Medical Specialties Commons^™

A Clustering Of Heterozygous Missense Variants In The Crucial Chromatin Modifier Wdr5 Defines A New Neurodevelopmental Disorder, Lot Snijders Blok, Jolijn Verseput, Dmitrijs Rots, Hanka Venselaar, A Micheil Innes, Connie Stumpel, Katrin Õunap, Karit Reinson, Eleanor G Seaby, Shane Mckee, Barbara Burton, Katherine Kim, Johanna M Van Hagen, Quinten Waisfisz, Pascal Joset, Katharina Steindl, Anita Rauch, Dong Li, Elaine H Zackai, Sarah E Sheppard, Beth Keena, Hakon Hakonarson, Andreas Roos, Nicolai Kohlschmidt, Anna Cereda, Maria Iascone, Erika Rebessi, Kristin D Kernohan, Philippe M Campeau, Francisca Millan, Jesse A Taylor, Hanns Lochmüller, Martin R Higgs, Amalia Goula, Birgitta Bernhard, Danita J Velasco, Andrew A Schmanski, Zornitza Stark, Lyndon Gallacher, Lynn Pais, Paul C Marcogliese, Shinya Yamamoto, Nicholas Raun, Taryn E Jakub, Jamie M Kramer, Joery Den Hoed, Simon E Fisher, Han G Brunner, Tjitske Kleefstra

Faculty, Staff and Students Publications

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features …

Antibody-Drug Conjugates In Lung Cancer: Dawn Of A New Era?, Niamh Coleman, Timothy A Yap, John V Heymach, Funda Meric-Bernstam, Xiuning Le

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, …

Reconstructing Mutational Lineages In Breast Cancer By Multi-Patient-Targeted Single-Cell Dna Sequencing, Jake Leighton, Min Hu, Emi Sei, Funda Meric-Bernstam, Nicholas E Navin

Faculty, Staff and Student Publications

Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells; however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were …

Inhibition Of Ribosome Assembly Factor Pno1 By Crispr/Cas9 Technique Suppresses Lung Adenocarcinoma And Notch Pathway: Clinical Application, Sanjit K. Roy, Shivam Srivastava, Andrew Hancock, Anju Shrivastava, Jason Morvant, Sharmila Shankar, Rakesh K. Srivastava

School of Medicine Faculty Publications

Growth is crucially controlled by the functional ribosomes available in cells. To meet the enhanced energy demand, cancer cells re-wire and increase their ribosome biogenesis. The RNA-binding protein PNO1, a ribosome assembly factor, plays an essential role in ribosome biogenesis. The purpose of this study was to examine whether PNO1 can be used as a biomarker for lung adenocarcinoma and also examine the molecular mechanisms by which PNO1 knockdown by CRISPR/Cas9 inhibited growth and epithelial–mesenchymal transition (EMT). The expression of PNO1 was significantly higher in lung adenocarcinoma compared to normal lung tissues. PNO1 expression in lung adenocarcinoma patients increased with …

Diverticular Disease And Cancer Risk: More Than A Gut Feeling, Veronika Fedirko, Scott Kopetz, Carrie R Daniel

Faculty, Staff and Student Publications

No abstract provided.

Many People With Chronic Lymphocytic Leukemia Or Small Lymphocytic Lymphoma Benefit From Ibrutinib Treatment Up To 8 Years: A Plain Language Summary, Paul M Barr, Carolyn Owen, Tadeusz Robak, Alessandra Tedeschi, Osnat Bairey, Jan A Burger, Peter Hillmen, Claire Dearden, Sebastian Grosicki, Helen Mccarthy, Jian Yong Li, Fritz Offner, Carol Moreno, Mandy Jermain, Cathy Zhou, Emily Hsu, Anita Szoke, Thomas J Kipps, Paolo Ghia

Faculty, Staff and Student Publications

What is this summary about?: This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022.

What were the results?: Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated …

Interdependent Progression Of Bidirectional Sister Replisomes In E Coli, Po Jui Chen, Anna B Mcmullin, Bryan J Visser, Qian Mei, Susan M Rosenberg, David Bates

Faculty, Staff and Students Publications

Bidirectional DNA replication complexes initiated from the same origin remain colocalized in a factory configuration for part or all their lifetimes. However, there is little evidence that sister replisomes are functionally interdependent, and the consequence of factory replication is unknown. Here, we investigated the functional relationship between sister replisomes in Escherichia coli, which naturally exhibits both factory and solitary configurations in the same replication cycle. Using an inducible transcription factor roadblocking system, we found that blocking one replisome caused a significant decrease in overall progression and velocity of the sister replisome. Remarkably, progression was impaired only if the block …

Histopathologic And Proteogenomic Heterogeneity Reveals Features Of Clear Cell Renal Cell Carcinoma Aggressiveness, Yize Li, Tung-Shing M Lih, Saravana M Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A Wyczalkowski, Michael C Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe Da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A Reimers, Russell Pachynski, Alexander J Lazar, Arul M Chinnaiyan, Brian A Van Tine, Bing Zhang, Karin D Rodland, Gad Getz, D R Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W Marston Linehan, David Fenyö, Scott D Jewell, Gilbert S Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W Chan, Christopher J Ricketts, Alexey I Nesvizhskii, Hui Zhang, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 …

Predicting The Risk Of A Clinical Event Using Longitudinal Data: The Generalized Landmark Analysis, Yi Yao, Liang Li, Brad Astor, Wei Yang, Tom Greene

Faculty, Staff and Student Publications

Background: In the development of prediction models for a clinical event, it is common to use the static prediction modeling (SPM), a regression model that relates baseline predictors to the time to event. In many situations, the data used in training and validation are from longitudinal studies, where predictor variables are time-varying and measured at clinical visits. But these data are not used in SPM. The landmark analysis (LA), previously proposed for dynamic prediction with longitudinal data, has interpretational difficulty when the baseline is not a risk-changing clinical milestone, as is often the case in observational studies of chronic disease …

Antagonistic Effect Of Cyclin-Dependent Kinases And A Calcium-Dependent Phosphatase On Polyglutamine-Expanded Androgen Receptor Toxic Gain Of Function, Diana Piol, Laura Tosatto, Emanuela Zuccaro, Eric N Anderson, Antonella Falconieri, Maria J Polanco, Caterina Marchioretti, Federica Lia, Joseph White, Elisa Bregolin, Giovanni Minervini, Sara Parodi, Xavier Salvatella, Giorgio Arrigoni, Andrea Ballabio, Albert R La Spada, Silvio C E Tosatto, Fabio Sambataro, Diego L Medina, Udai B Pandey, Manuela Basso, Maria Pennuto

Duncan NRI Faculty and Staff Publications

Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR …

Civicdb 2022: Evolution Of An Open-Access Cancer Variant Interpretation Knowledgebase, Kilannin Krysiak, Arpad M Danos, Jason Saliba, Joshua F Mcmichael, Adam C Coffman, Susanna Kiwala, Erica K Barnell, Lana Sheta, Cameron J Grisdale, Lynzey Kujan, Shahil Pema, Jake Lever, Sarah Ridd, Nicholas C Spies, Veronica Andric, Andreea Chiorean, Damian T Rieke, Kaitlin A Clark, Caralyn Reisle, Ajay C Venigalla, Mark Evans, Payal Jani, Hideaki Takahashi, Avila Suda, Peter Horak, Deborah I Ritter, Xin Zhou, Benjamin J Ainscough, Sean Delong, Chimene Kesserwan, Mario Lamping, Haolin Shen, Alex R Marr, My H Hoang, Kartik Singhal, Mariam Khanfar, Brian V Li, Wan-Hsin Lin, Panieh Terraf, Laura B Corson, Yasser Salama, Katie M Campbell, Kirsten M Farncombe, Jianling Ji, Xiaonan Zhao, Xinjie Xu, Rashmi Kanagal-Shamanna, Ian King, Kelsy C Cotto, Zachary L Skidmore, Jason R Walker, Jinghui Zhang, Aleksandar Milosavljevic, Ronak Y Patel, Rachel H Giles, Raymond H Kim, Lynn M Schriml, Elaine R Mardis, Steven J M Jones, Gordana Raca, Shruti Rao, Subha Madhavan, Alex H Wagner, Malachi Griffith, Obi L Griffith

Faculty, Staff and Students Publications

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination …

Human Generation Times Across The Past 250,000 Years, Richard J Wang, Samer I Al-Saffar, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

The generation times of our recent ancestors can tell us about both the biology and social organization of prehistoric humans, placing human evolution on an absolute time scale. We present a method for predicting historical male and female generation times based on changes in the mutation spectrum. Our analyses of whole-genome data reveal an average generation time of 26.9 years across the past 250,000 years, with fathers consistently older (30.7 years) than mothers (23.2 years). Shifts in sex-averaged generation times have been driven primarily by changes to the age of paternity, although we report a substantial increase in female generation …

Chronic Conditions, Late Mortality, And Health Status After Childhood Aml: A Childhood Cancer Survivor Study Report, Lucie M Turcotte, Jillian A Whitton, Wendy M Leisenring, Rebecca M Howell, Joseph P Neglia, Rachel Phelan, Kevin C Oeffinger, Kirsten K Ness, William G Woods, E Anders Kolb, Leslie L Robison, Gregory T Armstrong, Eric J Chow

Faculty, Staff and Student Publications

Five-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT], chemotherapy with cranial radiation [chemo + CRT], chemotherapy only [chemo-only]), and diagnosis decade. Self-reported health status was compared across treatments, diagnosis decade, and with siblings. Among 856 survivors (median diagnosis age, 7.1 years; median age at last follow-up, 29.4 years), …

Rare Eif4a2 Variants Are Associated With A Neurodevelopmental Disorder Characterized By Intellectual Disability, Hypotonia, And Epilepsy, Maimuna S Paul, Anna R Duncan, Casie A Genetti, Hongling Pan, Adam Jackson, Patricia E Grant, Jiahai Shi, Michele Pinelli, Nicola Brunetti-Pierri, Alexandra Garza-Flores, Dave Shahani, Russell P Saneto, Giuseppe Zampino, Chiara Leoni, Emanuele Agolini, Antonio Novelli, Ulrike Blümlein, Tobias B Haack, Wolfram Heinritz, Eva Matzker, Bader Alhaddad, Rami Abou Jamra, Tobias Bartolomaeus, Saber Alhamdan, Raphael Carapito, Bertrand Isidor, Seiamak Bahram, Alyssa Ritter, Kosuke Izumi, Ben Pode Shakked, Ortal Barel, Bruria Ben Zeev, Amber Begtrup, Deanna Alexis Carere, Sureni V Mullegama, Timothy Blake Palculict, Daniel G Calame, Katharina Schwan, Alicia R P Aycinena, Rasa Traberg, Genomics England Research Consortium, Sofia Douzgou, Harrison Pirt, Naila Ismayilova, Siddharth Banka, Hsiao-Tuan Chao, Pankaj B Agrawal

Faculty, Staff and Students Publications

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. …

The Lysosomal Ragulator Complex Activates Nlrp3 Inflammasome In Vivo Via Hdac6, Kohei Tsujimoto, Tatsunori Jo, Daiki Nagira, Hachiro Konaka, Jeong Hoon Park, Shin-Ichiro Yoshimura, Akinori Ninomiya, Fuminori Sugihara, Takehiro Hirayama, Eri Itotagawa, Yusei Matsuzaki, Yuki Takaichi, Wataru Aoki, Shotaro Saita, Shuhei Nakamura, Andrea Ballabio, Shigeyuki Nada, Masato Okada, Hyota Takamatsu, Atsushi Kumanogoh

Duncan NRI Faculty and Staff Publications

The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting …

Revision Of The Melanocytic Pathology Assessment Tool And Hierarchy For Diagnosis Classification Schema For Melanocytic Lesions: A Consensus Statement, Raymond L Barnhill, David E Elder, Michael W Piepkorn, Stevan R Knezevich, Lisa M Reisch, Megan M Eguchi, Boris C Bastian, Willeke Blokx, Marcus Bosenberg, Klaus J Busam, Richard Carr, Alistair Cochran, Martin G Cook, Lyn M Duncan, Rosalie Elenitsas, Arnaud De La Fouchardière, Pedram Gerami, Iva Johansson, Jennifer Ko, Gilles Landman, Alexander J Lazar, Lori Lowe, Daniela Massi, Jane Messina, Daniela Mihic-Probst, Douglas C Parker, Birgitta Schmidt, Christopher R Shea, Richard A Scolyer, Michael Tetzlaff, Xiaowei Xu, Iwei Yeh, Artur Zembowicz, Joann G Elmore

Faculty, Staff and Student Publications

Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose.

Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG).

Evidence review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study …

Evaluation Of Proton Therapy Reirradiation For Patients With Recurrent Head And Neck Squamous Cell Carcinoma, Anna Lee, Robbie Woods, Amgad Mahfouz, Sarin Kitpanit, Olivia Cartano, Nader Mohamed, Irini Youssef, Kathryn Marqueen, Kevin Sine, Dennis Mah, Brian Neal, Kaveh Zakeri, Jung J Kang, Nadeem Riaz, Yao Yu, Sean M Mcbride, Linda D Chen, C Jillian Tsai, Daphna Y Gelblum, Robert H Press, Loren S Michel, Eric J Sherman, David Pfister, Lara A Dunn, Alan L Ho, James Fetten, Richard J Wong, Jay O Boyle, Bhuvanesh Singh, Jennifer R Cracchiolo, Ian Ganly, Marc A Cohen, Nancy Y Lee

Faculty, Staff and Student Publications

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret.

Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma.

Design, setting, and participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and …

Antisense Oligonucleotide Therapy Rescues Disturbed Brain Rhythms And Sleep In Juvenile And Adult Mouse Models Of Angelman Syndrome, Dongwon Lee, Wu Chen, Heet Naresh Kaku, Xinming Zhuo, Eugene S Chao, Armand Soriano, Allen Kuncheria, Stephanie Flores, Joo Hyun Kim, Armando Rivera, Frank Rigo, Paymaan Jafar-Nejad, Arthur L Beaudet, Matthew S Caudill, Mingshan Xue

Faculty, Staff and Students Publications

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we …

Mitochondrial Dysfunction Reactivates Α-Fetoprotein Expression That Drives Copper-Dependent Immunosuppression In Mitochondrial Disease Models, Kimberly A Jett, Zakery N Baker, Amzad Hossain, Aren Boulet, Paul A Cobine, Sagnika Ghosh, Philip Ng, Orhan Yilmaz, Kris Barreto, John Decoteau, Karen Mochoruk, George N Ioannou, Christopher Savard, Sai Yuan, Osama Hmh Abdalla, Christopher Lowden, Byung-Eun Kim, Hai-Ying Mary Cheng, Brendan J Battersby, Vishal M Gohil, Scot C Leary

Faculty, Staff and Students Publications

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative …

Follistatin Regulates The Specification Of The Apical Cochlea Responsible For Low-Frequency Hearing In Mammals, Hei Yeun Koo, Min-A Kim, Hyehyun Min, Jae Yeon Hwang, Meenakshi Prajapati-Dinubila, Kwan Soo Kim, Martin M Matzuk, Juw Won Park, Angelika Doetzlhofer, Un-Kyung Kim, Jinwoong Bok

Faculty, Staff and Students Publications

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in …

An Initial Experience Of Completion Hemispherotomy Via Magnetic Resonance-Guided Laser Interstitial Therapy, Vijay M Ravindra, Lucia Ruggieri, Nisha Gadgil, Angela P Addison, Ilana Patino, David D Gonda, Jason Chu, Laura Whitehead, Anne Anderson, Gloria Diaz-Medina, Kimberly Houck, Akshat Katyayan, Laura Masters, Audrey Nath, Michael Quach, James John Riviello, Elaine Seto, Krystal Elizabeth Sully, Latanya Agurs, Sonali Sen, Maureen Handoko, Rohini Coorg, Irfan Ali, Daniel Ikeda, Howard Weiner, Daniel J Curry

Duncan NRI Faculty and Staff Publications

Introduction: In carefully selected patients with medically refractory epilepsy, disconnective hemispherotomy can result in significant seizure freedom; however, incomplete disconnection can result in ongoing seizures and poses a significant challenge. Completion hemispherotomy provides an opportunity to finish the disconnection. We describe the use of magnetic resonance-guided laser interstitial thermal ablation (MRgLITT) for completion hemispherotomy.

Methods: Patients treated with completion hemispherotomy using MRgLITT at our institution were identified. Procedural and seizure outcomes were evaluated retrospectively.

Results: Five patients (3 males) underwent six MRgLITT procedures (one child treated twice) for completion hemispherotomy at a median age of 6 years (range 1.8-12.9). Two …

Copy Number Alterations Of Aggressive Pituitary Neuroendocrine Tumors, Grace Zhang

Scripps Senior Theses

Pituitary neuroendocrine tumors (PitNETs) are tumors of the pituitary gland. Although most are benign, they can cause severe morbidity if compression of surrounding tissue and/or endocrinopathies occur.

Aggressive PitNETs are notably detrimental and difficult to predict, and their effects are further exacerbated by challenges in treatment. Although histological studies can detect certain markers of tumor aggressiveness, they are insufficient at wholly predicting PitNET aggressiveness, making the clinical behavior of PitNETs challenging to determine. Since treatment of aggressive tumors also remains suboptimal, this further results in negative impacts on health and quality of life.

Genetic markers, such as copy number variations …

Upregulation Of The Escrt Pathway And Multivesicular Bodies Accelerates Degradation Of Proteins Associated With Neurodegeneration, Ron Benyair, Sai Srinivas Panapakkam Giridharan, Pilar Rivero-Ríos, Junya Hasegawa, Emily Bristow, Eeva-Liisa Eskelinen, Merav D Shmueli, Vered Fishbain-Yoskovitz, Yifat Merbl, Lisa M Sharkey, Henry L Paulson, Phyllis I Hanson, Samarjit Patnaik, Ismael Al-Ramahi, Juan Botas, Juan Marugan, Lois S Weisman

Duncan NRI Faculty and Staff Publications

Many neurodegenerative diseases, including Huntington’s disease (HD) and Alzheimer’s disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotypes. We previously reported a small molecule, NCT-504, which reduces cellular levels of mutant huntingtin (mHTT) in patient fibroblasts as well as mouse striatal and cortical neurons from an HdhQ111 mutant mouse. Here, we show that NCT-504 has a broader potential, and in addition reduces levels of Tau, a protein associated with Alzheimer’s disease, as well as other tauopathies. We …

Using Rna-Based Therapies To Target The Kidney In Cardiovascular Disease, Trecia C Palmer, Robert W Hunter

Faculty, Staff and Student Publications

RNA-based therapies are currently used for immunisation against infections and to treat metabolic diseases. They can modulate gene expression in immune cells and hepatocytes, but their use in other cell types has been limited by an inability to selectively target specific tissues. Potential solutions to this targeting problem involve packaging therapeutic RNA molecules into delivery vehicles that are preferentially delivered to cells of interest. In this review, we consider why the kidney is a desirable target for RNA-based therapies in cardiovascular disease and discuss how such therapy could be delivered. Because the kidney plays a central role in maintaining cardiovascular …

Gibbs Process Distinguishes Survival And Reveals Contact-Inhibition Genes In Glioblastoma Multiforme, Afrooz Jahedi, Gayatri Kumar, Lavanya Kannan, Tarjani Agarwal, Jason Huse, Krishna Bhat, Kasthuri Kannan

Faculty, Staff and Student Publications

Tumor growth is a spatiotemporal birth-and-death process with loss of heterotypic contact-inhibition of locomotion (CIL) of tumor cells promoting invasion and metastasis. Therefore, representing tumor cells as two-dimensional points, we can expect the tumor tissues in histology slides to reflect realizations of spatial birth-and-death process which can be mathematically modeled to reveal molecular mechanisms of CIL, provided the mathematics models the inhibitory interactions. Gibbs process as an inhibitory point process is a natural choice since it is an equilibrium process of the spatial birth-and-death process. That is if the tumor cells maintain homotypic contact inhibition, the spatial distributions of tumor …

The Link Between Intracellular Calcium Signaling And Exosomal Pd-L1 In Cancer Progression And Immunotherapy, Rakibul Alam, Mizanur Rahman, Zhiguo Li

Markey Cancer Center Faculty Publications

Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exo- somes to reprogram the factors associated with the tumor microenvironment (TME) causing tu- mor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with re- ceptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some pa- tients show …

Payer Reimbursement Practices And Incentives For Improving Interpretation Of Germline Genetic Testing, Patricia Deverka, Janis Geary, Charles Mathews, Matan Cohen, Gillian Hooker, Mary Majumder, Zuzana Skvarkova, Robert Cook-Deegan

Center for Medical Ethics and Health Policy Staff Publications

Germline genetic testing for inherited cancer risk has shifted to multi-gene panel tests (MGPTs). While MGPTs detect more pathogenic variants, they also detect more variants of uncertain significance (VUSs) that increase the possibility of harms such as unnecessary surgery. Data sharing by laboratories is critical to addressing the VUS problem. However, barriers to sharing and an absence of incentives have limited laboratory contributions to the ClinVar database. Payers can play a crucial role in the expansion of knowledge and effectiveness of genetic testing. Current policies affecting MGPT reimbursement are complex and create perverse incentives. Trends in utilization and coverage for …

Methodological Considerations In Pisces 3: A Randomized, Placebo-Controlled Study Of Intracerebral Stem Cells In Subjects With Disability Following An Ischemic Stroke, Daniel T Laskowitz, Keith W Muir, Sean I Savitz, Lawrence R Wechsler, Julie G Pilitsis, Scott Y Rahimi, Richard L Beckman, Vincent Holmes, Peng R Chen, Laura Juel, Deborah Koltai, Brad J Kolls

Faculty, Staff and Student Publications

Background and hypothesis: At present, there are no medical interventions proven to improve functional recovery in patients with subacute stroke. We hypothesize that the intraparenchymal administration of CTX0E03, a conditionally immortalized neural stem cell line, linked with a standardized rehabilitation therapy regimen for the upper limb, would improve functional outcomes in patients 6-12 months after an index ischemic stroke.

Study design: PISCES III was designed as a multicenter prospective, sham-controlled, outcome-blinded randomized clinical trial. Eligibility required a qualifying ischemic stroke 6-12 months prior to surgical intervention. Patients must be between 35 and 75 years of age and have residual moderate …

Cerebellar Dysfunction In Rodent Models With Dystonia, Tremor, And Ataxia, Meike E Van Der Heijden, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents …

Function And Dysfunction Of The Dystonia Network: An Exploration Of Neural Circuits That Underlie The Acquired And Isolated Dystonias, Jason S Gill, Megan X Nguyen, Mariam Hull, Meike E Van Der Heijden, Ken Nguyen, Sruthi P Thomas, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is a highly prevalent movement disorder that can manifest at any time across the lifespan. An increasing number of investigations have tied this disorder to dysfunction of a broad "dystonia network" encompassing the cerebellum, thalamus, basal ganglia, and cortex. However, pinpointing how dysfunction of the various anatomic components of the network produces the wide variety of dystonia presentations across etiologies remains a difficult problem. In this review, a discussion of functional network findings in non-mendelian etiologies of dystonia is undertaken. Initially acquired etiologies of dystonia and how lesion location leads to alterations in network function are explored, first through …