Digital Commons Network^™

Pituitary Adenoma In Pediatric And Adolescent Populations, Jie Chen, Robert E Schmidt, Sonika Dahiya

Open Access Publications

Pituitary adenomas are rare in children and adolescents and although mostly benign, they can sometimes be challenging to manage due to their locally invasive nature. In this study, we examined the clinicopathologic features of 42 pituitary adenomas in patients ≤21 years of age. The youngest patient was 8 years old (median age: 18 years), and the female-to-male ratio was 1.8:1. Five patients had recurrence after resection. There was no obvious difference between the recurrent rates in the typical (11.7%) and atypical adenomas (12.5%) based on the 2004 WHO classification. However, the recurrence rate was much higher in adenomas with an …

Peroxidasin Is A Novel Target Of Autoantibodies In Lupus Nephritis, Pallavi Manral, Selene Colon, Gautam Bhave, Ming-Hui Zhao, Sanjay Jain, Dorin-Bogdan Borza

Open Access Publications

No abstract provided.

A Multimodality Approach To Assessing Factor I Genetic Variants In Atypical Hemolytic Uremic Syndrome, Anuja Java, Nicola Pozzi, Latisha D Love-Gregory, Jonathan W Heusel, Yun Ju Sung, Zheng Hu, Paula Bertram, M Kathryn Liszewski, Laura M Cline, Zhen Ren, John P Atkinson

Open Access Publications

No abstract provided.

Neil Schechter Oral History.

Pediatric Palliative Care Oral History Project

Dr. Neil Schechter begins this interview by describing the state of the pediatric pain field during the late 1970s. As he was training, he "felt it was a bit wrong" to have the disciplines dealing with physical and emotional/mental well-being so divorced from one another, especially with unaddressed psychosocial care for pediatric patients and families during complex chronic conditions such as cancer and sickle cell. Dr. Schechter also recalls a prevalent fear in the medical community of addicting children to pain medication, which kept clinicians from treating children's pain at all. Dr. Schechter questioned why pain was so chronically undertreated …

Unified Single-Cell Analysis Of Testis Gene Regulation And Pathology In Five Mouse Strains, Min Jung, Daniel Wells, Jannette Rusch, Suhaira Ahmad, Jonathan Marchini, Simon R. Myers, Donald F. Conrad

Open Access Publications

To fully exploit the potential of single-cell functional genomics in the study of development and disease, robust methods are needed to simplify the analysis of data across samples, time-points and individuals. Here we introduce a model-based factor analysis method, SDA, to analyze a novel 57,600 cell dataset from the testes of wild-type mice and mice with gonadal defects due to disruption of the genes

Stephen Liben Oral History.

Pediatric Palliative Care Oral History Project

Dr. Liben credits his initial venture into pediatric palliative care to his experiences of witnessing "unnecessary suffering" during his career in pediatric critical care. Dr. Liben states that he was attracted to how much "promise" that pediatric palliative care held in addressing more than just the medical needs of children and their families. He then recalls experiences he had with international leaders in the emerging field of pediatric palliative care. Dr. Liben describes how the field has evolved to be more patient- and family-centric while spanning across the intersections of pain management, chronic care, and complex care. Dr. Liben also …

Intracellular Retention Of Mutant Lysyl Oxidase Leads To Aortic Dilation In Response To Increased Hemodynamic Stress, Vivian S Lee, Carmen M Halabi, Thomas J Broekelmann, Philip C Trackman, Nathan O Stitziel, Robert P Mecham

Open Access Publications

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta although both the ascending and descending aortae showed changes in vessel wall structure, smooth muscle cell number and …

Reactive Microglia And Il1Β/Il-1r1-Signaling Mediate Neuroprotection In Excitotoxin-Damaged Mouse Retina, Levi Todd, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh V Hoang, Warren A Campbell, Seth Blackshaw, Ning Quan, Andy J Fischer

Open Access Publications

BACKGROUND: Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.

METHODS: Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell …

Eosinophils Downregulate Lung Alloimmunity By Decreasing Tcr Signal Transduction, Oscar Okwudiri Onyema, Yizhan Guo, Bayan Mahgoub, Qing Wang, Amir Manafi, Zhongcheng Mei, Anirban Banerjee, Dongge Li, Mark H. Stoler, Melissa T. Zaidi, Adam G. Schrum, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick

Open Access Publications

Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell-mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1-mediated synapse formation between eosinophils and T cells. …

Vesicular Glutamatergic Transmission In Noise-Induced Loss And Repair Of Cochlear Ribbon Synapses, Kyunghee X. Kim, Shelby Payne, Aizhen Yang-Hood, Song-Zhe Li, Bethany Davis, Jason Carlquist, Babak V-Ghaffari, Jay A. Gantz, Dorina Kallogjeri, James A.J. Fitzpatrick, Kevin K. Ohlemiller, Keiko Hirose, Mark A. Rutherford

Open Access Publications

Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3 (

Immunomodulatory Role Of Non-Neuronal Cholinergic Signaling In Myocardial Injury, Cibele Rocha-Resende, Carla Weinheimer, Geetika Bajpai, Luigi Adamo, Scot J. Matkovich, Joel Schilling, Philip M. Barger, Kory J. Lavine, Douglas L. Mann

Open Access Publications

Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic system is not well understood. To address the immunomodulatory role of the non-neuronal cholinergic system in the heart we used a previously validated diphtheria toxin (DT)-induced cardiomyocyte ablation model (Rosa26-DTMlc2v-Cre mice). DT-injected Rosa26-DTMlc2v-Cre mice were treated with diluent or Pyridostigmine Bromide (PYR), a reversible cholinesterase inhibitor. PYR treatment resulted in increased survival and decreased numbers of MHC-IIlowCCR2+ macrophages in DT-injected Rosa26-DTMlc2v-Cre mice compared to diluent treated Rosa26-DTMlc2v-Cre mice. Importantly, the expression of CCL2/7 mRNA and protein was …

Expression Of Factor V By Resident Macrophages Boosts Host Defense In The Peritoneal Cavity, Nan Zhang, Rafael S. Czepielewski, Nicholas N. Jarjour, Emma C. Erlich, Ekaterina Esaulova, Brian T. Saunders, Steven P. Grover, Audrey C. Cleuren, George J. Broze, Brian T. Edelson, Nigel Mackman, Bernd H. Zinselmeyer, Gwendalyn J. Randolph

Open Access Publications

Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-known but poorly understood "macrophage disappearance reaction." Intravital imaging revealed that resident macrophages were nonadherent in peritoneal fluid during homeostasis. Bacterial entry into the peritoneum acutely induced macrophage adherence and associated bacterial phagocytosis. However, optimal control of bacterial expansion in the peritoneum also required expression of FV by the macrophages to form …

Phase Ii Trial Of Levocetirizine With Capecitabine And Bevacizumab To Overcome The Resistance Of Antiangiogenic Therapies In Refractory Metastatic Colorectal Cancer, Manik Amin, Monica Desai, Kathryn Trinkaus, Amberly Brown, Andrea Wang-Gillam, Benjamin Tan, Joel Picus, Steven Sorscher, Maureen Highkin, Kim Lears, Albert C. Lockhart

Open Access Publications

Background: Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in development of resistance to anti-angiogenic therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC.

Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850 mg/m

Results: Forty-seven patients were enrolled in the trial …

The Current State Of Animal Models And Genomic Approaches Towards Identifying And Validating Molecular Determinants Of Mycobacterium Tuberculosis Infection And Tuberculosis Disease, Allison N Bucsan, Smriti Mehra, Shabaana A Khader, Deepak Kaushal

2010-2019 OA Pubs

Animal models are important in understanding both the pathogenesis of and immunity to tuberculosis (TB). Unfortunately, we are beginning to understand that no animal model perfectly recapitulates the human TB syndrome, which encompasses numerous different stages. Furthermore, Mycobacterium tuberculosis infection is a very heterogeneous event at both the levels of pathogenesis and immunity. This review seeks to establish the current understanding of TB pathogenesis and immunity, as validated in the animal models of TB in active use today. We especially focus on the use of modern genomic approaches in these models to determine the mechanism and the role of specific …

Peroxisomal Regulation Of Redox Homeostasis And Adipocyte Metabolism, Jingjing Liu, Wen Lu, Bimin Shi, Samuel Klein, Xiong Su

Open Access Publications

Peroxisomes are ubiquitous cellular organelles required for specific pathways of fatty acid oxidation and lipid synthesis, and until recently their functions in adipocytes have not been well appreciated. Importantly, peroxisomes host many oxygen-consumption reactions and play a major role in generation and detoxification of reactive oxygen species (ROS) and reactive nitrogen species (RNS), influencing whole cell redox status. Here, we review recent progress in peroxisomal functions in lipid metabolism as related to ROS/RNS metabolism and discuss the roles of peroxisomal redox homeostasis in adipogenesis and adipocyte metabolism. We provide a framework for understanding redox regulation of peroxisomal functions in adipocytes …

Genetic Approaches To Metabolic Bone Diseases, Fadil M Hannan, Paul J Newey, Michael P Whyte, Rajesh V Thakker

Open Access Publications

Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition …

Neuroendocrine Markers Insulinoma-Associated Protein 1, Chromogranin, Synaptophysin, And Cd56 Show Rare Positivity In Adenocarcinoma Ex-Goblet Cell Carcinoids, Chen Yang, Ivan Gonzalez, Lingxin Zhang, Dengfeng Cao

Open Access Publications

Background: Adenocarcinoma ex-goblet cell carcinoid (AdexGCC) was considered a neuroendocrine adenocarcinoma, despite majority of tumor cells being negative for conventional neuroendocrine markers such as chromogranin and synaptophysin. Recently, insulinoma-associated protein 1 (INSM1) has been identified as a novel neuroendocrine marker that is more sensitive than chromogranin, synaptophysin, and CD56 in pulmonary neuroendocrine tumors.

Methods: We studied this marker in conjunction with chromogranin, synaptophysin, and CD56 in 36 appendiceal AdexGCCs (21 primaries, 15 metastatic).

Results: Primary AdexGCCs showed staining for INSM1, chromogranin, synaptophysin, and CD56 in 13/21 (62%), 18/21 (86%), 18/21 (86%), and 9/19 (47%) cases, respectively. However, the mean proportion …

Apolipoprotein E Associated With Reconstituted High-Density Lipoprotein-Like Particles Is Protected From Aggregation., Ellen Hubin, Philip B Verghese, Nico Van Nuland, Kerensa Broersen

Open Access Publications

Apolipoprotein E (APOE) genotype determines Alzheimer's disease (AD) susceptibility, with the APOE ε4 allele being an established risk factor for late-onset AD. The ApoE lipidation status has been reported to impact amyloid-beta (Aβ) peptide metabolism. The details of how lipidation affects ApoE behavior remain to be elucidated. In this study, we prepared lipid-free and lipid-bound ApoE particles, mimicking the high-density lipoprotein particles found in vivo, for all three isoforms (ApoE2, ApoE3, and ApoE4) and biophysically characterized them. We find that lipid-free ApoE in solution has the tendency to aggregate in vitro in an isoform-dependent manner under near-physiological conditions and that …

Ddr2 Controls Breast Tumor Stiffness And Metastasis By Regulating Integrin Mediated Mechanotransduction In Cafs, Samantha V.H. Bayer, Whitney R. Grither, Audrey Brenot, Priscilla Y. Hwang, Craig E. Barcus, Melanie Ernst, Patrick Pence, Christopher Walter, Amit Pathak, Gregory D. Longmore

Open Access Publications

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors …

Thyroid Hormone Regulates Distinct Paths To Maturation In Pigment Cell Lineages, Lauren M. Saunders, Abhishek K. Mishra, Andrew J. Aman, Victor M. Lewis, Matthew B. Toomey, Jonathan S. Packer, Xiaojie Qiu, Jose L. Mcfaline-Figueroa, Joseph C. Corbo, Cole Trapnell, David M. Parichy

Open Access Publications

Thyroid hormone (TH) regulates diverse developmental events and can drive disparate cellular outcomes. In zebrafish, TH has opposite effects on neural crest derived pigment cells of the adult stripe pattern, limiting melanophore population expansion, yet increasing yellow/orange xanthophore numbers. To learn how TH elicits seemingly opposite responses in cells having a common embryological origin, we analyzed individual transcriptomes from thousands of neural crest-derived cells, reconstructed developmental trajectories, identified pigment cell-lineage specific responses to TH, and assessed roles for TH receptors. We show that TH promotes maturation of both cell types but in distinct ways. In melanophores, TH drives terminal differentiation, …

An Endogenous Peptide Marker Differentiates Sod1 Stability And Facilitates Pharmacodynamic Monitoring In Sod1 Amyotrophic Lateral Sclerosis, Ilya Gertsman, Joanne Wuu, Melissa Mcalonis-Downes, Majid Ghassemian, Karen Ling, Frank Rigo, Frank Bennett, Michael Benatar, Timothy M. Miller, Sandrine Da Cruz

Open Access Publications

The discovery of novel biomarkers has emerged as a critical need for therapeutic development in amyotrophic lateral sclerosis (ALS). For some subsets of ALS, such as the genetic superoxide dismutase 1 (SOD1) form, exciting new treatment strategies, such as antisense oligonucleotide-mediated (ASO-mediated) SOD1 silencing, are being tested in clinical trials, so the identification of pharmacodynamic biomarkers for therapeutic monitoring is essential. We identify increased levels of a 7-amino acid endogenous peptide of SOD1 in cerebrospinal fluid (CSF) of human SOD1 mutation carriers but not in other neurological cases or nondiseased controls. Levels of peptide elevation vary based on the specific …

Celltag Indexing: Genetic Barcode-Based Sample Multiplexing For Single-Cell Genomics, Chuner Guo, Wenjun Kong, Kenji Kamimoto, Guillermo C Rivera-Gonzalez, Xue Yang, Yuhei Kirita, Samantha A Morris

Open Access Publications

High-throughput single-cell assays increasingly require special consideration in experimental design, sample multiplexing, batch effect removal, and data interpretation. Here, we describe a lentiviral barcode-based multiplexing approach, CellTag Indexing, which uses predefined genetic barcodes that are heritable, enabling cell populations to be tagged, pooled, and tracked over time in the same experimental replicate. We demonstrate the utility of CellTag Indexing by sequencing transcriptomes using a variety of cell types, including long-term tracking of cell engraftment and differentiation in vivo. Together, this presents CellTag Indexing as a broadly applicable genetic multiplexing tool that is complementary with existing single-cell technologies.

Cns Myelination And Remyelination Depend On Fatty Acid Synthesis By Oligodendrocytes, Penelope Dimas, Laura Montani, Jorge A. Pereira, Daniel Moreno, Martin Trötzmüller, Joanne Gerber, Clay F. Semenkovich, Harald C. Köfeler, Ueli Suter

Open Access Publications

Oligodendrocytes (OLs) support neurons and signal transmission in the central nervous system (CNS) by enwrapping axons with myelin, a lipid-rich membrane structure. We addressed the significance of fatty acid (FA) synthesis in OLs by depleting FA synthase (FASN) from OL progenitor cells (OPCs) in transgenic mice. While we detected no effects in proliferation and differentiation along the postnatal OL lineage, we found that FASN is essential for accurate myelination, including myelin growth. Increasing dietary lipid intake could partially compensate for the FASN deficiency. Furthermore, FASN contributes to correct myelin lipid composition and stability of myelinated axons. Moreover, we depleted FASN …

Reaching The End Of The Line: Urinary Tract Infections, Kevin O Tamadonfar, Natalie S Omattage, Caitlin N Spaulding, Scott J Hultgren

Open Access Publications

Urinary tract infections (UTIs) cause a substantial health care burden. UTIs (i) are most often caused by uropathogenic

Partial Adaptation To The Value Range In The Macaque Orbitofrontal Cortex, Katherine E. Conen, Camillo Padoa-Schioppa

Open Access Publications

Values available for choice in different behavioral contexts can vary immensely. To compensate for this variability, neuronal circuits underlying economic decisions undergo adaptation. In orbitofrontal cortex (OFC), neurons encode the subjective value of offered and chosen goods in a quasilinear way. Previous experiments found that the gain of the encoding is lower when the value range is wider. However, the parameters OFC neurons adapted to remained unclear. Furthermore, previous studies did not examine additive changes in neuronal responses. Computational considerations indicate that these factors can directly impact choice behavior. Here we investigated how OFC neurons adapt to changes in the …

Genome-Wide Association Study In Finnish Twins Highlights The Connection Between Nicotine Addiction And Neurotrophin Signaling Pathway, Jenni Hällfors, Teemu Palviainen, Ida Surakka, Richa Gupta, Jadwiga Buchwald, Anu Raevuori, Samuli Ripatti, Tellervo Korhonen, Pekka Jousilahti, Pamela A F Madden, Jaakko Kaprio, Anu Loukola

Open Access Publications

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we …

High-Density Diffuse Optical Tomography For Imaging Human Brain Function, Muriah D Wheelock, Joseph P Culver, Adam T Eggebrecht

Open Access Publications

This review describes the unique opportunities and challenges for noninvasive optical mapping of human brain function. Diffuse optical methods offer safe, portable, and radiation free alternatives to traditional technologies like positron emission tomography or functional magnetic resonance imaging (fMRI). Recent developments in high-density diffuse optical tomography (HD-DOT) have demonstrated capabilities for mapping human cortical brain function over an extended field of view with image quality approaching that of fMRI. In this review, we cover fundamental principles of the diffusion of near infrared light in biological tissue. We discuss the challenges involved in the HD-DOT system design and implementation that must …

Brain Tumors In Neurofibromatosis Type 1, Amanda De Andrade Costa, David H Gutmann

Open Access Publications

As a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been …

Regulation Of Cilia Abundance In Multiciliated Cells, Rashmi Nanjundappa, Dong Kong, Kyuhwan Shim, Tim Stearns, Steven L. Brody, Jadranka Loncarek, Moe R. Mahjoub

Open Access Publications

Multiciliated cells (MCC) contain hundreds of motile cilia used to propel fluid over their surface. To template these cilia, each MCC produces between 100-600 centrioles by a process termed centriole amplification. Yet, how MCC regulate the precise number of centrioles and cilia remains unknown. Airway progenitor cells contain two parental centrioles (PC) and form structures called deuterosomes that nucleate centrioles during amplification. Using an ex vivo airway culture model, we show that ablation of PC does not perturb deuterosome formation and centriole amplification. In contrast, loss of PC caused an increase in deuterosome and centriole abundance, highlighting the presence of …

Mutant Huntingtin Enhances Activation Of Dendritic Kv4 K+ Channels In Striatal Spiny Projection Neurons, Luis Carrillo-Reid, Michelle Day, Zhong Xie, Alexandria E. Melendez, Jyothisri Kondapalli, Joshua L. Plotkin, David L. Wokosin, Yu Chen, Geraldine J. Kress, Michael Kaplitt, Ema Ilijic, Jaime N. Guzman, C Savio Chan, D James Surmeier

Open Access Publications

Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued …