Tubercular uveitis is an extrapulmonary form of TB characterized by ocular inflammation that clinically mimics other inflammatory eye diseases, including non-tubercular uveitis. Currently, no gold standard test is available for the diagnosis of tubercular uveitis, and it is primarily based on clinical presentation. OBJECTIVE:To characterise the transcriptional landscape of vitreous fluid of tubercular uveitis and non-tubercular uveitis patients for biomarker identification and gaining insights into disease pathology. DESIGN:Vitreous fluid samples from uveitis patients were processed for isolation of cells and RNA sequencing to compare the transcriptomic profiles of TB and non-TB uveitis entities. Differentially expressed genes were identified using the criteria of false discovery rate (FDR) < 0.25, fold-change (FC) ≥ 2 or ≤ -2, and p-value <0.05 and the top dysregulated genes were selected for biomarker validation. Additionally, gene set enrichment analysis (GSEA) was performed to explore underlying disease mechanisms. RESULTS:RNA sequencing revealed distinct vitreous fluid gene expression patterns in TB uveitis and non-TB uveitis. Notably, MIR581 and MIR4762, encoding miR-581 and miR-4762, respectively, were among the most upregulated genes. Validation via qRT-PCR confirmed the upregulation of mature miR-4762-5p, supporting its potential as a diagnostic biomarker. Pathway enrichment analysis based on transcriptional profiling revealed significant downregulation of immune-related pathways in tubercular uveitis. CONCLUSION:Unique transcripts are associated with TB uveitis, identifying miR-4762 as a potential diagnostic biomarker. Further, downregulation of transcripts associated with immune-related pathways suggests that Mycobacterium tuberculosis (Mtb) may utilize complex molecular strategies to evade host immune responses and establish infection in the ocular environment.

Squamous cell carcinoma of oropharynx (OPSCC), a head and neck squamous cell carcinoma (HNSCC) subtype, exhibits a remarkably high incidence rate in the North-Eastern regions of India. The development of OPSCC is associated with the exposure to smokeless tobacco with or without consumption of alcohol and smoking tobacco. Despite advanced treatment modalities, OPSCC patients still face a dismal prognosis, necessitating a deeper exploration of the underlying molecular characteristics of the disease. While promoter CpG methylation-driven gene expression alterations in OPSCC have been studied, DNA methylation within gene bodies and its biological significance in this cancer subtype remain largely uncharted. This study represents the first endeavour to investigate gene-body specific DNA methylation-driven transcriptome alterations leading to immune response modulation on a genome-wide scale in OPSCC. The genome-wide assay of DNA methylation and RNA-sequencing in paired tumour and adjacent normal tissues, employing high-throughput platforms (Illumina), identified gene-body specific somatic alterations within the DNA methylome that led to transcriptomic changes in OPSCC patients from Meghalaya. Integrative analysis of gene-body specific methylation and transcriptome data unveiled 98 epigenetically repressed and 39 epigenetically overexpressed genes. Major discoveries emerged from this study include deregulation of Tryptophan (Trp) metabolism pathway by the gene-body driven epigenetically modulated (TDO2, KYNU and TPH2) genes along with the conjoint impact of the upregulated IDO1, IDO2. The IFN-γ mediated PD-L1/PD-1, PD-L2/PD-1 interactions and dysregulation of Trp metabolism pathway collectively contributed to the depletion of cytotoxic T cells in OPSCC tissues. Upregulation of multiple chemokines—CCL2, CXCL1, CXCL2 promoting abundant infiltration of mast cell and neutrophils having pro-tumour phenotype in tumour microenvironment were observed. These key alterations within tumour cells might effectively modulate the immune dynamics, leading to immune evasion by oropharyngeal malignant cells. The findings offer deep understanding of OPSCC and suggests novel immunotherapeutic targets, for the treatment of this challenging disease.

Parsing the functions of the tumor suppressor tumor protein p53 (TP53) is complex due to the multiple isoforms it encodes. ∆40p53, an N-terminally truncated p53 isoform and the only translational isoform, modulates full-length p53 (FLp53) activity and independently regulates targets such as the miR-186-5p/transcriptional repressor protein YY1 axis. To identify additional miRNAs regulated by ∆40p53, we performed small RNA sequencing. We found that ectopic overexpression of ∆40p53, but not FLp53, significantly downregulated miR-4671-5p. Expression of both isoforms at varying ratios revealed that miR-4671-5p may be modulated by FLp53 in a ∆40p53-dependent manner. In silico analysis identified N-sulfoglucosamine sulfohydrolase (SGSH) as a potential miR-4671-5p target. SGSH expression showed an inverse correlation with miR-4671-5p in cancer datasets and had prognostic significance. SGSH mRNA and protein levels were reduced upon miR-4671-5p overexpression or si∆40p53 treatment, confirming regulatory linkage. Functionally, miR-4671-5p overexpression induced intra-S-phase cell cycle arrest, implicating SGSH in cell cycle regulation. These results reveal a previously unknown ∆40p53/miR-4671-5p/SGSH axis that, when dysregulated, induces intra-S-phase cell cycle arrest and may contribute to cancer outcomes. Our findings highlight the distinct regulatory role of ∆40p53, independent of FLp53, in maintaining cellular and metabolic homeostasis via miRNA-mediated mechanisms.

Abstract Mutations in p53 and its 12 isoforms can alter its functions. As N-terminally truncated isoforms of p53 (Δ40p53, Δ133p53, and Δ160p53) participate in tetramer formation, they are important regulators of cancer fate. Although Δ40p53- and Δ133p53-mediated regulation of cancer is well reported, the mechanism underlying Δ160p53 production and its functional role remains unclear. We investigated the internal ribosomal entry site (IRES)-mediated translation of Δ160p53 and its role in cancer regulation. As differential synthesis of Δ160p53 was observed under different stress conditions, IRES-mediated translation of this isoform was demonstrated using bicistronic luciferase constructs. No cryptic promoters or splicing sites were detected in the IRES sequence. Cell death and late apoptosis were significantly decreased, while proliferation, the number of cells in the S phase, and drug resistance were induced by Δ160p53. Furthermore, Δ160p53 did not induce p53-responsive promoters. RNA sequencing analysis of Δ160p53 overexpression showed similar results, along with the inhibition of other tumor suppressor genes. Overall, our results provide insights into IRES-mediated translation of Δ160p53, which can be considered a novel target for cancer treatment.

Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) is the most common cancer among males in India and the second most prevalent cancer overall. Therefore, there is an urgent need to develop precision therapies based on an evaluation of molecular heterogeneity and molecular subtyping. We performed bulk RNA-Seq on tumor and adjacent normal tissue samples from 72 OSCC-GB patients, as well as leukoplakia (precancerous) tissue from 25 patients with concurrent leukoplakia. Analysis of our data revealed activation of epithelial-mesenchymal transition, angiogenesis, and cell-cycle pathways. Metabolic analysis revealed enhanced glycolysis and reduced oxidative phosphorylation, consistent with the Warburg effect. Gene set enrichment analysis identified two distinct molecular subtypes, one of which comprises 76.4

Dengue virus is a global health concern resulting in approximately 100 million infections and 21 000 deaths annually. The disease progresses from dengue without warning signs (PLAN A) to dengue with warning signs (PLAN B) and then to severe dengue (PLAN C). However, the molecular mechanisms underlying this transition are not known. In the absence of effective antivirals and vaccines, predicting disease severity early is the only option for better disease management. Extracellular vesicles (EVs) are membrane-bound vesicles secreted from cells and contain miRNA, proteins, and mRNA, which play a crucial role in cell-to-cell communication. Our work involves identifying and characterizing the mRNAs in the EVs isolated from patients in different stages of dengue severity, i.e., PLAN A, PLAN B, and PLAN C. The pathway analysis of these mRNAs enriched in EVs revealed that they play crucial roles in cytokine and chemokine signaling and platelet degranulation, all of which are known to be dysregulated as dengue progresses to severe disease. Further validations using patient samples showed that the selective secretion of these mRNAs from platelets may affect platelet functions. Overall, our study is the first to show the full secretory mRNA profile across different stages of dengue disease severity and reveals a novel mechanism by which the selective secretion of specific mRNAs upon infection may dysregulate host immune responses and contribute to thrombocytopenia, thereby exacerbating disease severity.

Loss of BLM helicase leads to Bloom Syndrome, characterized by genomic instability, cancer predisposition and immunodeficiency. We now show that BLM is essential for the proliferation of cycling B cells and sustains B-cell development by maintaining NF-κB signalling. Hence, in the absence of BLM, the NF-κB pathway is impaired as visualized by the lack of the nuclear translocation of RelA. This action of BLM is due to its binding to the MALT1 promoter (a key positive regulator of NF-κB signalling) and activating its transcription. Reintroduction of MALT1 and constitutively active IKKβ rescues B-cell development in BLM-deficient bone marrow and spleen cells of BLM knockout mice. This indicates that downregulation of MALT1 in BLM-deficient cells is the primary cause of deregulated NF-κB signalling and impaired B-cell development. Interestingly, the pro-proliferative role of BLM can be exploited in the treatment of B-cell malignancies. Here, we demonstrate that depletion of BLM (phenocopied by the inhibition of MALT1) suppresses the progression of lymphoma and leukaemia by inhibiting MALT1-dependent NF-κB signalling and sensitizing malignant B cells to chemotherapy. Together, our findings establish the BLM-MALT1-NF-κB axis as a critical regulator of B-cell development and demonstrate its therapeutic potential in B-cell malignancies. Hence, both upregulation and downregulation of BLM contribute to oncogenesis, underscoring the need to maintain its expression within a tightly controlled threshold.

Abstract Background India represents 18% of the global population yet remains underrepresented in health research. Moreover, existing national surveys miss critical variation across its 4,600 ethnolinguistic groups. We present a comprehensive phenotypic characterisation of 81 populations from the GenomeIndia project. Methods We analysed 67 sociodemographic, anthropometric, and blood biochemistry variables from 17,777 individuals sampled across 81 ethnolinguistic populations from India, examining population-level variation, disease reporting fractions, and age- and sex-specific life-course trends. Findings Ethnolinguistic identity predicted health outcomes independently of administrative state, improving phenotypic variance explained by an average of 7·4%. 95% of participants had at least one abnormal biochemical or anthropometric marker, driven by low HDL (52·2%) and elevated triglycerides (43·6%). Metabolic risk, however, was highly stratified: adjusted prevalence for low HDL ranged four-fold across ancestry groups from 17·2% to 67·7%. We also identified an “awareness gap”; only 17·6% of people with hypertension and 2·2% of people with dyslipidemia were aware of their condition. This awareness gap was higher in tribal populations, in which women did not show the higher HDL levels typically seen compared to men, pointing to distinct metabolic profiles and healthcare access barriers across India. Interpretation The Indian phenotypic landscape is highly structured along ethnolinguistic lines, where ancestry and environment both influence risk. The high systemic burden of abnormalities necessitates population-specific reference intervals. GenomeIndia provides a foundational map for precision public health, shifting the focus from state-level averages to population-specific risk profiles.

We report presence of cholinergic nerve fibers in the periphery and stroma of colon cancer tissues and their correlation with poor T cell and increased macrophage infiltration. We employed hydrogel-mediated localized delivery of an FDA-approved local anesthetic, bupivacaine (BUP), to target acetylcholine (ACh)-mediated crosstalk of cholinergic neurons with cancer and immune cells. Localized BUP-Gel therapy promotes T cell-mediated tumor inhibition and enhances the antitumor response of systemic chemotherapy and immunotherapy. Further, blockade of cancer- and immune cell-specific ACh receptors inhibits tumor growth, alters the TME, and augments the impact of chemotherapy and immunotherapy. Finally, we demonstrate that ACh receptor antagonists polarize macrophages toward an M1-like phenotype and activate T cell immunity in tumor explants of patients. Therefore, targeting cholinergic signals through localized delivery of anesthetics, as well as direct immune reprogramming via cholinergic receptor antagonists, may provide a means to modulate this tripartite crosstalk, with potential implications for therapeutic strategies.

Abstract Background Dengue virus (DENV) infection poses a major global public health burden, particularly in endemic regions where repeated exposure increases the risk of severe disease. Despite revisions to the World Health Organization (WHO) dengue classification, early prediction of progression to severe dengue remains challenging due to overlapping clinical and laboratory features. Current management strategies rely primarily on supportive care and reactive monitoring, underscoring the need for predictive biomarkers that enable early risk stratification and timely intervention. Methods COMBAT is a prospective, multicenter, observational longitudinal study conducted in dengue-endemic regions of Guatemala and India. Patients will be classified according to WHO 2009 criteria into dengue without warning signs, dengue with warning signs, and severe dengue, alongside age- and sex-matched healthy controls. A single blood sample will be collected from non-hospitalized patients while two blood samples per participant will be collected during hospitalization and one at discharge. Multi-omics analyses, including transcriptomics, proteomics, glycomics and metabolomics, will be performed in a discovery cohort and validated in an independent cohort. Integrated systems biology approaches will be used to identify host immune and metabolic pathways associated with dengue severity in a mechanism-based prognostic biomarker discovery. Discussion This study aims to generate comprehensive systems-level insights into host–virus interactions driving dengue severity and to identify biomarkers predictive of disease progression. The findings may inform improved patient triage, early intervention strategies, and the identification of novel therapeutic targets. Trial registration ClinicalTrials.gov ID NCT06751836 Registration Date: December 13, 2024, CTRI/2022/10/046293 (MAHE) Registration Date: October 10, 2022.

Abstract Background Oral squamous cell carcinoma (OSCC) exhibits high incidences of relapse and treatment failure. To understand the molecular mechanisms driving these poor outcomes, we explored the spatial and temporal heterogeneity of primary tumors and their circulating tumor cells (CTCs) using whole transcriptome analysis. Methods Bulk RNAseq was performed on three tumor regions (T1-invasive front, T2, T3) and the tumor-free margin (TFM) from early (EarlyR) and no recurrence till 2 years (NoR) patients (N=5 per group). Ultra-low cell RNAseq of CTCs was performed at diagnosis and at post-therapy/recurrence. Differential gene expression analysis and pathway enrichment using fgsea and clusterProfiler, with the Hallmark and Reactome databases, were performed to identify biologically relevant genes/pathways. Results Spatially distant tumor regions of EarlyR patients were highly diversified from their adjacent free margin in comparison to the NoR group, as indicated by a significantly high number of DEGs - T1 vs TFM (EarlyR-2969, NoR-23), T2 vs TFM (EarlyR-4220 vs NoR-50), and T3 vs TFM (EarlyR-3883 vs NoR-1239). We ruled out that these increases in DEGs were not due to differences in TFMs of the EarlyR and NoR groups (DEGs-17). The pathway analysis revealed enrichment of metastasis-related pathways, including EMT, TNFA signalling via NFκB, and ECM remodelling, in the T1-invasive front of the EarlyR tumor, while the other regions(T2/T3) showed enrichment of proliferation-related pathways, indicating that the invasive front -T1 might be the source of release of aggressive CTCs. We identified SERPINE1, BMP2, CXCL10, CXCL11, ICAM1, IFIH1, IFIT2, IL15, IL15RA, IRF1, JUNB, TGFB1, and TNC as hub genes across multiple pathways enriched in T1, which may contribute to the aggressiveness of this tumor region. Among these genes, IFIT2, IRF1, and JUNB were also upregulated in baseline CTCs of the EarlyR group, indicating the importance of tracking these genes as markers of aggressive CTCs. The PCA analysis of CTC data revealed that, although baseline CTCs are transcriptomically similar between the EarlyR and NoR groups, the post-therapy CTCs are more evolved in the EarlyR group than in the NoR group. We also identified a key molecular marker, FNBP1L, overexpressed in the tumor invasive front (T1) of EarlyR and in their CTCs at pretherapy and posttherapy. However, FNBP1L was downregulated in other regions of the primary tumor (T2/T3), suggesting that aggressive CTCs originate primarily from the invasive front, and FNBP1L (implicated in cytoskeletal reorganisation) might be a key player driving early recurrence and metastasis. Conclusion OSCC tumors from EarlyR patients undergo extensive spatial and temporal transcriptomic evolution, and the invasive front is plausibly involved in the release of aggressive CTCs marked by expression of IFIT2, IRF1, JUNB, and FNBP1L. Citation Format: Geeta S. Boora, Anshika Chauhan, Suvradeep Mitra, Arindam Maitra, Sushmita Ghoshal, Arnab Pal. Spatial gene expression profile of primary tumor is associated with the release of aggressive CTCs from the invasive front, leading to early recurrence in OSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2119.

Oral Squamous Cell Carcinoma (OSCC), one of the most prevalent cancers in developing countries. It is associated with poor prognosis due to relapse in a significant number of patients. Circulating tumour cells (CTCs) are precursors for metastasis and thought to be key players in early relapse in various cancers including OSCC. Though CTC enumeration has been associated with disease outcome, in-depth molecular analysis of CTCs remained minimal as the techniques for CTC isolation and analysis are challenging. While exploring gene expression in CTCs, we performed whole transcriptome analysis of paired primary tumour and CTCs isolated from Oral Squamous Cell Carcinoma (OSCC) patients. Various genes were found to be differentially expressed in CTCs. We found PADI4 gene was significantly upregulated in CTCs. PADI4 gene encodes for an enzyme that converts arginine to citrulline.PADI4 expression in primary tumours was previously observed to be associated with metastasis. Here, we are reporting PADI4 expression for the first time in CTCs and its association with relapse. Interestingly in our data, PADI4 expression was more seen in CTCs with EMT (epithelial to mesenchymal transition)-phenotype than with CTCs only epithelial-phenotype. In conclusion, this is the first study presenting the potential prognostic utility of PADI4 expression in CTCs isolated from OSCC patients.

Blood coagulation and cancer are intricately related. Hypercoagulation associated with cancer leads to aberrant thrombin generation, which contributes to thrombosis. Thrombin also activates anticoagulant protein C and the activated protein C (aPC), in addition to regulating the coagulation pathway, it also elicits cell signaling by binding to endothelial cell protein C receptor (EPCR) and activating protease-activated receptor 1 (PAR1)-mediated cell signaling. Earlier studies showed that aPC promotes lung adenocarcinoma survival and metastasis. However, the underlying mechanism remains largely unknown. Our present study provides mechanistic insight into how aPC promotes lung adenocarcinoma survival, metastasis, and drug resistance. Our study shows that aPC, through EPCR-PAR1-driven activation of RhoA-ROCKII-JNK1/2-MLC2 signaling, triggers extracellular vesicle (EV) release from lung adenocarcinoma cells. aPC-EVs, via the transfer of microRNA (miR)-200a, promote proliferation, migration, and invasion of normal lung epithelial cells. They also confer resistance to lung cancer against chemotherapeutic agents. Inhibition of miR-200a functions through the incorporation of anti-miR-200a abrogates aPC-EVs-mediated tumorigenic effects. Furthermore, loading miR-200a mimic into control EVs showed similar phenotypic responses to that of aPC-EVs. miR-200a is shown to target SOX17 in the recipient cells, leading to tumorigenesis. miR-200a upregulation and SOX17 downregulation are consistently observed in lung cancer tissues in the UALCAN portal database of clinical specimens. Consistent with these findings, our in vivo studies in BALB/c nude mice showed that aPC-EVs from lung cancer cells promote tumor growth, metastasis, and drug resistance through miR-200a transfer. Targeting EV biogenesis, EV’s miR-200a, and/or EV uptake mechanisms may offer novel therapeutic strategies in limiting lung tumorigenesis, thereby increasing patients’ survival.

ER/PR+HER2- breast tumours are the most predominant subtype of breast cancer worldwide, including India. Unlike TNBCs, these tumours can be treated with anti-estrogens or aromatase inhibitors. Despite the success of endocrine therapy, a fraction of patients with ER/PR+ breast tumours do not respond to hormone-receptor-specific treatment and encounter disease recurrence contributing to their poor survival. The genomic underpinnings of therapy resistance in ER/PR+HER2- breast tumours are incompletely understood. We have performed whole genome sequencing (WGS) from tumour and normal tissue samples from endocrine-therapy resistant ER/PR+HER2- breast cancer patients who have relapsed on endocrine therapy and have conducted a comparative analysis of WGS data generated from tissues of endocrine therapy sensitive patients who remained free of disease during a minimum 5-year follow-up. Our analysis shows (a) a three-gene (PIK3CA-ESR1-TP53) resistance signature, and (b) impaired DNA double-strand break repair and homologous recombination pathways, were significantly associated with endocrine-therapy resistance and disease recurrence in ER/PR+HER2- tumours. Genome instability, contributing to high burden of copy-number, structural alterations and telomere-shortening identified as major markers of endocrine treatment resistance. Early prediction of endocrine-therapy resistance from the genomic landscape of breast tumours will aid therapeutics. Our finding also opens up the possibility of repurposing PARP inhibitors in treating endocrine therapy-resistant breast cancer patients.

In search of salivary biomarkers for Head Neck Squamous Cell Carcinoma (HNSCC), we found Cornulin to be the most downregulated(~10-fold) protein during our previous study, which identified 135 dysregulated proteins in the saliva of the patients. The current study aimed to explore the role(s) of Cornulin in pathophysiology of HNSCC and its translational application. The sandwich ELISA and immunohistochemistry assessed the levels of Cornulin in the saliva and primary tumour tissues, respectively, in a cohort of 128 HNSCC patients. The effects of Cornulin modulation were evaluated in-vitro and in-vivo HNSCC models and associated mechanisms were explored by analysis of transcriptomic and proteomic signatures. Cornulin was significantly downregulated in saliva and tumour tissue, which was also associated with tumour differentiation and poor survival. Cell proliferation, migration, viability, and invasion were decreased in Cornulin overexpressed HNSCC cell lines, which was substantiated using in-vivo model, suggesting the anti-tumour role of Cornulin. We identified the probable mechanism through cell cycle arrest in the G1 phase by upregulating p18 and reducing the free intracellular calcium. In conclusion, we report the multifaceted roles of Cornulin in HNSCC, as a potential prognostic biomarker with anti-tumour properties.

Acute myeloid leukemia (AML), the most prevalent type of blood cancer, is initiated in the bone marrow and eventually migrates into the blood. It accounts for a 5-year overall survival rate of 29.8 %. AML results from the formation of immature white blood cells, also called AML blasts, from hematopoietic stem cells which eventually give rise to abnormal white blood cells, termed AML cells. The interaction of AML cells with their microenvironment appears to be significantly important in the pathogenesis of AML. A growing body of evidence identifies extracellular vesicles (EVs) to be a key component in intercellular communication via the transfer of biomolecules, such as DNA, RNAs, proteins, non-coding RNAs, lipids, metabolites etc. Although the role of EVs in various solid tumors is well-established, EVs' contribution to the pathogenesis of blood cancer, such as AML remains ill-defined. The present review highlights how EVs promote the progression of AML by influencing leukemogenesis, survival, angiogenesis, chemotherapeutic resistance, and immune evasion. A significant number of EVs are found in the biofluids of AML patients which are shown to carry signature cargo molecules, thereby rendering the EVs as predictive biomarkers for AML pathogenesis. EV-based clinical trials are mentioned in the later part of the review. Finally, EV-based therapeutics and their limitations are also briefly discussed in the context of AML.

MicroRNAs (miRNAs) are a class of small non-coding RNAs which are associated with post-transcriptional regulation of gene expression. Dysfunction or aberrant expression of miRNAs is predominant in various malignancies including lung cancer. Lung cancer is one of the commonest causes of cancer-related death worldwide, with a five-year survival of only 10–20