Digital Commons Network^™

Systematic Perturbations Of Setd2, Nsd1, Nsd2, Nsd3, And Ash1l Reveal Their Distinct Contributions To H3k36 Methylation, Gerry A Shipman, Reinnier Padilla, Cynthia Horth, Bo Hu, Eric Bareke, Francisca N Vitorino, Joanna M Gongora, Benjamin A Garcia, Chao Lu, Jacek Majewski

2020-Current year OA Pubs

BACKGROUND: Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development and disease, how the molecular agents collectively shape the H3K36me landscape is unclear.

RESULTS: We use mouse mesenchymal stem cells to perturb the H3K36me methyltransferases (K36MTs) and infer the activities of the five most prominent enzymes: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and is predominantly deposited at intergenic regions by NSD1, and partly by NSD2. In contrast, H3K36me1/3 are most …

Symposium: What Does The Microbiome Tell Us About Prevention And Treatment Of Ad/Adrd?, Joia K Capocchi, Claudia Figueroa-Romero, Sage J B Dunham, Gina Faraci, Jason A Rothman, Katrine L Whiteson, Dong-Oh Seo, David M Holtzman, Stefanie Grabrucker, Yvonne M Nolan, Rima Kaddurah-Daouk, David A Jett

2020-Current year OA Pubs

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota-gut-brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD.

Enhanced Staphylococcus Aureus Protection By Uncoupling Of The Α-Toxin-Adam10 Interaction During Murine Neonatal Vaccination, Kelly L Tomaszewski, Meagan Blanchard, Reuben Olaniyi, Hannah R Brenton, Samantha Hayes, Farheen Fatma, Gaya K Amarasinghe, Byoung-Kyu Cho, Young Ah Goo, Andrea C Dedent, Stephanie A Fritz, Juliane Bubeck Wardenburg

2020-Current year OA Pubs

Staphylococcus aureus remains a leading global cause of bacterial infection-associated mortality and has eluded prior vaccine development efforts. S. aureus α-toxin (Hla) is an essential virulence factor in disease, impairing the T cell response to infection. The anti-Hla antibody response is a correlate of human protective immunity. Here we observe that this response is limited early in human life and design a vaccine strategy to elicit immune protection against Hla in a neonatal mice. By targeted disruption of the interaction of Hla with its receptor ADAM10, we identify a vaccine antigen (Hla

Estimates Of Actual And Potential Lives Saved In The United States From The Use Of Covid-19 Convalescent Plasma, Quigly Dragotakes, Jeffrey P Henderson, Et Al.

2020-Current year OA Pubs

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in …

An Iron-Rich Subset Of Macrophages Promotes Tumor Growth Through A Bach1-Ednrb Axis, Ian W Folkert, Mai T Dang, Et Al.

2020-Current year OA Pubs

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional …

Xenotransplanted Human Organoids Identify Transepithelial Zinc Transport As A Key Mediator Of Intestinal Adaptation, Maame Efua S Sampah, Vered Gazit, Deborah C Rubin, Et Al.

2020-Current year OA Pubs

Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, …

25-Hydroxycholesterol Promotes Brain Cytokine Production And Leukocyte Infiltration In A Mouse Model Of Lipopolysaccharide-Induced Neuroinflammation, Johnathan Romero, Danira Toral-Rios, Jinsheng Yu, Steven M Paul, Anil G Cashikar

2020-Current year OA Pubs

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and, in response to different inflammatory stimuli, overexpress a proinflammatory signature of genes. Among these, Ch25h is a gene overexpressed in brain tissue from Alzheimer's disease as well as various mouse models of neuroinflammation. Ch25h encodes cholesterol 25-hydroxylase, an enzyme upregulated in activated microglia under conditions of neuroinflammation, that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC can be further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant of leukocytes. We have previously shown that 25HC increases the production and secretion of …

Distinct Visual Processing Networks For Foveal And Peripheral Visual Fields, Jie Zhang, Huihui Zhou, Shuo Wang

2020-Current year OA Pubs

Foveal and peripheral vision are two distinct modes of visual processing essential for navigating the world. However, it remains unclear if they engage different neural mechanisms and circuits within the visual attentional system. Here, we trained macaques to perform a free-gaze visual search task using natural face and object stimuli and recorded a large number of 14588 visually responsive units from a broadly distributed network of brain regions involved in visual attentional processing. Foveal and peripheral units had substantially different proportions across brain regions and exhibited systematic differences in encoding visual information and visual attention. The spike-local field potential (LFP) …

Cell Type-Specific Epigenetic Priming Of Gene Expression In Nucleus Accumbens By Cocaine, Philipp Mews, Yentl Van Der Zee, Ashik Gurung, Molly Estill, Rita Futamura, Hope Kronman, Aarthi Ramakrishnan, Meagan Ryan, Abner A Reyes, Benjamin A Garcia, Caleb J Browne, Simone Sidoli, Li Shen, Eric J Nestler

2020-Current year OA Pubs

A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe an epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we …

Endosomal Fusion Of Ph-Dependent Enveloped Viruses Requires Ion Channel Trpm7, Catherine A Doyle, Marta E Stremska, Louis-Marie Bloyet, Cassandra E Thompson, Paul W Rothlauf, Sean P J Whelan, Et Al.

2020-Current year OA Pubs

The majority of viruses classified as pandemic threats are enveloped viruses which enter the cell through receptor-mediated endocytosis and take advantage of endosomal acidification to activate their fusion machinery. Here we report that the endosomal fusion of low pH-requiring viruses is highly dependent on TRPM7, a widely expressed TRP channel that is located on the plasma membrane and in intracellular vesicles. Using several viral infection systems expressing the envelope glycoproteins of various viruses, we find that loss of TRPM7 protects cells from infection by Lassa, LCMV, Ebola, Influenza, MERS, SARS-CoV-1, and SARS-CoV-2. TRPM7 ion channel activity is intrinsically necessary to …

Deletion Of Tissue Factor Pathway Inhibitor Isoform Beta Or Gamma, But Not Alpha, Improves Clotting In Hemophilic Mice, Irem Eldem, Lilian Antunes-Heck, Renumathi Subramanian, Nina M Lasky, Katrina Ashworth, Jorge Di Paola, Thomas J Girard

2020-Current year OA Pubs

BACKGROUND: Tissue factor pathway inhibitor (TFPI) regulates tissue factor-triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane-anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein-associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein-associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks.

OBJECTIVES: To determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice.

METHODS: Engineered TFPI isoform-specific, hemophilic …

A Modular Chemigenetic Calcium Indicator For Multiplexed In Vivo Functional Imaging, Helen Farrants, Christian Monroy Hernandez, Yao Chen, Et Al.

2020-Current year OA Pubs

Genetically encoded fluorescent calcium indicators allow cellular-resolution recording of physiology. However, bright, genetically targetable indicators that can be multiplexed with existing tools in vivo are needed for simultaneous imaging of multiple signals. Here we describe WHaloCaMP, a modular chemigenetic calcium indicator built from bright dye-ligands and protein sensor domains. Fluorescence change in WHaloCaMP results from reversible quenching of the bound dye via a strategically placed tryptophan. WHaloCaMP is compatible with rhodamine dye-ligands that fluoresce from green to near-infrared, including several that efficiently label the brain in animals. When bound to a near-infrared dye-ligand, WHaloCaMP shows a 7× increase in fluorescence …

Type I Ifn Signaling In The Absence Of Irgm1 Promotes M. Tuberculosis Replication In Immune Cells By Suppressing T Cell Responses, Sumanta K Naik, Michael E Mcnehlan, Yassin Mreyoud, Rachel L Kinsella, Asya Smirnov, Chanchal Sur Chowdhury, Samuel R Mckee, Neha Dubey, Reilly Woodson, Darren Kreamalmeyer, Christina L Stallings

2020-Current year OA Pubs

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infection in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion leads …

Microfracture For Medium Size To Large Knee Chondral Defects Has Limited Long-Term Efficacy: A Systematic Review, Varun Gopinatth, Garrett R Jackson, Daniel C Touhey, Jorge Chahla, Matthew V Smith, Matthew J Matava, Robert H Brophy, Derrick M Knapik

2020-Current year OA Pubs

PURPOSE: To evaluate clinical and radiographic outcomes, return to sport, failure rate, operations and complications in patients undergoing microfracture of the knee, including the femoral condyle, tibial plateau, patella and trochlea, at a mean 10-year or greater follow-up.

METHODS: A literature search was performed by querying SCOPUS, PubMed, Medline and the Cochrane Central Register for Controlled Trials from database inception through May 2023 according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Inclusion criteria were level I-IV human studies reporting on outcomes, reoperations and complications following microfracture of the knee at a mean 10-year or greater …

Western Diet Reduces Small Intestinal Intraepithelial Lymphocytes Via Fxr-Interferon Pathway, Chen-Ting Hung, Changqing Ma, Santosh K Panda, Tihana Trsan, Miki Hodel, Jennifer Frein, Amanda Foster, Shengxiang Sun, Hung-Ting Wu, Justin Kern, Richa Mishra, Umang Jain, Marco Colonna, Ta-Chiang Liu, Et Al.

2020-Current year OA Pubs

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL …

Metabolically Active Neutrophils Represent A Permissive Niche For Mycobacterium Tuberculosis, J Tucker Andrews, G V R Krishna Prasad, Jennifer A Philips, Et Al.

2020-Current year OA Pubs

Mycobacterium tuberculosis (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils …

Dopamine-Mediated Interactions Between Short- And Long-Term Memory Dynamics, Cheng Huang, Junjie Luo, Seung Je Woo, Lucas A Roitman, Jizhou Li, Vincent A Pieribone, Madhuvanthi Kannan, Ganesh Vasan, Mark J Schnitzer

2020-Current year OA Pubs

In dynamic environments, animals make behavioural decisions on the basis of the innate valences of sensory cues and information learnt about these cues across multiple timescales

Dominantly Inherited Muscle Disorders: Understanding Their Complexity And Exploring Therapeutic Approaches, Andrew R Findlay

2020-Current year OA Pubs

Treatments for disabling and life-threatening hereditary muscle disorders are finally close to becoming a reality. Research has thus far focused primarily on recessive forms of muscle disease. The gene replacement strategies that are commonly employed for recessive, loss-of-function disorders are not readily translatable to most dominant myopathies owing to the presence of a normal chromosome in each nucleus, hindering the development of novel treatments for these dominant disorders. This is largely due to their complex, heterogeneous disease mechanisms that require unique therapeutic approaches. However, as viral and RNA interference-based therapies enter clinical use, key tools are now in place to …

Pkmyt1 Is A Marker Of Treatment Response And A Therapeutic Target For Cdk4/6 Inhibitor-Resistance In Er+ Breast Cancer, Anran Chen, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast …

Mucosal Adenovirus Vaccine Boosting Elicits Iga And Durably Prevents Xbb.1.16 Infection In Nonhuman Primates, Matthew Gagne, James Brett Case, Igor P Dmitriev, Elena A Kashentseva, Baoling Ying, David T Curiel, Michael S Diamond, Et Al.

2020-Current year OA Pubs

A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1-BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG …

Sequential Early-Life Viral Infections Modulate The Microbiota And Adaptive Immune Responses To Systemic And Mucosal Vaccination, Yuhao Li, Jerome M. Molleston, Crystal Lovato, Jasmine Wright, Isabel Erickson, Duyen Bui, Andrew H. Kim, Harshad Ingle, Somya Aggarwal, Lila S Nolan, Ahmed O. Hassan, Lynne Foster, Michael S. Diamond, Megan T. Baldridge

2020-Current year OA Pubs

Increasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, …

Htlv-1 Infected T Cells Cause Bone Loss Via Small Extracellular Vesicles, Nitin Kumar Pokhrel, Haniya Habib, Shamreethaa Seeniraj, Ancy Joseph, Daniel Rauch, Linda Cox, Robert Sprung, Petra Erdmann Gilmore, Qiang Zhang, Robert Reid Townsend, Lee Ratner, Katherine N Weilbaecher, Deborah J Veis, Et Al.

2020-Current year OA Pubs

Adult T cell leukaemia (ATL), caused by infection with human T- lymphotropic virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV/T leads to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV/T cells persisted in the bone. To study the direct effect of HTLV/T and ATL-PDX on osteoclasts, supernatants were added to murine and human osteoclast …

Neuroimmune Interactions In The Development And Chronification Of Migraine Headache, Jintao Zhang, Roli Simoes, Tingting Guo, Yu-Qing Cao

2020-Current year OA Pubs

Migraine is highly prevalent and debilitating. The persistent headaches in this condition are thought to arise from the activation and sensitization of the trigeminovascular pathway. Both clinical and animal model studies have suggested that neuroimmune interactions contribute to the pathophysiology of migraine headache. In this review, we first summarize the findings from human studies implicating the dysregulation of the immune system in migraine, including genetic analyses, measurement of circulatory factors, and neuroimaging data. We next discuss recent advances from rodent studies aimed at elucidating the neuroimmune interactions that manifest at various levels of the trigeminovascular pathway and lead to the …

Three Classes Of Propofol Binding Sites On Gabaa Receptors, Zi-Wei Chen, Satyanarayana M Chintala, John Bracamontes, Yusuke Sugasawa, Spencer R Pierce, Balazs R Varga, Edward H Smith, Christopher J Edge, Nicholas P Franks, Wayland W L Cheng, Gustav Akk, Alex S Evers

2020-Current year OA Pubs

Propofol is a widely used anesthetic and sedative that acts as a positive allosteric modulator of gamma-aminobutyric acid type A (GABA

New Insights Into Innate Immunity In Alzheimer's Disease: From Apoe Protective Variants To Therapies, Yun Chen, David M Holtzman

2020-Current year OA Pubs

Recent discoveries of rare variants of human APOE may shed light on novel therapeutic strategies for Alzheimer's disease (AD). Here, we highlight the newly identified protective variant [APOE3 Christchurch (APOE3ch, R136S)] as an example. We summarize human AD and mouse amyloidosis and tauopathy studies from the past 5 years that have been associated with this R136S variant. We also propose a potential mechanism for how this point mutation might lead to protection against AD pathology, from the molecular level, to cells, to mouse models, and potentially, to humans. Lastly, we extend our discussion of the recent insights gained regarding different …

Evaluation Of Forces Applied To Tissues During Robotic-Assisted Surgical Tasks Using A Novel Force Feedback Technology, Michael M Awad, Mathew C Raynor, Mika Padmanabhan-Kabana, Lana Y Schumacher, Jeffrey A Blatnik

2020-Current year OA Pubs

BACKGROUND: The absence of force feedback (FFB) is considered a technical limitation in robotic-assisted surgery (RAS). This pre-clinical study aims to evaluate the forces applied to tissues using a novel integrated FFB technology, which allows surgeons to sense forces exerted at the instrument tips.

METHODS: Twenty-eight surgeons with varying experience levels employed FFB instruments to perform three robotic-assisted surgical tasks, including retraction, dissection, and suturing, on inanimate or ex-vivo models, while the instrument sensors recorded and conveyed the applied forces to the surgeon hand controllers of the robotic system. Generalized Estimating Equations (GEE) models were used to analyze the mean …

Negative Effect Of Treatment With Mglur5 Negative Allosteric Modulator Afq056 On Blood Biomarkers In Young Individuals With Fragile X Syndrome, Dragana Protic, Stephanie Morris, Et Al.

2020-Current year OA Pubs

BACKGROUND: Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show …

Inorganic Polyphosphate Promotes Colorectal Cancer Growth Via Trpm8 Receptor Signaling Pathway, Valentina Arrè, Chen Shen, Et Al.

2020-Current year OA Pubs

BACKGROUND: Colorectal cancer (CRC) is characterized by a pro-inflammatory microenvironment and features high-energy-supply molecules that assure tumor growth. A still less studied macromolecule is inorganic polyphosphate (iPolyP), a high-energy linear polymer that is ubiquitous in all forms of life. Made up of hundreds of repeated orthophosphate units, iPolyP is essential for a wide variety of functions in mammalian cells, including the regulation of proliferative signaling pathways. Some evidence has suggested its involvement in carcinogenesis, although more studies need to be pursued. Moreover, iPolyP regulates several homeostatic processes in animals, spanning from energy metabolism to blood coagulation and tissue regeneration.

RESULTS: …

Safety Of Dostarlimab In Combination With Chemotherapy In Patients With Primary Advanced Or Recurrent Endometrial Cancer In A Phase Iii, Randomized, Placebo-Controlled Trial (Engot-En6-Nsgo/Gog-3031/Ruby), Annika Auranen, Matthew A Powell, Et Al.

2020-Current year OA Pubs

BACKGROUND: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin-paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting.

OBJECTIVES: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial.

DESIGN: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared …

Massively Parallel Characterization Of Insulator Activity Across The Genome, Clarice K Y Hong, Yawei Wu, Alyssa A Erickson, Jie Li, Arnold J Federico, Barak A Cohen

2020-Current year OA Pubs

A key question in regulatory genomics is whether cis-regulatory elements (CREs) are modular elements that can function anywhere in the genome, or whether they are adapted to certain genomic locations. To distinguish between these possibilities we develop MPIRE (Massively Parallel Integrated Regulatory Elements), a technology for recurrently assaying CREs at thousands of defined locations across the genome in parallel. MPIRE allows us to separate the intrinsic activity of CREs from the effects of their genomic environments. We apply MPIRE to assay three insulator sequences at thousands of genomic locations and find that each insulator functions in locations with distinguishable properties. …