Digital Commons Network^™

Comprehensive Characterization Of The Multiple Myeloma Immune Microenvironment Using Integrated Scrna-Seq, Cytof, And Cite-Seq Analysis, Lijun Yao, Reyka G Jayasinghe, Mark A Fiala, Michael C Wendl, Stephen T Oh, John F Dipersio, Ravi Vij, Li Ding

2020-Current year OA Pubs

UNLABELLED: As part of the Multiple Myeloma Research Foundation (MMRF) immune atlas pilot project, we compared immune cells of multiple myeloma bone marrow samples from 18 patients assessed by single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to understand the concordance of measurements among single-cell techniques. Cell type abundances are relatively consistent across the three approaches, while variations are observed in T cells, macrophages, and monocytes. Concordance and correlation analysis of cell type marker gene expression across different modalities highlighted the importance of choosing cell type marker genes best suited to …

Gynecologic Oncology Patient Perspectives And Knowledge On Advance Care Planning: A Quality Improvement Intervention, Sarah P. Huepenbecker, Sophia Lewis, Mark C. Valentine, Marguerite L. Palisoul, Premal H. Thaker, Andrea R. Hagemann, Carolyn K. Mccourt, Katherine C. Fuh, Matthew A. Powell, David G. Mutch, Lindsay M. Kuroki

2020-Current year OA Pubs

OBJECTIVES: Assess and improve advance care planning (ACP) awareness and uptake among gynecologic oncology patients.

METHODS: Using a quality improvement Plan-Do-Check-Act framework, we completed a single institution needs assessment and intervention. The needs assessment was a 26-question survey assessing baseline ACP knowledge and preferences of gynecologic oncology patients. We used this survey to implement an outpatient intervention in which patients were offered ACP resources (pamphlet, discussion with their gynecologic oncologist, and/or social work referral). We conducted a post-intervention survey among patients who had and had not received ACP resource(s) to assess whether our intervention increased ACP knowledge, discussions, or uptake. …

Stress Radiography Is A Reliable Method To Quantify Posterior Cruciate Ligament Insufficiency: A Systematic Review, J. Jared Guth, Robert H. Brophy, Matthew J. Matava, R. Garrett Steinmetz, Matthew V. Smith

2020-Current year OA Pubs

PURPOSE: To perform a systematic review of posterior tibial stress radiography techniques and radiographic measurement methods to compare their accuracy and efficacy to aid clinicians in quantifying posterior cruciate ligament laxity.

METHODS: Electronic databases, including PubMed, MEDLINE, Embase.com 1947- , Ovid Medline 1946- , Scopus 1823- , Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov 1997- were queried in December 2020. The abstracts of articles were reviewed by 2 authors for published studies comparing posterior tibial stress radiography techniques, describing, and comparing radiographic measurement methods, and comparing stress radiographs with instrumented knee testing.

RESULTS: The systematic review included 13 …

Telomere Biology Disorders: Time For Moving Towards The Clinic?, Luis F Z Batista, Inderjeet Dokal, Roy Parker

2020-Current year OA Pubs

Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and …

Evaluating Brain Damage In Multiple Sclerosis With Simultaneous Multi-Angular-Relaxometry Of Tissue, Biao Xiang, Jie Wen, Robert E Schmidt, Alexander L Sukstanskii, Daniel Mamah, Dmitriy A Yablonskiy, Anne H Cross

2020-Current year OA Pubs

OBJECTIVE: Multiple sclerosis (MS) is a common demyelinating central nervous system disease. MRI methods that can quantify myelin loss are needed for trials of putative remyelinating agents. Quantitative magnetization transfer MRI introduced the macromolecule proton fraction (MPF), which correlates with myelin concentration. We developed an alternative approach, Simultaneous-Multi-Angular-Relaxometry-of-Tissue (SMART) MRI, to generate MPF. Our objective was to test SMART-derived MPF metric as a potential imaging biomarker of demyelination.

METHODS: Twenty healthy control (HC), 11 relapsing-remitting MS (RRMS), 22 progressive MS (PMS), and one subject with a biopsied tumefactive demyelinating lesion were scanned at 3T using SMART MRI. SMART-derived MPF metric …

Phase Ib Study Of Eprenetapopt (Apr-246) In Combination With Pembrolizumab In Patients With Advanced Or Metastatic Solid Tumors, H Park, Et Al.

2020-Current year OA Pubs

BACKGROUND: We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938).

PATIENTS AND METHODS: For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with …

Multi-Modulated Frequency Domain High Density Diffuse Optical Tomography, Guy A. Perkins, Adam T. Eggebrecht, Hamid Dehghani

2020-Current year OA Pubs

No abstract provided.

Quantitative Single-Cell Analysis Of Leishmania Major Amastigote Differentiation Demonstrates Variably Extended Expression Of The Lipophosphoglycan (Lpg) Virulence Factor In Different Host Cell Types, Michael A. Mandell, Wandy L. Beatty, Stephen M. Beverley

2020-Current year OA Pubs

Immediately following their deposition into the mammalian host by an infected sand fly vector, Leishmania parasites encounter and are engulfed by a variety of cell types. From there, parasites may transit to other cell types, primarily macrophages or dendritic cells, where they replicate and induce pathology. During this time, Leishmania cells undergo a dramatic transformation from the motile non-replicating metacyclic stage to the non-motile replicative amastigote stage, a differentiative process that can be termed amastigogenesis. To follow this at the single cell level, we identified a suite of experimental 'landmarks' delineating different stages of amastigogenesis qualitatively or quantitatively, including new …

Choline, Dha, And Diarrheal Disease Associated With Growth Faltering In A Case-Control Study, Jenna N Diaz, Sherlie Jean Louis Dulience, Noah Wolthausen, Xuntian Jiang, Emmanuel Gyimah, Francesca J Marhône Pierre, F Matthew Kuhlmann, Lora L Iannotti

2020-Current year OA Pubs

BACKGROUND: Children with recurrent infectious diarrhea are susceptible to growth faltering. DHA and choline may play a role in this relationship due to their involvement in lipid metabolism, gut immunity, and inflammatory pathways.

OBJECTIVES: This study aimed to characterize the contributions made by DHA and choline status and enteric damage in young children in the association between diarrheal illness and child growth.

METHODS: A longitudinal case-control study was conducted among children aged 6-36 mo (

RESULTS: At baseline, mean plasma DHA concentrations (1.03 µg/mL; 95% CI: 0.91, 1.15) were not significantly different between cases and controls, nor was there a …

Early Preclinical Experience Of A Mixed Reality Ultrasound System With Active Guidance For Needle-Based Interventions: The Guide Study, David Bloom, Jamie N Colombo, Nathan Miller, Michael K Southworth, Christopher Andrews, Alexander Henry, William B Orr, Jonathan R Silva, Jennifer N Avari Silva

2020-Current year OA Pubs

BACKGROUND: Use of ultrasound (US) to facilitate vascular access has increased compared to landmark-based procedures despite ergonomic challenges and need for extrapolation of 2-dimensional images to understand needle position. The MantUS™ system (Sentiar, Inc.,) uses a mixed reality (MxR) interface to display US images and integrate real-time needle tracking.

OBJECTIVE: The purpose of this prospective preclinical study was to evaluate the feasibility and usability of MantUS in a simulated environment.

METHODS: Participants were recruited from pediatric cardiology and critical care. Access was obtained in 2 vascular access training models: a femoral access model and a head and neck model for …

Sweat Icu-An Observational Study Of Physician Workload And The Association Of Physician Outcomes In Academic Icus, Ankita Agarwal, Patrick G. Lyons, Et Al.

2020-Current year OA Pubs

UNLABELLED: The optimal staffing model for physicians in the ICU is unknown. Patient-to-intensivist ratios may offer a simple measure of workload and be associated with patient mortality and physician burnout. To evaluate the association of physician workload, as measured by the patient-to-intensivist ratio, with physician burnout and patient mortality.

DESIGN: Cross-sectional observational study.

SETTING: Fourteen academic centers in the United States from August 2020 to July 2021.

SUBJECTS: We enrolled ICU physicians and collected data on adult ICU patients under the physician's care on the single physician-selected study day for each physician.

MEASUREMENTS AND MAIN RESULTS: The primary exposure was …

Semiautomated Analysis Of An Optical Atp Indicator In Neurons, Taher Dehkharghanian, Arsalan Hashemiaghdam, Ghazaleh Ashrafi

2020-Current year OA Pubs

No abstract provided.

Paediatrician's Guide To Post-Operative Care For Functionally Univentricular Chd: A Review, Christina Ronai, Sarosh P Batlivala, Quang-Tuyen Nguyen, Markus S Renno, Lindsay Arthur, Julie Glickstein, Jonathan N Johnson, Jacob R Miller, Carolyn A Altman, Elif Seda Selamet Tierney

2020-Current year OA Pubs

IMPORTANCE: Single ventricle CHD affects about 5 out of 100,000 newborns, resulting in complex anatomy often requiring multiple, staged palliative surgeries. Paediatricians are an essential part of the team that cares for children with single ventricle CHD. These patients often encounter their paediatrician first when a complication arises, so it is critical to ensure the paediatrician is knowledgeable of these issues to provide optimal care.

OBSERVATIONS: We reviewed the subtypes of single ventricle heart disease and the various palliative surgeries these patients undergo. We then searched the literature to detail the general paediatrician's approach to single ventricle patients at different …

Congenital Aneurysm Of The Muscular Interventricular Septum Associated With Bifascicular Block, Hoang H. Nguyen, Patrick Y. Jay

2020-Current year OA Pubs

Isolated congenital aneurysm of the muscular interventricular septum is rare. We present a patient with congenital aneurysm of the basal muscular ventricular septum, who also develops conduction abnormalities with first-degree heart block, right bundle branch block, and left posterior fascicular block. The case details the natural history of the aneurysm over a 10-year period follow-up during which the patient remained asymptomatic with evidence of regression of the aneurysm. Given the aneurysm's location close to the proximal right bundle and left posterior fascicle, we believe that the cause for the aneurysm also injured both fascicles resulting in bifascicular block. The diagnosis …

The Inner Nuclear Membrane Protein Nemp1 Supports Nuclear Envelope Openings And Enucleation Of Erythroblasts, Didier Hodzic, Jun Wu, Karen Krchma, Andrea Jurisicova, Yonit Tsatskis, Yijie Liu, Peng Ji, Kyunghee Choi, Helen Mcneill

2020-Current year OA Pubs

Nuclear envelope membrane proteins (NEMPs) are a conserved family of nuclear envelope (NE) proteins that reside within the inner nuclear membrane (INM). Even though Nemp1 knockout (KO) mice are overtly normal, they display a pronounced splenomegaly. This phenotype and recent reports describing a requirement for NE openings during erythroblasts terminal maturation led us to examine a potential role for Nemp1 in erythropoiesis. Here, we report that Nemp1 KO mice show peripheral blood defects, anemia in neonates, ineffective erythropoiesis, splenomegaly, and stress erythropoiesis. The erythroid lineage of Nemp1 KO mice is overrepresented until the pronounced apoptosis of polychromatophilic erythroblasts. We show …

Functional Characterization Of Enhancer Activity During A Long Terminal Repeat's Evolution, Alan Y Du, Xiaoyu Zhuo, Vasavi Sundaram, Nicholas O Jensen, Hemangi G Chaudhari, Nancy L Saccone, Barak A Cohen, Ting Wang

2020-Current year OA Pubs

Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements. However, TEs are rarely functionally tested for regulatory activity, which in turn limits our understanding of how TE regulatory activity has evolved. We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1- and CEBP-related binding motifs as drivers of enhancer activity. Functional analysis of evolutionarily reconstructed ancestral sequences revealed that LTR18A elements have generally lost regulatory activity over time through sequence changes, with the largest effects occurring owing to mutations in the AP-1 and CEBP …

Peristaltic Pumps Adapted For Laminar Flow Experiments Enhance In Vitro Modeling Of Vascular Cell Behavior, Javier Abello, Shreya Raghavan, Yvette Y. Yien, Amber N. Stratman

2020-Current year OA Pubs

Endothelial cells (ECs) are the primary cellular constituent of blood vessels that are in direct contact with hemodynamic forces over their lifetime. Throughout the body, vessels experience different blood flow patterns and rates that alter vascular architecture and cellular behavior. Because of the complexities of studying blood flow in an intact organism, particularly during development, the field has increasingly relied on in vitro modeling of blood flow as a powerful technique for studying hemodynamic-dependent signaling mechanisms in ECs. While commercial flow systems that recirculate fluids exist, many commercially available pumps are peristaltic and best model pulsatile flow conditions. However, there …

Calciphylaxis Arising Following Bariatric Surgery: A Case Series, Bethany Cucka, Bianca Biglione, Lauren Ko, Emily D Nguyen, Charbel C Khoury, Sagar U Nigwekar, Malcolm K Robinson, Daniela Kroshinsky

2020-Current year OA Pubs

No abstract provided.

Margetuximab With Retifanlimab As First-Line Therapy In Her2+/Pd-L1+ Unresectable Or Metastatic Gastroesophageal Adenocarcinoma: Mahogany Cohort A, D. V. T. Catenacci, H. Park, Et Al.

2020-Current year OA Pubs

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA.

PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort …

Incisionless Targeted Adeno-Associated Viral Vector Delivery To The Brain By Focused Ultrasound-Mediated Intranasal Administration, Dezhuang Ye, Jinyun Yuan, Yaoheng Yang, Yimei Yue, Zhongtao Hu, Siaka Fadera, Hong Chen

2020-Current year OA Pubs

BACKGROUND: Adeno-associated viral (AAV) vectors are currently the leading platform for gene therapy with the potential to treat a variety of central nervous system (CNS) diseases. There are numerous methods for delivering AAVs to the CNS, such as direct intracranial injection (DI), intranasal delivery (IN), and intravenous injection with focused ultrasound-induced blood-brain barrier disruption (FUS-BBBD). However, non-invasive and efficient delivery of AAVs to the brain with minimal systemic toxicity remain the major challenge. This study aims to investigate the potential of focused ultrasound-mediated intranasal delivery (FUSIN) in AAV delivery to brain.

METHODS: Mice were intranasally administered with AAV5 encoding enhanced …

Neuroinflammation And Covid-19, Abigail Vanderheiden, Robyn S. Klein

2020-Current year OA Pubs

Coronavirus disease 2019 (COVID-19) has caused a historic pandemic of respiratory disease. COVID-19 also causes acute and post-acute neurological symptoms, which range from mild, such as headaches, to severe, including hemorrhages. Current evidence suggests that there is no widespread infection of the central nervous system (CNS) by SARS-CoV-2, thus what is causing COVID-19 neurological disease? Here, we review potential immunological mechanisms driving neurological disease in COVID-19 patients. We begin by discussing the implications of imbalanced peripheral immunity on CNS function. Next, we examine the evidence for dysregulation of the blood-brain barrier during SARS-CoV-2 infection. Last, we discuss the role myeloid …

Ischemic Dual Papillary Muscle Rupture In A Postpartum Patient With Vascular Ehlers-Danlos Syndrome, J. Mark Erfe, Paul Devlin, Jonathan Rich, Lisa Wilsbacher, Daniel Schimmel, Patrick Mccarthy, Amit Pawale

2020-Current year OA Pubs

No abstract provided.

Tnfr1 Contributes To Activation-Induced Cell Death Of Pathological Cd4+ T Lymphocytes During Ischemic Heart Failure, Vinay Kumar, Rachel Rosenzweig, Suman Asalla, Sarita Nehra, Sumanth D Prabhu, Shyam S Bansal

2020-Current year OA Pubs

CD4

Six-Year Results From Relevance: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed By Rituximab Maintenance In Untreated Advanced Follicular Lymphoma, Franck Morschhauser, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

No abstract provided.

Neoadjuvant Atezolizumab For Resectable Non-Small Cell Lung Cancer: An Open-Label, Single-Arm Phase Ii Trial, Jamie E Chaft, G Alexander Patterson, Saiama N Waqar, Et Al.

2020-Current year OA Pubs

In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) …

Targeting Pim2 By Jp11646 Results In Significant Antitumor Effects In Solid Tumors, Eriko Katsuta, Malgorzata Gil-Moore, Justine Moore, Mohamed Yousif, Alex A Adjei, Yi Ding, Justin Caserta, Carmen M Baldino, Kelvin P Lee, Irwin H Gelman, Kazuaki Takabe, Mateusz Opyrchal

2020-Current year OA Pubs

Proviral integration of Moloney virus 2 (PIM2) is a pro‑survival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel pan‑PIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic …

Response To Brentuximab Vedotin By Cd30 Expression In Non-Hodgkin Lymphoma, Deepa Jagadeesh, Steve Horwitz, Nancy L Bartlett, Youn Kim, Eric Jacobsen, Madeleine Duvic, Meredith Little, William Trepicchio, Keenan Fenton, Matthew Onsum, Julie Lisano, Ranjana Advani

2020-Current year OA Pubs

BACKGROUND: The safety and efficacy of brentuximab vedotin (BV), an antibody-drug conjugate directed to the CD30 antigen, has been assessed in several trials in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin lymphoma (NHL). The objective of this research was to examine the relationship between CD30 expression level and clinical response to BV.

PATIENTS AND METHODS: We analyzed response in patients treated with BV monotherapy in 5 prospective clinical studies in relapsed or refractory PTCL, CTCL, or B-cell NHL. CD30 expression was assessed by immunohistochemistry (IHC) using the Ber H2 antibody for 275 patients.

RESULTS: …

A Saturated Map Of Common Genetic Variants Associated With Human Height, Loïc Yengo, E Warwick Daw, Lihua Wang, Mary F. Feitosa, Michael A. Province, Dabeeru C. Rao, Adam E. Locke, Et Al.

2020-Current year OA Pubs

No abstract provided.

Lung Allograft Standardized Histological Analysis (Lasha) Template: A Research Consensus Proposal, Fiorella Calabrese, Chieh-Yu Lin, Et Al.

2020-Current year OA Pubs

BACKGROUND: Routine monitoring of lung-transplanted patients is crucial for the identification of immunological and non-immunological complications. Determining the etiology of acute allograft dysfunction, particularly in alloimmune-mediated disorders, relies heavily on the lung biopsy with histopathologic analysis. Standardization of the pathologic diagnosis of rejection (e.g., cellular and antibody-mediated) is based on consensus statements and guidelines, indicating the importance of a multidisciplinary approach to achieve a definitive etiological diagnosis. In addition to these statements and guidelines, refinements and standardizations are feasible through systematic analysis morphological, immunophenotypic and molecular alterations observed in transbronchial biopsies. This study is to identify key morphologic features to …

Antimicrobial Stewardship For Sepsis In The Intensive Care Unit: Survey Of Critical Care And Infectious Diseases Physicians, M Cristina Vazquez Guillamet, Jason P Burnham, Maria Pérez, Marin H Kollef, Constantine A Manthous, Donna B Jeffe

2020-Current year OA Pubs

OBJECTIVE: To evaluate the attitudes of infectious diseases (ID) and critical care physicians toward antimicrobial stewardship in the intensive care unit (ICU).

DESIGN: Anonymous, cross-sectional, web-based surveys.

SETTING: Surveys were completed in March-November 2017, and data were analyzed from December 2017 to December 2019.

PARTICIPANTS: ID and critical care fellows and attending physicians.

METHODS: We included 10 demographic and 17 newly developed, 5-point, Likert-scaled items measuring attitudes toward ICU antimicrobial stewardship and transdisciplinary collaboration. Exploratory principal components analysis (PCA) was used for data reduction. Multivariable linear regression models explored demographic and attitudinal variables.

RESULTS: Of 372 respondents, 315 physicians had …