Digital Commons Network^™

Pathogenesis And Current Treatment Of Osteosarcoma: Perspectives For Future Therapies, Richa Rathore, Brian A Van Tine

Open Access Publications

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. The standard-of-care curative treatment for osteosarcoma utilizes doxorubicin, cisplatin, and high-dose methotrexate, a standard that has not changed in more than 40 years. The development of patient-specific therapies requires an in-depth understanding of the unique genetics and biology of the tumor. Here, we discuss the role of normal bone biology in osteosarcomagenesis, highlighting the factors that drive normal osteoblast production, as well as abnormal osteosarcoma development. We then describe the pathology and current standard of care of osteosarcoma. Given the complex heterogeneity of osteosarcoma tumors, we …

Identification Of A Novel Genetic Marker For Risk Of Degenerative Rotator Cuff Disease Surgery In The Uk Biobank, Elizabeth L Yanik, Jay D Keener, Shiow J Lin, Graham A Colditz, Rick W Wright, Bradley A Evanoff, Nitin B Jain, Nancy L Saccone

Open Access Publications

BACKGROUND: While evidence indicates that familial predisposition influences the risk of developing degenerative rotator cuff disease (RCD), knowledge of specific genetic markers is limited. We conducted a genome-wide association study of RCD surgery using the UK Biobank, a prospective cohort of 500,000 people (40 to 69 years of age at enrollment) with genotype data.

METHODS: Cases with surgery for degenerative RCD were identified using linked hospital records. The cases were defined as an International Classification of Diseases, Tenth Revision (ICD-10) code of M75.1 determined by a trauma/orthopaedic specialist and surgery consistent with RCD treatment. Cases were excluded if a diagnosis …

Postnatal Expression Profiles Of Atypical Cadherin Fat1 Suggest Its Role In Autism, Jeannine A Frei, Cheryl J Brandenburg, Jonathan E Nestor, Didier M Hodzic, Celine Plachez, Helen Mcneill, Derek M Dykxhoorn, Michael W Nestor, Gene J Blatt, Yu-Chih Lin

Open Access Publications

Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and …

Telomere Erosion In Human Pluripotent Stem Cells Leads To Atr-Mediated Mitotic Catastrophe, Alexandre T. Vessoni, Tianpeng Zhang, Annabel Quinet, Ho-Chang Jeong, Michael Munroe, Matthew Wood, Enzo Tedone, Alessandro Vindigni, Jerry W. Shay, Roger A. Greenberg, Luis F.Z. Batista

Open Access Publications

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic …

Endothelial Ether Lipids Link The Vasculature To Blood Pressure, Behavior, And Neurodegeneration, Larry D. Spears, Sangeeta Adak, Guifang Dong, Xiaochao Wei, George Spyropoulos, Qiang Zhang, Li Yin, Chu Feng, Donghua Hu, Irfan J. Lodhi, Fong-Fu Hsu, Rithwick Rajagopal, Kevin K. Noguchi, Carmen M. Halabi, Lindsey Brier, Annie R. Bice, Brian V. Lananna, Erik S. Musiek, Oshri Avraham, Valeria Cavalli, Jerrah K. Holth, David M. Holtzman, David F. Wozniak, Joseph P. Culver, Clay F. Semenkovich

Open Access Publications

No abstract provided.

Acitretin Mitigates Uroporphyrin‑Induced Bone Defects In Congenital Erythropoietic Porphyria Models, Juliana Bragazzi Cunha, Jared S. Elenbaas, Dhiman Maitra, Ning Kuo, Rodrigo Azuero-Dajud, Allison C. Ferguson, Megan S. Griffin, Stephen I. Lentz, Jordan A. Shavit, M. Bishr Omary

Open Access Publications

No abstract provided.

Informative Regions In Viral Genomes, Jaime Leonardo Moreno-Gallego, Alejandro Reyes

Open Access Publications

Viruses, far from being just parasites affecting hosts' fitness, are major players in any microbial ecosystem. In spite of their broad abundance, viruses, in particular bacteriophages, remain largely unknown since only about 20% of sequences obtained from viral community DNA surveys could be annotated by comparison with public databases. In order to shed some light into this genetic dark matter we expanded the search of orthologous groups as potential markers to viral taxonomy from bacteriophages and included eukaryotic viruses, establishing a set of 31,150 ViPhOGs (Eukaryotic Viruses and Phages Orthologous Groups). To do this, we examine the non-redundant viral diversity …

Acceleration Of Small Intestine Development And Remodeling Of The Microbiome Following Hyaluronan 35 Kda Treatment In Neonatal Mice, Hala Chaaban, Kathryn Burge, Jeffrey Eckert, Majoi Trammell, David Dyer, Ravi S Keshari, Robert Silasi, Girija Regmi, Cristina Lupu, Misty Good, Steven J Mcelroy, Florea Lupu

Open Access Publications

The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 …

Prospective Spect-Ct Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using The In-111 (111in)/Yttrium 90 (90y) Ibritumomab Tiuxetan (Zevalin ®) Theranostic Pair In Patients With Lymphoma At Myeloablative Dose Levels, Richard L Wahl, Eric C Frey, Heather A Jacene, Brad S Kahl, Steven Piantadosi, Jesus A Bianco, Richard J Hammes, Miah Jung, Wayne Kasecamp, Bin He, George Sgouros, Ian W Flinn, Lode J Swinnen

Open Access Publications

PURPOSE: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin's lymphoma using the theranostic pair of

METHODS: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm

RESULTS: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of

CONCLUSIONS: Patient-specific outpatient

Single Cell Transcriptional And Chromatin Accessibility Profiling Redefine Cellular Heterogeneity In The Adult Human Kidney, Yoshiharu Muto, Parker C. Wilson, Nicolas Ledru, Haojia Wu, Henrik Dimke, Sushrut S. Waikar, Benjamin D. Humphreys

Open Access Publications

No abstract provided.

Spatially Interacting Phosphorylation Sites And Mutations In Cancer, Kuan-Lin Huang, Adam D. Scott, Daniel Cui Zhou, Liang-Bo Wang, Amila Weerasinghe, Ruiyang Liu, Yige Wu, Michael C. Wendl, Matthew A. Wyczalkowski, Jessika Baral, Sohini Sengupta, Chin-Wen Lai, Li Ding, Et Al.

Open Access Publications

No abstract provided.

Bispecific T Cell Engagers For The Treatment Of Multiple Myeloma: Achievements And Challenges, Kinan Alhallak, Jennifer Sun, Amanda Jeske, Chaelee Park, Jessica Yavner, Hannah Bash, Berit Lubben, Ola Adebayo, Ayah Khaskiah, Abdel Kareem Azab

Open Access Publications

MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising modality for the treatment of MM. This review article discusses the advancements and future directions of BTCE treatments for MM.

Etv4 And Etv5 Drive Synovial Sarcoma Through Cell Cycle And Dux4 Embryonic Pathway Control, Joanna Desalvo, Yuguang Ban, Luyuan Li, Xiaodian Sun, Zhijie Jiang, Darcy A Kerr, Mahsa Khanlari, Maria Boulina, Mario R Capecchi, Juha M Partanen, Lin Chen, Tadashi Kondo, David M Ornitz, Jonathan C Trent, Josiane E Eid

Open Access Publications

Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that …

Bnp Facilitates Nmb-Encoded Histaminergic Itch Via Nprc-Nmbr Crosstalk, Qing-Tao Meng, Xian-Yu Liu, Xue-Ting Liu, Juan Liu, Admire Munanairi, Devin M. Barry, Benlong Liu, Hua Jin, Yu Sun, Qianyi Yang, Fang Gao, Li Wan, Jiahang Peng, Jin-Hua Jin, Kai-Feng Shen, Ray Kim, Jun Yin, Ailin Tao, Zhou-Feng Chen

Open Access Publications

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by

Response To Ibudilast Treatment According To Progressive Multiple Sclerosis Disease Phenotype, Andrew D Goodman, Janel K Fedler, Jon Yankey, Elizabeth A Klingner, Dixie J Ecklund, Christopher V Goebel, Robert A Bermel, Marianne Chase, Christopher S Coffey, Eric C Klawiter, Robert T Naismith, Robert J Fox, Sprint-Ms Investigators

Open Access Publications

OBJECTIVE: Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis.

BACKGROUND: Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown.

DESIGN/METHODS: SPRINT-MS was a randomized, placebo-controlled 96-week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three-way interaction linear-mixed model. Adjustment for …

Despite Increasing Aldosterone, Elevated Potassium Is Not Necessary For Activating Aldosterone-Sensitive Hsd2 Neurons Or Sodium Appetite, Frederico S Fazan, Eduardo Colombari, Arthur D Loewy, Joel C Geerling

Open Access Publications

Restricting dietary sodium promotes sodium appetite in rats. Prolonged sodium restriction increases plasma potassium (pK), and elevated pK is largely responsible for a concurrent increase in aldosterone, which helps promote sodium appetite. In addition to increasing aldosterone, we hypothesized that elevated potassium directly influences the brain to promote sodium appetite. To test this, we restricted dietary potassium in sodium-deprived rats. Potassium restriction reduced pK and blunted the increase in aldosterone caused by sodium deprivation, but did not prevent sodium appetite or the activation of aldosterone-sensitive HSD2 neurons. Conversely, supplementing potassium in sodium-deprived rats increased pK and aldosterone, but did not …

Rna-Seq Identifies Genes Whose Proteins Are Upregulated During Syncytia Development In Murine C2c12 Myoblasts And Human Bewo Trophoblasts, Christopher Azar, Mark C Valentine, Julie Trausch-Azar, Lisa Rois, Moe Mahjoub, D Michael Nelson, Alan L Schwartz

Open Access Publications

The fusion of villous cytotrophoblasts into the multinucleated syncytiotrophoblast is critical for the essential functions of the mammalian placenta. Using RNA-Seq gene expression, quantitative protein expression, and siRNA knockdown we identified genes and their cognate proteins which are similarly upregulated in two cellular models of mammalian syncytia development (human BeWo cytotrophoblast to syncytiotrophoblast and murine C2C12 myoblast to myotube). These include DYSF, PDE4DIP, SPIRE2, NDRG1, PLEC, GPR146, HSPB8, DHCR7, and HDAC5. These findings provide avenues for further understanding of the mechanisms underlying mammalian placental syncytiotrophoblast development.

Lack Of Association Between Acute Stroke, Post-Stroke Dementia, Race, And Β-Amyloid Status, Lauren N Koenig, Lena M Mccue, Elizabeth Grant, Parinaz Massoumzadeh, Catherine M Roe, Chengjie Xiong, Krista L Moulder, Liang Wang, Allyson R Zazulia, Peggy Kelly, Aylin Dincer, Aiad Zaza, Joshua S Shimony, Tammie L S Benzinger, John C Morris

Open Access Publications

INTRODUCTION: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship.

METHODS: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in …

Substance Use Disorders And Behavioral Addictions During The Covid-19 Pandemic And Covid-19-Related Restrictions, Nicole M Avena, Julia Simkus, Anne Lewandowski, Mark S Gold, Marc N Potenza

Open Access Publications

COVID-19 was first identified in Wuhan, China in December of 2019 and appeared in the United States 1 month later. Between the onset of the pandemic and January 13, 2021, over 92 million people have tested positive for the virus and over 1.9 million people have died globally. Virtually every country in the world has been impacted by this virus. Beginning in March 2020, many U.S. state governments enforced a "quarantine" to respond to the growing health crisis. Citizens were required to remain at home; schools, restaurants, and non-essential businesses were forced to close, and large gatherings were prohibited. Americans' …

The Kinase Specificity Of Protein Kinase Inhibitor Peptide, Yao Chen, Bernardo L Sabatini

Open Access Publications

G-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested in

Excessive White Matter Hyperintensity Increases Susceptibility To Poor Functional Outcomes After Acute Ischemic Stroke, Sungmin Hong, Laura Heitsch, Chia-Ling Phuah, Et Al

Open Access Publications

No abstract provided.

Reproductive Aging In Caenorhabditis Elegans: From Molecules To Ecology, Andrea Scharf, Franziska Pohl, Brian M Egan, Zuzana Kocsisova, Kerry Kornfeld

Open Access Publications

Aging animals display a broad range of progressive degenerative changes, and one of the most fascinating is the decline of female reproductive function. In the model organism

Longitudinal Prediction Of Infant Mr Images With Multi-Contrast Perceptual Adversarial Learning, Liying Peng, Robert C Mckinstry, Kelly N Botteron, Et Al

Open Access Publications

The infant brain undergoes a remarkable period of neural development that is crucial for the development of cognitive and behavioral capacities (Hasegawa et al., 2018). Longitudinal magnetic resonance imaging (MRI) is able to characterize the developmental trajectories and is critical in neuroimaging studies of early brain development. However, missing data at different time points is an unavoidable occurrence in longitudinal studies owing to participant attrition and scan failure. Compared to dropping incomplete data, data imputation is considered a better solution to address such missing data in order to preserve all available samples. In this paper, we adapt generative adversarial networks …

Antigen Presenting Cells Link The Female Genital Tract Microbiome To Mucosal Inflammation, With Hormonal Contraception As An Additional Modulator Of Inflammatory Signatures, Elizabeth H Byrne, Barry L Hykes, Scott A Handley, Et Al

Open Access Publications

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low

Targeting Host Glycolysis As A Strategy For Antimalarial Development, Andrew J Jezewski, Yu-Hsi Lin, Julie A Reisz, Rachel Culp-Hill, Yasaman Barekatain, Victoria C Yan, Angelo D'Alessandro, Florian L Muller, Audrey R Odom John

Open Access Publications

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase - a critical enzyme in glycolysis - and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather …

Direct N-Glycosylation Profiling Of Urine And Prostatic Fluid Glycoproteins And Extracellular Vesicles, Calvin R K Blaschke, Jordan P Hartig, Grace Grimsley, Liping Liu, O John Semmes, Jennifer D Wu, Joseph E Ippolito, Chanita Hughes-Halbert, Julius O Nyalwidhe, Richard R Drake

Open Access Publications

Expressed prostatic secretions (EPS), also called post digital rectal exam urines, are proximal fluids of the prostate that are widely used for diagnostic and prognostic assays for prostate cancer. These fluids contain an abundant number of glycoproteins and extracellular vesicles secreted by the prostate gland, and the ability to detect changes in their N-glycans composition as a reflection of disease state represents potential new biomarker candidates. Methods to characterize these N-glycan constituents directly from clinical samples in a timely manner and with minimal sample processing requirements are not currently available. In this report, an approach is described to directly profile …

The Crossroads Of Glycoscience, Infection, And Immunology, Tanya R Mckitrick, Margaret E Ackerman, Robert M Anthony, Clay S Bennett, Michael Demetriou, Gregory A Hudalla, Katharina Ribbeck, Stefan Ruhl, Christina M Woo, Loretta Yang, Seth J Zost, Ronald L Schnaar, Tamara L Doering

Open Access Publications

Advances in experimental capabilities in the glycosciences offer expanding opportunities for discovery in the broad areas of immunology and microbiology. These two disciplines overlap when microbial infection stimulates host immune responses and glycan structures are central in the processes that occur during all such encounters. Microbial glycans mediate host-pathogen interactions by acting as surface receptors or ligands, functioning as virulence factors, impeding host immune responses, or playing other roles in the struggle between host and microbe. In the context of the host, glycosylation drives cell-cell interactions that initiate and regulate the host response and modulates the effects of antibodies and …

Antidiabetic Dpp-4 Inhibitors Reprogram Tumor Microenvironment That Facilitates Murine Breast Cancer Metastasis Through Interaction With Cancer Cells Via A Ros-Nf-Кb-Nlrp3 Axis, Rui Li, Xin Zeng, Meihua Yang, Jinmei Feng, Xiaohui Xu, Liming Bao, Tingbo Ye, Xin Wang, Bingqian Xue, Yi Huang

Open Access Publications

Improvement of understanding of the safety profile and biological significance of antidiabetic agents in breast cancer (BC) progression may shed new light on minimizing the unexpected side effect of antidiabetic reagents in diabetic patients with BC. Our recent finding showed that Saxagliptin (Sax) and Sitagliptin (Sit), two common antidiabetic dipeptidyl peptidase-4 inhibitors (DPP-4i) compounds, promoted murine BC 4T1 metastasis

Conserved Mechanism Of Bicarbonate-Induced Sensitization Of Catsper Channels In Human And Mouse Sperm, Juan J Ferreira, Pascale Lybaert, Lis C Puga-Molina, Celia M Santi

Open Access Publications

To fertilize an egg, mammalian sperm must undergo capacitation in the female genital tract. A key contributor to capacitation is the calcium (Ca

Phylum-Spanning Neuropeptide Gpcr Identification And Prioritization: Shaping Drug Target Discovery Pipelines For Nematode Parasite Control, Louise E Atkinson, Ciaran J Mccoy, Bethany A Crooks, Fiona M Mckay, Paul Mcveigh, Darrin Mckenzie, Allister Irvine, John Harrington, Bruce A Rosa, Makedonka Mitreva, Nikki J Marks, Aaron G Maule, Angela Mousley

Open Access Publications

Nematode parasites undermine human health and global food security. The frontline anthelmintic portfolio used to treat parasitic nematodes is threatened by the escalation of anthelmintic resistance, resulting in a demand for new drug targets for parasite control. Nematode neuropeptide signalling pathways represent an attractive source of novel drug targets which currently remain unexploited. The complexity of the nematode neuropeptidergic system challenges the discovery of new targets for parasite control, however recent advances in parasite 'omics' offers an opportunity for the