes, Jie Wu, Malcolm Casale, David Kilburn, Laura M Heiser, James E Korkola, David Van Vactor, Juan Botas, Katherine L Thompson-Peer, Leslie M Thompson

Faculty, Staff and Students Publications

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may …

Development And Characterization Of Inducible Astrocyte-Specific Aromatase Knockout Mice, Jing Wang, Uday P Pratap, Yujiao Lu, Gangadhara R Sareddy, Rajeshwar R Tekmal, Ratna K Vadlamudi, Darrell W Brann

Faculty, Staff and Student Publications

17β-estradiol (E2) is produced in the brain as a neurosteroid, in addition to being an endocrine signal in the periphery. The current animal models for studying brain-derived E2 include global and conditional non-inducible knockout mouse models. The aim of this study was to develop a tamoxifen (TMX)-inducible astrocyte-specific aromatase knockout mouse line (GFAP-ARO-iKO mice) to specifically deplete the E2 synthesis enzymes and aromatase in astrocytes after their development in adult mice. The characterization of the GFAP-ARO-iKO mice revealed a specific and robust depletion in the aromatase expressions of their astrocytes and a significant decrease in their hippocampal E2 levels after …

Assessment And Prediction Of Glioblastoma Therapy Response: Challenges And Opportunities, Dan Qi, Jing Li, C Chad Quarles, Ekokobe Fonkem, Erxi Wu

Faculty, Staff and Student Publications

Glioblastoma is the most aggressive type of primary adult brain tumour. The median survival of patients with glioblastoma remains approximately 15 months, and the 5-year survival rate is < 10%. Current treatment options are limited, and the standard of care has remained relatively constant since 2011. Over the last decade, a range of different treatment regimens have been investigated with very limited success. Tumour recurrence is almost inevitable with the current treatment strategies, as glioblastoma tumours are highly heterogeneous and invasive. Additionally, another challenging issue facing patients with glioblastoma is how to distinguish between tumour progression and treatment effects, especially when relying on routine diagnostic imaging techniques in the clinic. The specificity of routine imaging for identifying tumour progression early or in a timely manner is poor due to the appearance similarity of post-treatment effects. Here, we concisely describe the current status and challenges in the assessment and early prediction of therapy response and the early detection of tumour progression or recurrence. We also summarize and discuss studies of advanced approaches such as quantitative imaging, liquid biomarker discovery and machine intelligence that hold exceptional potential to aid in the therapy monitoring of this malignancy and early prediction of therapy response, which may decisively transform the conventional detection methods in the era of precision medicine.

Sptssa Variants Alter Sphingolipid Synthesis And Cause A Complex Hereditary Spastic Paraplegia, Siddharth Srivastava, Hagar Mor Shaked, Kenneth Gable, Sita D Gupta, Xueyang Pan, Niranjanakumari Somashekarappa, Gongshe Han, Payam Mohassel, Marc Gotkine, Elizabeth Doney, Paula Goldenberg, Queenie K G Tan, Yi Gong, Benjamin Kleinstiver, Brian Wishart, Heidi Cope, Claudia Brito Pires, Hannah Stutzman, Rebecca C Spillmann, Undiagnosed Disease Network, Reza Sadjadi, Orly Elpeleg, Chia-Hsueh Lee, Hugo J Bellen, Simon Edvardson, Florian Eichler, Teresa M Dunn

Faculty, Staff and Students Publications

Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting …

The Non-Coding Rna Journal Club: Highlights On Recent Papers—12, Patrick K T Shiu, Mirolyuba Ilieva, Anja Holm, Shizuka Uchida, Johanna K Distefano, Agnieszka Bronisz, Ling Yang, Yoh Asahi, Ajay Goel, Liuqing Yang, Ashok Nuthanakanti, Alexander Serganov, Suresh K Alahari, Chunru Lin, Barbara Pardini, Alessio Naccarati, Jing Jin, Beshoy Armanios, Xiao-Bo Zhong, Nikolaos Sideris, Salih Bayraktar, Leandro Castellano, André P Gerber, He Lin, Simon J Conn, Doha Magdy Mostafa Sleem, Lisa Timmons

Faculty, Staff and Student Publications

We are delighted to share with you our twelfth Journal Club and highlight some of the most interesting papers published recently [...].

Phase I Study Of Sapanisertib With Carboplatin And Paclitaxel In Mtor Pathway Altered Solid Malignancies, Omar Alhalabi, Roman Groisberg, Ralph Zinner, Andrew W Hahn, Aung Naing, Shizhen Zhang, Apostolia M Tsimberidou, Jordi Rodon, Siqing Fu, Timothy A Yap, David S Hong, Ming Sun, Yunfang Jiang, Shubham Pant, Amishi Y Shah, Amado Zurita, Nizar M Tannir, Raghunandan Vikram, Jason Roszik, Funda Meric-Bernstam, Vivek Subbiah

Faculty, Staff and Student Publications

Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival. One patient had a dose-limiting toxicity at dose level 4. There were no unanticipated toxicities. Grade 3-4 treatment-related adverse events included anemia (21%), neutropenia (21%), thrombocytopenia (10.5%), and transaminitis (5%). Of 17 patients evaluable for response, 2 and 11 patients achieved partial response and stable disease, respectively. Responders included a patient with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion …