Ajit Johnson Nirmal

Ajit Johnson Nirmal
Harvard University | Harvard

Doctor of Philosophy

About

51
Publications
9,079
Reads
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726
Citations
Citations since 2017
41 Research Items
721 Citations
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2017201820192020202120222023050100150200
2017201820192020202120222023050100150200
Introduction
Multi-dimensional characterization of the tumor ecosystem at a single-cell level.
Additional affiliations
January 2013 - September 2014
National University of Singapore
Position
  • Research Officer
Description
  • Genome editing using site specific genome modification tools such as Zinc finger nucleases
January 2012 - December 2012
Indian Institute of Science
Position
  • Research Assistant
Description
  • Working on interaction of Hop1 protein to DNA and other proteins during meiosis stage of cell division
July 2011 - December 2011
University College London
Position
  • Student
Education
September 2010 - September 2011
University College London
Field of study
  • Molecular Medicine

Publications

Publications (51)
Article
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are es...
Preprint
In this study, we demonstrate the utility of whole-slide CyCIF (tissue-based cyclic immunofluorescence) imaging for characterizing immune cell infiltrates in immune checkpoint inhibitor (ICI)-induced dermatologic adverse events (dAEs). We analyzed six cases of ICI-induced dAEs, including lichenoid, bullous pemphigoid, psoriasis, and eczematous erup...
Article
Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending...
Article
Cancer immunotherapies that activate cytotoxic T cell responses against tumors have been remarkably effective in some patients, but the determinants of response remain unclear. To investigate how spatial organization of T cells might influence immunotherapy response, we developed a tissue-based cyclic immunofluorescence (t-CyCIF) platform to charac...
Article
Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse...
Article
In cancer, complex ecosystems of interacting cell types play fundamental roles in tumor development, progression, and response to therapy. However, the cellular organization, community structure, and spatially defined microenvironments of human tumors remain poorly understood. With the emergence of new technologies for high-throughput spatial profi...
Article
Full-text available
High-throughput measurement of cells perturbed using libraries of small molecules, gene knockouts, or different microenvironmental factors is a key step in functional genomics and pre-clinical drug discovery. However, it remains difficult to perform accurate single-cell assays in 384-well plates, limiting many studies to well-average measurements (...
Article
New highly-multiplexed imaging technologies have enabled the study of tissues in unprecedented detail. These methods are increasingly being applied to understand how cancer cells and immune response change during tumor development, progression, and metastasis, as well as following treatment. Yet, existing analysis approaches focus on investigating...
Preprint
Full-text available
Highly multiplexed tissue imaging (MTI) is accomplished by applying powerful antibody-based spatial proteomics technologies that characterize tissues in situ at single-cell and potentially subcellular resolution and enable the creation of two-dimensional tissue maps. Example MTI methods include cyclic immunofluorescence (CyCIF), multiplex immunohis...
Preprint
Full-text available
Lymphocytes play a key role in immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. Here, we used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of tumor-bearing lung tissues fro...
Preprint
Full-text available
High-throughput measurement of cells perturbed using libraries of small molecules, gene knockouts, or different microenvironmental factors is a key step in functional genomics and pre-clinical drug discovery. However, it remains difficult to perform accurate single-cell assays in 384-well plates, limiting many studies to well-average measurements (...
Article
Cutaneous melanoma is a highly immunogenic malignancy, surgically curable at early stages, but life-threatening when metastatic. The spatial organization of the tumor ecosystem during early-stage melanoma is not well understood. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics t...
Preprint
Full-text available
ThiNew multiplexed tissue imaging technologies have enabled the study of normal and diseased tissues in unprecedented detail. These methods are increasingly being applied to understand how cancer cells and immune response change during tumor development, progression, and metastasis as well as following treatment. Yet, existing analysis approaches f...
Article
Full-text available
Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular n...
Article
Full-text available
Highly multiplexed tissue imaging makes detailed molecular analysis of single cells possible in a preserved spatial context. However, reproducible analysis of large multichannel images poses a substantial computational challenge. Here, we describe a modular and open-source computational pipeline, MCMICRO, for performing the sequential steps needed...
Article
Full-text available
The imminent release of tissue atlases combining multichannel microscopy with single-cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards to guide data deposition, curation and release. We describe a Minimum Information about Highly Multiplexed Tissue Imaging (MITI) standard...
Article
Full-text available
Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here...
Preprint
Full-text available
Cutaneous melanoma is a highly immunogenic disease, surgically curable at early stages, but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborh...
Preprint
Full-text available
Spatial transcriptomics and multiplexed imaging are complementary methods for studying tissue biology. Recent advances in spatial transcriptomics rely on fresh frozen specimens making years of archived tissues samples unusable. Here we describe a method, called Pick-Seq, for spatial transcriptional profiling of formalin fixed histology specimens ba...
Preprint
Normal tissue physiology and repair depends on communication with the immune system. Understanding this communication at the molecular level in intact tissue requires new methods. The consequences of SARS-CoV-2 infection, which can result in acute respiratory distress, thrombosis and death, has been studied primarily in accessible liquid specimens...
Article
Crucial transitions in cancer—including tumor initiation, local expansion, metastasis, and therapeutic resistance—involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecede...
Article
Introduction Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm induced by human T-cell leukemia virus type 1 (HTLV-1). In endemic areas, HTLV-1 infection typically occurs during breastfeeding but the median age of ATLL presentation in Japan is >70. Approximately 5% of ATLL patients in Japan present at age <50. Here, we hypothesized that AT...
Article
Full-text available
Tail amputation by tail docking or as an extreme consequence of tail biting in commercial pig production potentially has serious implications for animal welfare. Tail amputation causes peripheral nerve injury that might be associated with lasting chronic pain. The aim of this study was to investigate the short- and long-term effects of tail amputat...
Article
Full-text available
The immune composition of the tumor microenvironment regulates processes including angiogenesis, metastasis, and the response to drugs or immunotherapy. To facilitate the characterization of the immune component of tumors from transcriptomics data, a number of immune cell transcriptome signatures have been reported that are made up of lists of mark...
Conference Paper
Full-text available
Aim of Investigations: The aim of this study was to conduct a transcriptome analysis of gene expression patterns in the caudal dorsal root ganglia of pigs subjected to tail amputation at two different stages of development consistent with tail docking age (neonate) and tail biting outbreaks (juvenile) to develop a better understanding of the short...
Thesis
The immune response to a given cancer can profoundly influence a tumour’s trajectory and response to treatment, but the ability to analyse this component of the microenvironment is still limited. To this end, a number of immune marker gene signatures have been reported which were designed to enable the profiling of the immune system from transcript...
Article
Full-text available
Genetically modified FVIII‐expressing autologous bone marrow‐derived mesenchymal stromal cells (BMSCs) could cure haemophilia A. However, culture‐expanded BMSCs engraft poorly in extramedullary sites. Here, we compared the intramedullary cavity, skeletal muscle, subcutaneous tissue and systemic circulation as tissue microenvironments that could sup...
Article
Signaling via the colony-stimulating factor 1 receptor (CSF1R) controls the survival, differentiation, and proliferation of macrophages. Mutations in CSF1 or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of pig CSF1-Fc fusion protein as a therapy for low birth weight (LBW) at term, u...
Data
Table S1 Details on the datasets used in this study The subject details, experimental design, data source, and comparisons for all datasets included in this study are listed in Table S1. This includes the three primary data datasets, 22 validation datasets for skin conditions, three psoriasis datasets for integrating the keratinocyte differentiatio...
Data
Table S3 Gene ontology enrichment and example genes for each signature In addition to highlighting a number of key genes and significant gene ontology (GO) enrichment result for each SkinSig, the supplementary file also includes the full set results from gene ontology enrichment.
Data
Table S4 Comparison between SkinSig and genes found to be significantly altered during ageing Genes reported to change in their expression during ageing are compared with SkinSig, showing a high percentage of the sebaceous gland and hair signatures being reported to alter with ageing by Glass et al [19].
Data
Supplementary discussion. Further discussion on other gene clusters of interest and justifications for the assignation of annotation of co‐expression signatures without a significant or relevant gene ontology term
Data
Figure S1 Sample–sample correlation and signal comparisons between the RNA‐seq and microarray datasets. (A) Sample–sample correlation plots of data used in these studies, using the maximum Pearson correlation coefficient threshold that still retained all samples for the RNA‐seq (r ≥ 0.93) and (B) the microarray (r ≥ 0.97) datasets. There is minimal...
Data
Table S2 SkinSig and co‐expression signatures derived from the analysis of different datasets derived from normal human skin The supplementary file includes the co‐expression signatures for all network analysis, including the individual full original datasets, gene‐symbol restricted datasets, and SkinSig.
Data
Figure S2 Pearson correlation thresholds in randomized and original data. (A) When expression values for each gene were randomized across the samples of the RNA‐seq dataset, only 95 pairing (edges) were observed at a threshold used in this analysis (r ≥ 0.73), whilst the untransformed data yielded 87 121 edges. Taking into account that a total of 1...
Article
Full-text available
Numerous studies have explored the altered transcriptional landscape associated with skin diseases to understand the nature of these disorders. However, data interpretation represents a significant challenge due to a lack of good maker sets for many of the specialised cell types that make up this tissue, whose composition may fundamentally alter du...
Preprint
Full-text available
The outcome of many diseases is commonly correlated with the immune response at the site of pathology. The ability to monitor the status of the immune system in situ provides a mechanistic understanding of disease progression, a prognostic assessment and a guide for therapeutic intervention. Global transcriptomic data can be deconvoluted to provide...
Article
Full-text available
Costly coagulation factor VIII (FVIII) replacement therapy is a barrier to optimal clinical management of hemophilia A. Therapy using FVIII-secreting autologous primary cells is potentially efficacious and more affordable. Zinc finger nucleases (ZFN) mediate transgene integration into the AAVS1 locus but comprehensive evaluation of off-target genom...
Article
Full-text available
Colorectal cancer is the third most common cause of cancer-related deaths and the second most prevalent (after breast cancer) in the western world. High metastatic relapse rates and severe side effects associated with the adjuvant treatment have urged oncologists and clinicians to find a novel, less toxic therapeutic strategy. Considering the limit...
Conference Paper
Full-text available
Transcriptomics data is a valuable resource for understanding a system’s response to disease or other perturbation. Frequently, pathological states are associated with the recruitment of immune cells to the site of disease and/or changes in the relative numbers or activation state of other cell types. Identifying these alterations are key to the co...
Article
Full-text available
Micronuclei (MN) formation is generally attributed to error in DNA synthesis or mitosis, which are represented by the S or G(2)/M phase respectively, in the cell-cycle histogram. Interestingly, many of the known anticancer drugs target these cell-cycle phases to elicit cytotoxicity. Here, we attempted to identify whether any correlation exists betw...
Article
Full-text available
Colorectal cancer is the third most common cause of cancer-related deaths and the second most prevalent (after breast cancer) in the western world. High metastatic relapse rates and severe side effects associated with the adjuvant treatment have urged oncologists and clinicians to find a novel, less toxic therapeutic strategy. Considering the limit...

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