Publications by authors named "Isar Nassiri"

Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn's disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn's disease but the functional mechanisms are unknown.

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To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm.

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SETD2-dependent H3 Lysine-36 trimethylation (H3K36me3) has been recently linked to the deposition of de-novo DNA methylation. SETD2 is frequently mutated in cancer, however, the functional impact of SETD2 loss and depletion on DNA methylation across cancer types and tumorigenesis is currently unknown. Here, we perform a pan-cancer analysis and show that both SETD2 mutation and reduced expression are associated with DNA methylation dysregulation across 21 out of the 24 cancer types tested.

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Background: Systematic description of library quality and sequencing performance of single-cell RNA sequencing (scRNA-seq) data is imperative for subsequent downstream modules, including re-pooling libraries. While several packages have been developed to visualise quality control (QC) metrics for scRNA-seq data, they do not include expression-based QC to discriminate between true variation and background noise.

Results: We present scQCEA (acronym of the single-cell RNA sequencing Quality Control and Enrichment Analysis), an R package to generate reports of process optimisation metrics for comparing sets of samples and visual evaluation of quality scores.

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Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients.

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NP-B*07:02-specific CD8 T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52).

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The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8 T cells. How sensitivity to ICB varies across CD8 T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8 T cell clones, identify baseline markers of CD8 T cell clonal sensitivity, and chart how CD8 T cell transcriptional changes vary according to phenotypic subset and clonal size.

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Article Synopsis
  • The study investigates immune checkpoint inhibitor (ICI)-colitis to understand its causes and similarities to idiopathic ulcerative colitis, aiming to find new treatment targets.
  • Key findings reveal that activated CD8 T cells are predominant in ICI-colitis, and their activation is linked to the severity of the condition, differing from the patterns seen in ulcerative colitis.
  • The research highlights that targeting these activated CD8 T cells with the JAK inhibitor tofacitinib shows promise as a treatment for ICI-colitis.
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We present EPISPOT, a fully joint framework which exploits large panels of epigenetic annotations as variant-level information to enhance molecular quantitative trait locus (QTL) mapping. Thanks to a purpose-built Bayesian inferential algorithm, EPISPOT accommodates functional information for both cis and trans actions, including QTL hotspot effects. It effectively couples simultaneous QTL analysis of thousands of genetic variants and molecular traits with hypothesis-free selection of biologically interpretable annotations which directly contribute to the QTL effects.

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  • Immune checkpoint blockers (ICBs) can activate CD8 T cells, leading to both positive anti-cancer effects and adverse immune-related events (irAEs), but their link to overall clinical outcomes is not well understood.* -
  • A study examined the connection between irAE development and patient survival in metastatic melanoma by analyzing data from two groups of patients receiving different ICB treatments and assessing gene expression in CD8 T cells.* -
  • Results showed that over half of the patients experienced early irAEs, which correlated with longer progression-free and overall survival, indicating that irAEs might reflect baseline immune activation and influence treatment outcomes.*
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  • Immune checkpoint blockade (ICB) treatments for metastatic melanoma show varying effectiveness, so researchers studied CD8 T cell gene expression from patients receiving either anti-PD-1 alone or combined with anti-CTLA-4.
  • The combination therapy (cICB) resulted in a significantly stronger T cell response, with a notable increase in genes related to mitosis and interferon.
  • Active patients benefiting from treatment exhibited a higher frequency of large CD8 T cell clones that express cytotoxicity-related genes, suggesting that the size of these clones after treatment can help predict long-term treatment outcomes.
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We present a new model of ESR1 network regulation based on analysis of Doxorubicin, Estradiol, and TNFα combination treatment in MCF-7. We used Doxorubicin as a therapeutic agent, TNFα as marker and mediator of an inflammatory microenvironment and 17β-Estradiol (E2) as an agonist of Estrogen Receptors, known predisposing factor for hormone-driven breast cancer, whose pharmacological inhibition reduces the risk of breast cancer recurrence. Based on the results of transcriptomics analysis, we found 71 differentially expressed genes that are specific for the combination treatment with Doxorubicin + Estradiol + TNFα in comparison with single or double treatments.

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IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide.

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Cell morphological phenotypes, including shape, size, intensity, and texture of cellular compartments have been shown to change in response to perturbation with small molecule compounds. Image-based cell profiling or cell morphological profiling has been used to associate changes of cell morphological features with alterations in cellular function and to infer molecular mechanisms of action. Recently, the Library of Integrated Network-based Cellular Signatures (LINCS) Project has measured gene expression and performed image-based cell profiling on cell lines treated with 9515 unique compounds.

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The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e.

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Article Synopsis
  • A signaling pathway consists of proteins and molecules that relay information from the cell surface to target molecules, crucial for understanding cell communication.
  • This study presents a new method for identifying dominant signaling pathways and responses to stimuli by simulating signal flow and analyzing network structures.
  • The method was applied to eighty-three signaling networks, successfully matching known pathways and enhancing the understanding of molecular interactions, as well as identifying key intervention points in signal transduction.
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Simulating signal transduction in cellular signaling networks provides predictions of network dynamics by quantifying the changes in concentration and activity-level of the individual proteins. Since numerical values of kinetic parameters might be difficult to obtain, it is imperative to develop non-parametric approaches that combine the connectivity of a network with the response of individual proteins to signals which travel through the network. The activity levels of signaling proteins computed through existing non-parametric modeling tools do not show significant correlations with the observed values in experimental results.

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PTEN/MMAC1/TEP1 encodes a tumor suppressor protein, which regulates cell cycle progression, translation, and apoptosis by blocking the activation of Akt/PKB. The loss of PTEN function increases cell survival and induces tumor invasion. In this study, PTEN promoter status and its correlation with genetic and pathologic parameters were analyzed in genomic DNA from Iranian patients with breast cancer.

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The single-strand conformation polymorphism (SSCP), accompanied by sequencing, is a useful methods for identifying mutations in a DNA fragment. In this study, we have developed a modified SSCP with the aid of sodium bisulfite treatment. The corresponding PCR products for exon 3 of Hb gene were sequenced and samples with homozygote and heterozygote single nucleotide substitutions were identified.

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Article Synopsis
  • p16(INK4A) is a tumor suppressor gene that inhibits Cdk4/6, and its inactivation can occur through various mechanisms such as promoter hypermethylation.
  • The study analyzed the methylation status of the p16(INK4A) gene in 70 Iranian breast cancer patients using methylation-specific PCR and other methods, finding significant hypermethylation in about 35.7% to 40% of samples.
  • Results suggest that the hypermethylation of the p16(INK4A) promoter may play a key role in the early stages of breast cancer development in these patients.
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