Sriram Sridhar - Academia.edu (original) (raw)

Papers by Sriram Sridhar

Cell, 2020

Highlights d Diverse neoantigen predictions on shared genomic data from a global consortium d 37 ... more Highlights d Diverse neoantigen predictions on shared genomic data from a global consortium d 37 out of 608 tested peptide-MHCs are bound by patientmatched T cells d Epitope presentation and recognition characteristics predict immunogenicity d Model-based interventions improve neoantigen prediction

Journal of Cellular and Molecular Medicine, 2020

Randomized controlled trials have shown that blood eosinophil counts are a biomarker that predict... more Randomized controlled trials have shown that blood eosinophil counts are a biomarker that predict the effects of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) patients at increased exacerbation risk. 1,2 The Global initiative for the management of Obstructive Lung Disease (GOLD) report recommends the use of blood eosinophil measurements to

C31. COPD BASIC MECHANISMS, 2020

Additional supporting information may be found online in the Supporting Information section. This... more Additional supporting information may be found online in the Supporting Information section. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Journal of Allergy and Clinical Immunology, 2020

RATIONALE: Skin prick testing (SPT) better correlates with clinical allergy, however, many atopic... more RATIONALE: Skin prick testing (SPT) better correlates with clinical allergy, however, many atopic dermatitis (AD) cohorts use IgE to detect sensitization. Longitudinal food and aeroallergen sensitization patterns via SPT have not been evaluated in a large pediatric AD cohort. METHODS: The Mechanisms of Progression of AD to Asthma in Children (MPAACH) cohort followed children with AD annually from age 1-2 years. SPT data for six food and eleven aeroallergens from 203 subjects who completed visits 1 (V1) and 2 (V2) were analyzed. Sensitization patterns were defined as: non-sensitized (no sensitization in V1 or V2), acquired (sensitized in V2 only), transient (sensitized in V1 only) and persistent (sensitized in V1 and V2). RESULTS: At V1 and V2, 51.5% and 49.5% of children were sensitized overall, respectively. Aeroallergen sensitization increased from 37.6% to 43.9% from V1 to V2 while food sensitization decreased from 38.1% to 30.3%. The most common sensitizations at V1 were egg (28.2%), peanut (22.8%), and dog (14.9%). Over one-third (35.0%) of the cohort had persistent sensitization, 12.8% were acquired, 16.3% were transient and 33.0% were non-sensitized. The top persistent allergens were peanut (16.3%), egg (12.8%) and dog (11.3%), the top transient allergens were egg (14.8%), trees (9.4%), and mold (8.4%). The top acquired allergens were trees (13.8%), dog (9.9%), and cat (8.4%). CONCLUSIONS: Predominance of aeroallergen sensitization occurred in V2 of MPAACH which was younger than observed in existing AD cohorts. Peanut was one of the most frequent and persistent sensitizations, supporting early food allergy assessment in children with AD.

Clinical Lung Cancer, 2019

The prognostic value of baseline liver metastases (LMs) was evaluated in 569 patients with advanc... more The prognostic value of baseline liver metastases (LMs) was evaluated in 569 patients with advanced/metastatic nonesmall-cell lung cancer receiving the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab. LMs were an independent negative prognostic factor for survival and were associated with significantly lower objective response rates. However, PD-L1 as an independent factor predicted benefit from durvalumab. Introduction: Two clinical studies (Study 1108 and ATLANTIC) were analyzed to evaluate the prognostic value of baseline liver metastases (LMs) in advanced/metastatic nonesmall-cell lung cancer patients treated with durvalumab 10 mg/kg every 2 weeks. Patients and Methods: A multivariate Cox proportional hazards analysis was conducted; covariates included performance status, tumor stage, histology, sex, age, smoking status, and programmed cell death ligand 1 (PD-L1) status. Results: In all, 569 patients were included. LMs were present in 31.6% (96/304) of Study 1108 patients and 17.9% (47/263) of ATLANTIC patients. Median overall survival (OS) was shorter in patients with LMs than in those without in both studies. In both studies, LMs were an independent negative prognostic factor for OS and progression-free survival. Objective response rates were also significantly lower. PD-L1 independently predicted benefit across all patients. Conclusion: Liver metastases were associated with worse outcomes irrespective of PD-L1 status, but PD-L1 status predicted benefit from durvalumab irrespective of LMs.

Respiratory Research, 2019

Background: Benralizumab, a humanized, afucosylated, monoclonal antibody that targets interleukin... more Background: Benralizumab, a humanized, afucosylated, monoclonal antibody that targets interleukin-5 receptor α, depletes eosinophils and basophils by enhanced antibody-dependent cell-mediated cytotoxicity. It demonstrated efficacy for patients with moderate to severe asthma and, in a Phase IIa trial, for chronic obstructive pulmonary disease (COPD) with eosinophilic inflammation. We investigated effects of benralizumab 100 mg every 8 weeks (first three doses every 4 weeks) subcutaneous on blood inflammatory markers through proteomic and geneexpression analyses collected during two Phase II studies of patients with eosinophilic asthma and eosinophilic COPD. Methods: Serum samples for proteomic analysis and whole blood for gene expression analysis were collected at baseline and 52 weeks (asthma study) or 32 weeks (COPD study) post-treatment. Proteomic analyses were conducted on a custom set of 90 and 147 Rules-Based Medicine analytes for asthma and COPD, respectively. Gene expression was profiled by Affymetrix Human Genome U133 plus 2 arrays (~54 K probes). Gene set variation analysis (GSVA) was used to determine transcriptomic activity of immune signatures. Treatment-related differences between analytes, genes, and gene signatures were analyzed for the overall population and for patient subgroups stratified by baseline blood eosinophil count (eosinophil-high [≥300 cells/μL] and eosinophil-low [< 300 cells/μL]) via t-test and repeated measures analysis of variance. Results: Eosinophil chemokines eotaxin-1 and eotaxin-2 were significantly upregulated (false discovery rate [FDR] < 0.05) by approximately 2.1-and 1.4-fold in the asthma study and by 2.3-and 1.7-fold in the COPD study following benralizumab treatment. Magnitude of upregulation of these two chemokines was greater for eosinophil-high patients than eosinophil-low patients in both studies. Benralizumab was associated with significant reductions (FDR < 0.05) in expression of genes associated with eosinophils and basophils, such as CLC, IL-5Rα, and PRSS33; immunesignaling complex genes (FCER1A); G-protein-coupled receptor genes (HRH4, ADORA3, P2RY14); and further immune-related genes (ALOX15 and OLIG2). The magnitude of downregulation of gene expression was greater for eosinophil-high than eosinophil-low patients. GSVA on immune signatures indicated significant treatment reductions (FDR < 0.05) in eosinophil-associated signatures. Conclusions: Benralizumab is highly selective, modulating blood proteins or genes associated with eosinophils or basophils. Modulated protein and gene expression patterns are most prominently altered in eosinophilhigh vs. eosinophil-low patients. Trial registration: NCT01227278 and NCT01238861.

Arthritis & rheumatology (Hoboken, N.J.), Jan 29, 2018

B cells impact systemic sclerosis (SSc) progression through multiple pathogenic mechanisms. CD19 ... more B cells impact systemic sclerosis (SSc) progression through multiple pathogenic mechanisms. CD19 inhibition in mice reduced skin thickness, collagen production, and autoantibody levels, consistent with CD19 expression on plasma cells (PCs), the source of antibody production. Plasma cell depletion could effectively reduce collagen deposition and inflammation in SSc; therefore, we investigated effects on SSc disease activity. A PC gene signature was evaluated in SSc skin biopsies in two phase I clinical trials. Microarray data from tissue from public studies of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), dermatomyositis (DM), systemic lupus erythematous (SLE), atopic dermatitis (AD), and blood from a phase IIb clinical trial in SLE were assessed. The PC signature was elevated (FC=5, p<0.0001) in SSc skin specimens compared to healthy donor skin and correlated with baseline modified Rodnan skin score (mRSS) (r=0.64, p=0.0004). High baseline PC ...

PLoS ONE, 2009

Background: Although prior studies have demonstrated a smoking-induced field of molecular injury ... more Background: Although prior studies have demonstrated a smoking-induced field of molecular injury throughout the lung and airway, the impact of smoking on the airway epithelial proteome and its relationship to smoking-related changes in the airway transcriptome are unclear. Methodology/Principal Findings: Airway epithelial cells were obtained from never (n = 5) and current (n = 5) smokers by brushing the mainstem bronchus. Proteins were separated by one dimensional polyacrylamide gel electrophoresis (1D-PAGE). After in-gel digestion, tryptic peptides were processed via liquid chromatography/ tandem mass spectrometry (LC-MS/MS) and proteins identified. RNA from the same samples was hybridized to HG-U133A microarrays. Protein detection was compared to RNA expression in the current study and a previously published airway dataset. The functional properties of many of the 197 proteins detected in a majority of never smokers were similar to those observed in the never smoker airway transcriptome. LC-MS/MS identified 23 proteins that differed between never and current smokers. Western blotting confirmed the smoking-related changes of PLUNC, P4HB1, and uteroglobin protein levels. Many of the proteins differentially detected between never and current smokers were also altered at the level of gene expression in this cohort and the prior airway transcriptome study. There was a strong association between protein detection and expression of its corresponding transcript within the same sample, with 86% of the proteins detected by LC-MS/MS having a detectable corresponding probeset by microarray in the same sample. Forty-one proteins identified by LC-MS/MS lacked detectable expression of a corresponding transcript and were detected in #5% of airway samples from a previously published dataset. Conclusions/Significance: 1D-PAGE coupled with LC-MS/MS effectively profiled the airway epithelium proteome and identified proteins expressed at different levels as a result of cigarette smoke exposure. While there was a strong correlation between protein and transcript detection within the same sample, we also identified proteins whose corresponding transcripts were not detected by microarray. This noninvasive approach to proteomic profiling of airway epithelium may provide additional insights into the field of injury induced by tobacco exposure.

Nature Medicine, 2007

Lung cancer is the leading cause of death from cancer in the US and the world 1. The high mortali... more Lung cancer is the leading cause of death from cancer in the US and the world 1. The high mortality rate (80-85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage 2-4. Given that cigarette smoke creates a field of injury throughout the airway 5-11 , we sought to determine if gene expression in histologically normal large-airway epithelial cells obtained at bronchoscopy from smokers with suspicion of lung cancer could be used as a lung cancer biomarker. Using a training set (n ¼ 77) and gene-expression profiles from Affymetrix HG-U133A microarrays, we identified an 80-gene biomarker that distinguishes smokers with and without lung cancer. We tested the biomarker on an independent test set (n ¼ 52), with an accuracy of 83% (80% sensitive, 84% specific), and on an additional validation set independently obtained from five medical centers (n ¼ 35). Our biomarker had B90% sensitivity for stage 1 cancer across all subjects. Combining cytopathology of lower airway cells obtained at bronchoscopy with the biomarker yielded 95% sensitivity and a 95% negative predictive value. These findings indicate that gene expression in cytologically normal large-airway epithelial cells can serve as a lung cancer biomarker, potentially owing to a cancer-specific airway-wide response to cigarette smoke.

BMC Genomics, 2008

Background Cigarette smoking is a leading cause of preventable death and a significant cause of l... more Background Cigarette smoking is a leading cause of preventable death and a significant cause of lung cancer and chronic obstructive pulmonary disease. Prior studies have demonstrated that smoking creates a field of molecular injury throughout the airway epithelium exposed to cigarette smoke. We have previously characterized gene expression in the bronchial epithelium of never smokers and identified the gene expression changes that occur in the mainstem bronchus in response to smoking. In this study, we explored relationships in whole-genome gene expression between extrathorcic (buccal and nasal) and intrathoracic (bronchial) epithelium in healthy current and never smokers. Results Using genes that have been previously defined as being expressed in the bronchial airway of never smokers (the "normal airway transcriptome"), we found that bronchial and nasal epithelium from non-smokers were most similar in gene expression when compared to other epithelial and nonepithelial tis...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 21, 2018

Antibody-drug conjugates (ADCs) utilizing non-cleavable linker-drugs have been approved for clini... more Antibody-drug conjugates (ADCs) utilizing non-cleavable linker-drugs have been approved for clinical use, and several are in development targeting solid and hematological malignancies including multiple myeloma (MM). Currently there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance. The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the non-cleavable linker pyrrolobenzodiazepine payload SG3376 in vitro. The functional relevance of SLC46A3, a lysosomal transporter of non-cleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EphA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3. SLC46A3 expression was also examined in patient-derived xenograft...

Nucleic acids …, 2005

The SIEGE (Smoking Induced Epithelial Gene Expression) database is a clinical resource for compil... more The SIEGE (Smoking Induced Epithelial Gene Expression) database is a clinical resource for compiling and analyzing gene expression data from epithelial cells of the human intra-thoracic airway. This database supports a translational research study whose goal is to profile the ...

PLoS ONE, 2012

Blood consists of different cell populations with distinct functions and correspondingly, distinc... more Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocyte and pDC specific, miR-150; lymphoid cell specific, miR-652 and miR-223; both myeloid cell specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs which negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA/mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA/mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p,9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity.