A5070645277- Cancer Immunotherapy and Biomarkers
- Renal cell carcinoma treatment
- Renal and related cancers
- Renal Diseases and Glomerulopathies
- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- T-cell and B-cell Immunology
- Bioinformatics and Genomic Networks
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Cancer Genomics and Diagnostics
- Peptidase Inhibition and Analysis
- Cancer Cells and Metastasis
- Lung Cancer Research Studies
- Lung Cancer Diagnosis and Treatment
- Ferroptosis and cancer prognosis
- Lung Cancer Treatments and Mutations
- Gene expression and cancer classification
- RNA Research and Splicing
- Immune cells in cancer
- RNA modifications and cancer
- Genetic Associations and Epidemiology
- Glycosylation and Glycoproteins Research
- NF-κB Signaling Pathways
- Biomedical Text Mining and Ontologies
AstraZeneca (United States)
2019-2024
AstraZeneca (Japan)
2023
AstraZeneca (Germany)
2022
AstraZeneca (Singapore)
2021
AstraZeneca (Brazil)
2019
University of Arizona
2014-2017
University of Illinois Chicago
2012-2017
Illinois College
2012-2017
University of Illinois Urbana-Champaign
2012-2017
Institute for Medical Informatics and Biostatistics
2016
The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate significant immune-related adverse events suboptimally limiting the doses anti-CTLA4 mAb that used. MEDI5752 a monovalent bispecific antibody designed to suppress pathway and provide modulated favoring enhanced on PD-1+ activated T cells. We show preferentially saturates cells versus PD-1- cells, reducing dose required elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, leads...
Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little known about acquired resistance. Among 1,201 patients non-small cell cancer (NSCLC) treated blockade, resistance common, occurring in >60% of initial responders. Acquired shows differential expression inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable IFNγ response genes. Upregulation genes associated putative routes characterized signatures persistent IFN...
Camelid immunoglobulin variable (IGV) regions were found homologous to their human counterparts; however, the germline V repertoires of camelid heavy and light chains are still incomplete therapeutic potential is only beginning be appreciated. We therefore leveraged publicly available HTG WGS databases Lama pacos Camelus ferus retrieve repertoire genes using IGV as reference. In addition, we amplified IGKV IGLV uncover glama sequenced BAC clones covering part IGK IGL loci. Our in silico...
In addition to producing conventional tetrameric IgGs, camelids have the particularity of a functional homodimeric IgG type lacking L (light) chains and only made up two H (heavy) chains. This nonconventional is characterized by variable constant regions referred as V(H)H C(H)H, respectively, which differ from V(H) C(H) counterparts. Although structural properties IgGs been well investigated, genetic bases involved in their generation are still largely unknown. this study, we organization...
Applying the science of networks to quantify discriminatory impact ICD-9-CM ICD-10-CM transition between clinical specialties.Datasets were Center for Medicaid and Medicare Services mapping files, general equivalence mappings, statewide emergency department billing. Diagnoses represented as nodes their mappings directional relationships. The complex network was synthesized an aggregate simpler motifs tabulation per specialty.We identified five motif categories: identity, class-to-subclass,...
Objectives: Volrustomig (MEDI5752) is a monovalent bispecific antibody (DuetMab) with an Fc-domain engineered to reduce effector function, targeting two clinically validated negative T cell regulators, Programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). The has been designed suppress the PD-1 pathway provide enhanced CTLA4 inhibition in context of PD1 expression, such as PD1+/CTLA4+ activated cells. Our goal was develop validate dual TMDD model by...
V(D)J joining is mediated by RAG recombinase during early B-lymphocyte development in the bone marrow (BM). Activation-induced deaminase initiates isotype switching mature B cells of secondary lymphoid structures. Previous studies questioned strict ontological partitioning these processes. We show that pro-B undergo robust to a subset immunoglobulin H (IgH) isotypes. Chromatin reveal cells, spatial organization Igh locus may restrict this demonstrate BM, and are interchangeably inducible,...
While genome-wide association studies (GWAS) of complex traits have revealed thousands reproducible genetic associations to date, these loci collectively confer very little the heritability their respective diseases and, in general, contributed our understanding underlying disease biology. Physical protein interactions been utilized increase human Mendelian but yet be fully exploited for traits.We hypothesized that interaction modeling GWAS findings could highlight important...
The emergence of precision medicine allowed the incorporation individual molecular data into patient care. Indeed, DNA sequencing predicts somatic mutations in patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but underpowered for marker discovery.'N-of-1-pathways' is a global...
9050 Background: PD-1 and TIGIT are implicated in cancer-related T cell immunosuppression. AZD2936 is a bispecific, humanized IgG1 (triple-mutated to minimize Fc effector function) targeting TIGIT. It has demonstrated encouraging activity compared both anti-PD-1 anti-PD-1/-TIGIT combinations murine models. We report data from dose escalation (Part A) an expansion cohort B) of the first-in-human study ARTEMIDE-01 (NCT04995523). Methods: This open-label, multicenter enrolled pts with advanced...
Abstract In B lymphocytes, Ig class switch recombination (CSR) is induced by activation-induced cytidine deaminase, which initiates a cascade of events leading to DNA double-strand break formation in (S) regions. Resolution breaks proceeds through S–S synaptic complexes. synapsis mediated chromatin loop that spans the C region domain Igh locus. junctions are joined via nonhomologous end joining repair process. CSR occurs an intrachromosomal looping out and deletion mechanism 53BP1 dependent....
Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate individualized treatment decisions, these methods not designed address single-patient transcriptome analyses. We previously developed validated the N-of-1-pathways framework using two methods, Wilcoxon Mahalanobis Distance (MD), for personal analysis derived from a pair of samples single patient. Although, both uncover...
The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study advanced solid malignancies. was administered intravenously once every 2 weeks (Q2W) or 3 at 0.1, 0.5, 2.5, 10 20 mg/kg. Two cohorts received mg/kg week for 4 weeks, then Q2W. All treated 12 months until progression. primary endpoint safety. Secondary endpoints efficacy pharmacokinetics. Exploratory included...
Abstract Motivation: The conventional approach to personalized medicine relies on molecular data analytics across multiple patients. path precision lies with that can discover interpretable single-subject signals (N-of-1). We developed a global framework, N-of-1-pathways, for mechanistic-anchored gene expression analysis. previously employed metric could prioritize the statistical significance of deregulated pathway in single subjects, however, it lacked quantitative interpretability (e.g....
Abstract Engagement of promoters with distal elements in long-range looping interactions has been implicated regulation Ig class switch recombination (CSR). The principles determining the spatial and regulatory relationships among Igh transcriptional remain poorly defined. We examined chromosome conformation C region (CH) loci that are targeted for CSR a cytokine-dependent fashion mature B lymphocytes. Germline transcription (GLT) γ1 ε CH is controlled by two factors, IL-4–inducible STAT6...
Immunoglobulin (Ig) class switch recombination (CSR) is responsible for diversification of antibody effector function during an immune response. This region‐specific event, between repetitive (S) DNA elements, unique to B lymphocytes and induced by activationinduced deaminase (AID). CSR critically dependent on transcription noncoding RNAs across S regions. However, mechanistic insight regarding this process has remained unclear. New studies indicate that long‐range intrachromosomal...
To introduce a disease prognosis framework enabled by robust classification scheme derived from patient-specific transcriptomic response to stimulation.Within an illustrative case study predict asthma exacerbation, we designed stimulation assay that reveals individualized human rhinovirus. Gene expression peripheral blood mononuclear cells was quantified 23 pediatric asthmatic patients and stimulated in vitro with Responses were obtained via the single-subject gene set testing methodology...
Abstract Functionally altered biological mechanisms arising from disease-associated polymorphisms, remain difficult to characterise when those variants are intergenic, or, fall between genes. We sought identify shared downstream by which inter- and intragenic single-nucleotide polymorphisms (SNPs) contribute a specific physiopathology. Using computational modelling of 2 million pairs SNPs drawn genome-wide association studies (GWAS), integrated with expression Quantitative Trait Loci (eQTL)...
Abstract Purpose: MEDI0680 is a humanized anti–programmed cell death-1 (PD-1) antibody, and durvalumab an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity safety plus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal carcinoma who received at least one prior line antiangiogenic therapy. Patients Methods: either (20 mg/kg) (750 mg) or (240 mg),...