Digital Commons Network^™

Cxcl16-Dependent Scavenging Of Oxidized Lipids By Islet Macrophages Promotes Differentiation Of Pathogenic Cd8+ T Cells In Diabetic Autoimmunity, Neetu Srivastava, Hao Hu, Orion J Peterson, Anthony N Vomund, Marta Stremska, Mohammad Zaman, Shilpi Giri, Tiandao Li, Cheryl F Lichti, Pavel N Zakharov, Bo Zhang, Nada A Abumrad, Yi-Guang Chen, Kodi S Ravichandran, Emil R Unanue, Xiaoxiao Wan

2020-Current year OA Pubs

The pancreatic islet microenvironment is highly oxidative, rendering β cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Tex

Attenuating Midline Thalamus Bursting To Mitigate Absence Epilepsy, Ping Dong, Konstantin Bakhurin, Yuhui Li, Mohamad A Mikati, Jianmin Cui, Warren M Grill, Henry H Yin, Huanghe Yang

2020-Current year OA Pubs

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, …

Where Are We Now With Oncolytic Viruses In Melanoma And Nonmelanoma Skin Malignancies?, George Nassief, Angela Anaeme, Karen Moussa, David Chen, George Ansstas

2020-Current year OA Pubs

Skin cancer prognosis has greatly improved recently due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients with advanced skin cancer still experience immunotherapy resistance and disease progression during ICI treatment, thus calling for novel therapeutics which address this treatment gap. Talimogene laherparepvec (T-VEC) has gained popularity in recent years as a viable treatment option for patients with skin cancer. In preclinical studies, T-VEC demonstrated both a direct anti-tumor effect in injected lesions as well as a systemic immune-mediated effect in non-injected lesions, which could pose additional benefits when combined with ICI therapy. Following promising results from the …

Progenitors Of Distinct Lineages Shape The Diversity Of Mature Type 2 Conventional Dendritic Cells, Patrick Fernandes Rodrigues, Tihana Trsan, Grozdan Cvijetic, Darya Khantakova, Santosh K Panda, Zhaoyuan Liu, Florent Ginhoux, Marina Cella, Marco Colonna

2020-Current year OA Pubs

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8

Defining Primary Refractory Large B-Cell Lymphoma, Allison M Bock, Brad S Kahl, Et Al.

2020-Current year OA Pubs

Patients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have "primary refractory disease." However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological …

Displace Study Shows Poor Quality Of Transcranial Doppler Ultrasound For Stroke Risk Screening In Sickle Cell Anemia, Kimberly A Davidow, Robin E Miller, Shannon M Phillips, Alyssa M Schlenz, Martina Mueller, Monica L Hulbert, Lewis L Hsu, Neha Bhasin, Robert J Adams, Julie Kanter

2020-Current year OA Pubs

Children with sickle cell anemia (SCA) are at increased risk of stroke when compared with their age-based counterparts. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) previously demonstrated that with the use of transcranial Doppler ultrasound (TCD; Sickle Stroke Screen) and chronic red cell transfusion, the risk of stroke is reduced by over 90%. The STOP criteria detailed the type and method of measurement required; the time-averaged mean maximum velocity (TAMMV). Unfortunately, it has been difficult to adhere to the appropriate TAMMV measurements. The objectives of this study were to assess the quality of TCD and transcranial Doppler imaging …

Unraveling Facets Of Mecom-Associated Syndrome: Somatic Genetic Rescue, Clonal Hematopoiesis, And Phenotype Expansion, Parvathy Venugopal, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

No abstract provided.

The Cns Relapse In T-Cell Lymphoma Index Predicts Cns Relapse In Patients With T- And Nk-Cell Lymphomas, Rahul S Bhansali, Neha Mehta-Shah, Et Al.

2020-Current year OA Pubs

Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. …

Multi-Scale Signaling And Tumor Evolution In High-Grade Gliomas, Jingxian Liu, Song Cao, Yize Li, Ilya Strunilin, Andrew Shinkle, Nataly Naser Al Deen, Wagma Caravan, Andrew Houston, Faria Anjum Simin, Matthew A Wyczalkowski, Liang-Bo Wang, Erik Storrs, Siqi Chen, Ritvik Illindala, Yuping D Li, Reyka G Jayasinghe, Austin N Southard-Smith, Yang E Li, Rita Jui-Hsien Lu, Feng Chen, Milan G Chheda, Li Ding, Et Al.

2020-Current year OA Pubs

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream …

Cell-Specific Single Viral Vector Crispr/Cas9 Editing And Genetically Encoded Tool Delivery In The Central And Peripheral Nervous Systems, Jamie C Moffa, India N Bland, Jessica R Tooley, Vani Kalyanaraman, Monique Heitmeier, Meaghan C Creed, Bryan A Copits

2020-Current year OA Pubs

CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function and can be combined with genetically encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs). To overcome these constraints, we developed an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific …

Rate Of Abnormalities In Quantitative Mr Neuroimaging Of Persons With Chronic Traumatic Brain Injury, Farzaneh Rahmani, Richard D Batson, Alexandra Zimmerman, Samir Reddigari, Erin D Bigler, Shawn C Lanning, Eveline Ilasa, Jordan H Grafman, Hanzhang Lu, Alexander P Lin, Cyrus A Raji

2020-Current year OA Pubs

BACKGROUND: Mild traumatic brain injury (mTBI) can result in lasting brain damage that is often too subtle to detect by qualitative visual inspection on conventional MR imaging. Although a number of FDA-cleared MR neuroimaging tools have demonstrated changes associated with mTBI, they are still under-utilized in clinical practice.

METHODS: We investigated a group of 65 individuals with predominantly mTBI (60 mTBI, 48 due to motor-vehicle collision, mean age 47 ± 13 years, 27 men and 38 women) with MR neuroimaging performed in a median of 37 months post-injury. We evaluated abnormalities in brain volumetry including analysis of left-right asymmetry by …

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Ascending Dose Study To Evaluate The Safety, Tolerability, Pharmacokinetics (Pk) And Pharmacodynamic (Pd) Effects Of Posiphen In Subjects With Early Alzheimer's Disease, Douglas Galasko, Martin R Farlow, Brendan P Lucey, Lawrence S Honig, Donald Elbert, Randall Bateman, Jeremiah Momper, Ronald G Thomas, Robert A Rissman, Judy Pa, Vahan Aslanyan, Archana Balasubramanian, Tim West, Maria Maccecchini, Howard H Feldman

2020-Current year OA Pubs

BACKGROUND: Amyloid beta protein (Aβ) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.

METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by …

Oral Sebetralstat For On-Demand Treatment Of Hereditary Angioedema Attacks, Marc A Riedl, H James Wedner, Et Al.

2020-Current year OA Pubs

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy.

METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the …

Evaluating The Quality Of Serial Em Sections With Deep Learning, Mahsa Bank Tavakoli, Josh L Morgan

2020-Current year OA Pubs

Automated image acquisition can significantly improve the throughput of serial section scanning electron microscopy (ssSEM). However, image quality can vary from image to image depending on autofocusing and beam stigmation. Automatically evaluating the quality of images is, therefore, important for efficiently generating high-quality serial section scanning electron microscopy (ssSEM) datasets. We tested several convolutional neural networks for their ability to reproduce user-generated evaluations of ssSEM image quality. We found that a modification of ResNet-50 that we term quality evaluation Network (QEN) reliably predicts user-generated quality scores. Running QEN in parallel to ssSEM image acquisition therefore allows users to quickly identify …

Shp2 As A Primordial Epigenetic Enzyme Expunges Histone H3 Ptyr-54 To Amend Androgen Receptor Homeostasis, Surbhi Chouhan, Dhivya Sridaran, Cody Weimholt, Jingqin Luo, Tiandao Li, Kiran Mahajan, Nupam P Mahajan, Et Al.

2020-Current year OA Pubs

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors …

Ledoxy-Sl: A Placebo-Controlled, Double-Blind, Randomized, 24-Month Trial Of Six Weeks Of Daily Doxycycline Plus Hygiene-Based Essential Care For Reducing Progression Of Filarial Lymphedema In Sri Lanka, Thishan Channa Yahathugoda, Nirmitha Lalindi De Silva, Janaka Ruben, Sharmini Gunawardena, Mirani Vasanthamala Weerasooriya, John Horton, Philip Budge, Eric Ottesen, Sarah Mary Sullivan, Mariana Stephens, John Shen, Ute Klarmann-Schulz, Achim Hoerauf, Joseph Patrick Shott, Charles Mackenzie

2020-Current year OA Pubs

Morbidity management of filarial lymphedema remains a challenge even during the post-lymphatic filariasis elimination era in Sri Lanka despite provision of the predominantly hygiene-based WHO Essential Package of Care. Because prior studies have suggested that 6 weeks of doxycycline may reduce progression of limb lymphedema, we conducted a randomized, placebo-controlled, superiority study to evaluate this possibility in Sri Lanka. Patients aged 14 to 65 years with lymphedema in one or both legs received either 200 mg of doxycycline daily for 6 weeks or matching placebo. The primary efficacy endpoint was improvement or lack of progression in lymphedema stage at 24 …

Task And Stimulus Coding In The Multiple-Demand Network, Sneha Shashidhara, Moataz Assem, Matthew F Glasser, John Duncan

2020-Current year OA Pubs

In the human brain, a multiple-demand (MD) network plays a key role in cognitive control, with core components in lateral frontal, dorsomedial frontal and lateral parietal cortex, and multivariate activity patterns that discriminate the contents of many cognitive activities. In prefrontal cortex of the behaving monkey, different cognitive operations are associated with very different patterns of neural activity, while details of a particular stimulus are encoded as small variations on these basic patterns (Sigala et al, 2008). Here, using the advanced fMRI methods of the Human Connectome Project and their 360-region cortical parcellation, we searched for a similar result in …

A "Prime And Expand" Strategy Using The Multifunctional Fusion Proteins To Generate Memory-Like Nk Cells For Cell Therapy, Niraj Shrestha, Michelle Becker-Hapak, Mark Foster, Ethan Mcclain, Melissa M Berrien-Elliott, Todd A Fehniger, Et Al.

2020-Current year OA Pubs

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold …

O-Glcnacylation Of Mitf Regulates Its Activity And Cdk4/6 Inhibitor Resistance In Breast Cancer, Yi Zhang, Shuyan Zhou, Yan Kai, Ya-Qin Zhang, Changmin Peng, Zhuqing Li, Muhammad Jameel Mughal, Belmar Julie, Xiaoyan Zheng, Junfeng Ma, Cynthia X Ma, Min Shen, Matthew D Hall, Shunqiang Li, Wenge Zhu

2020-Current year OA Pubs

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or …

Pathogenic Variants In Autism Gene Katnal2 Cause Hydrocephalus And Disrupt Neuronal Connectivity By Impairing Ciliary Microtubule Dynamics, Tyrone Despenza, Shujuan Zhao, Sheng Chih Jin, Et Al.

2020-Current year OA Pubs

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD).

Assessment Of Patient-Derived Xenograft Growth And Antitumor Activity: The Nci Pdxnet Consensus Recommendations, Funda Meric-Bernstam, Ramaswamy Govinden, Li Ding, Ryan Fields, Et Al.

2020-Current year OA Pubs

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification …

A Pan-Cancer Patient-Derived Xenograft Histology Image Repository With Genomic And Pathologic Annotations Enables Deep Learning Analysis, Brian S White, R Jay Mashl, Sherri R Davies, Ryan C Fields, Jacqueline L Mudd, Ramaswamy Govindan, Shunqiang Li, Li Ding, Et Al.

2020-Current year OA Pubs

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a …

Validating A Curvature-Based Marker Of Cervical Carotid Tortuosity For Risk Assessment In Heritable Aortopathies, Jin Vivian Lee, Anna L Huguenard, Ralph G Dacey, Alan C Braverman, Joshua W Osbun

2020-Current year OA Pubs

BACKGROUND: Cervical arterial tortuosity is associated with adverse outcomes in Loeys-Dietz syndrome and other heritable aortopathies.

METHODS AND RESULTS: A method to assess tortuosity based on curvature of the vessel centerline in 3-dimensional space was developed. We measured cervical carotid tortuosity in 65 patients with Loeys-Dietz syndrome from baseline computed tomography angiogram/magnetic resonance angiogram and all serial images during follow-up. Relations between baseline carotid tortuosity, age, aortic root diameter, and its change over time were compared. Patients with unoperated aortic roots were assessed for clinical end point (type A aortic dissection or aortic root surgery during 4 years of follow-up). …

Baseline Levels And Longitudinal Changes In Plasma Aβ42/40 Among Black And White Individuals, Chengjie Xiong, Jingqin Luo, Rachel L Henson, Tammie L S Benzinger, Quoc Bui, Folasade Agboola, Elizabeth Grant, Emily N Gremminger, Krista L Moulder, Ganesh Babulal, Carlos Cruchaga, David M Holtzman, Randall J Bateman, John C Morris, Suzanne E Schindler, Et Al.

2020-Current year OA Pubs

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C

Identification Of Unique Cell Type Responses In Pancreatic Islets To Stress, Marlie M Maestas, Matthew Ishahak, Punn Augsornworawat, Daniel A Veronese-Paniagua, Kristina G Maxwell, Leonardo Velazco-Cruz, Erica Marquez, Jiameng Sun, Mira Shunkarova, Sarah E Gale, Fumihiko Urano, Jeffrey R Millman

2020-Current year OA Pubs

Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that …

Poglut2/3 Double Knockout In Mice Results In Neonatal Lethality With Reduced Levels Of Fibrillin In Lung Tissues, Sanjiv Neupane, Daniel B Williamson, Robyn A Roth, Carmen M Halabi, Robert S Haltiwanger, Bernadette C Holdener

2020-Current year OA Pubs

Fibrillin microfibrils play a critical role in the formation of elastic fibers, tissue/organ development, and cardiopulmonary function. These microfibrils not only provide structural support and flexibility to tissues, but they also regulate growth factor signaling through a plethora of microfibril-binding proteins in the extracellular space. Mutations in fibrillins are associated with human diseases affecting cardiovascular, pulmonary, skeletal, and ocular systems. Fibrillins consist of up to 47 epidermal growth factor-like repeats, of which more than half are modified by protein O-glucosyltransferase 2 (POGLUT2) and/or POGLUT3. Loss of these modifications reduces secretion of N-terminal fibrillin constructs overexpressed in vitro. Here, we investigated …

Il2 Targeted To Cd8+ T Cells Promotes Robust Effector T-Cell Responses And Potent Antitumor Immunity, Kelly D Moynihan, Hussein Sultan, Robert D Schreiber, Et Al.

2020-Current year OA Pubs

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells …

Tumor-Immune Signatures Of Treatment Resistance To Brentuximab Vedotin With Ipilimumab And/Or Nivolumab In Hodgkin Lymphoma, Edgar Gonzalez-Kozlova, Brad S Kahl, Et Al.

2020-Current year OA Pubs

UNLABELLED: To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed …

Evaluation Of Markers Of Immunity In Different Metastatic Immune Microenvironments Suggests More Suppression Within Breast To Liver Metastases In Breast Cancer, Robert Hsu, Foluso O Ademuyiwa, Et Al.

2020-Current year OA Pubs

PURPOSE: Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease.

METHODS: 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell …

Pharmacokinetic Modeling Of The Effect Of Tariquidar On Ondansetron Disposition Into The Central Nervous System, Manting Chiang, Hyunmoon Back, Jong Bong Lee, Sarah Oh, Tiffany Guo, Simone Girgis, Celine Park, Simon Haroutounian, Leonid Kagan

2020-Current year OA Pubs

PURPOSE: Serotonin (5-HT

METHODS: Ondansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data.

RESULTS: The results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination. …