Biology subjects

Rajput, M.

Publications and source records attributed to Rajput, M..

5 recordsLinked to original sources

bioRxiv2026

Tumour neoantigen repertoire prediction in malignant peripheral nerve sheath tumours define private and public targets for immunotherapy

Malignant peripheral nerve sheath tumours (MPNSTs) are high grade soft-tissue sarcomas with an unmet need for novel therapies. Tumour antigen-based approaches, including neoantigen and tumour-associated antigens (TAA) directed therapies, offer potential opportunities for immunotherapy. Here, we integrated public domain tumour DNA and RNA sequencing data with in-silico predictions in order to characterise the potential (neo)antigenic landscape of MPNST. We stratified the computational predictions across the two known sub-groups of MPNST, those associated without and with Polycomb Repressor Complex 2 (PRC2) loss of function variants (PRC2-Loss). Using pVACtools, computationally identified high-confidence neoantigens based on predicted pMHC affinity were derived from somatic mutations and gene fusions, as well as recurrently overexpressed cell-surface TAAs. All predicted neoantigens were private to individual MPNST cases and across both tumour subtypes. Using ImSig and CIBERSORTx, PRC2-Loss tumours displayed reduced immune infiltration with downregulation of antigen processing and presentation pathways compared to PRC2-WT, confirming known intrinsic constraints to effective neoantigen-directed immune priming. Moreover, PRC2-Loss MPNSTs demonstrated recurrent copy number driven overexpression of cell surface TAAs derived from chromosome 8 amplification, providing potential immunotherapeutic targets that are pMHC independent. Overall, these predictive findings confirm a PRC2-independent private immuno-antigenic peptide repertoire, with an immune resistant MPNST microenvironment in PRC-Loss. These data provide further impetus for personalised functional validation and immune based treatment strategies, including personalised neoantigen vaccines and cell surface protein TAA-directed therapies dependent on PRC2 status.

cancer biology↗

bioRxiv2026

Ciliogenic pancreatopathy reveals a link between ciliopathies and exocrine pancreatic disease

BackgroundWhile pancreatic cysts have been described in syndromic ciliopathies, the pancreas is not commonly recognized as a target organ. However, several ciliary gene knockout mouse models develop a pancreatic phenotype combining acinar atrophy and adipocyte accumulation, hereby called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. ObjectiveWe investigated whether mutations in ciliopathy-associated genes are linked to pancreatic dysfunction in humans. DesignWe analyzed a cohort of 341 patients with pediatric-onset pancreatic anomalies and characterized the pancreatic phenotype of new mouse models with conditional Nphp3 inactivation or bearing Nphp3 mutations recapitulating human mutations. In patients, pancreatic fat content was quantified using Dixon-MRI. ResultsMutations in the cilium-related HNF1B and NPHP3 were identified in patients presenting with both renal and pancreatic dysfunction. Nphp3 mutant mice developed acinar atrophy, adipopancreatosis, and moderate inflammation. Adipocytes in the pancreas exhibited a white adipocyte-like profile and likely originated from mesothelial-derived fibroblasts. Reduced numbers and altered length of ductal cilia were monitored. Interestingly, secretory canaliculi, typically unnoticed structures found within and between acinar cells and connected to the acinar lumen, exhibited a microcystic morphology. Consistent with the mouse phenotype, Dixon-MRI revealed significantly increased pancreatic fat content in patients with HNF1B and NPHP3 mutations. ConclusionWe describe a previously unrecognized pancreatic manifestation of ciliopathies, which we name ciliogenic pancreatopathy. Patients with known ciliopathy-causing mutations should be evaluated for this pancreatic condition, particularly those with kidney disease, as concomitant exocrine pancreatic insufficiency may further compromise renal function or the outcome of kidney graft. What is already known on this topicO_LICiliopathies, resulting from defects in primary cilia, are genetic disorders primarily affecting the kidney and liver. C_LIO_LIPancreatic cysts have been sporadically reported in syndromic ciliopathies. C_LIO_LIThe pancreas is not currently recognized as a major target organ of ciliary dysfunction. C_LIO_LIA clear link between ciliary gene mutations and pancreatic anomalies is still unknown. C_LIO_LIAnimal studies have suggested a possible association between ciliary dysfunction and pancreatic anomalies. C_LI What this study addsO_LIIdentifies HNF1B and NPHP3 mutations as genetic causes of a pancreatic phenotype characterized by acinar atrophy and adipose replacement (adipopancreatosis). C_LIO_LIDemonstrates the presence of defective ductal cilia and moderate inflammation in the pancreas of Nphp3 mutant mice. C_LIO_LIReveals that secretory canaliculi in the exocrine pancreas of Nphp3 mutant mice acquire a microcystic morphology. C_LIO_LIShows that patients with HNF1B or NPHP3 mutations have significantly increased pancreatic fat content by Dixon-MRI. C_LIO_LIDefines a new disease entity, ciliogenic pancreatopathy, as a pancreatic manifestation of ciliopathies. C_LI How this study might affect research, practice or policyO_LIEstablishes the pancreas as a novel and clinically relevant target of ciliopathies. C_LIO_LIExpands the phenotypic spectrum of HNF1B- and NPHP3-related diseases to include exocrine pancreatic dysfunction. C_LIO_LISuggests that patients with ciliopathy-causing mutations should be evaluated for exocrine pancreatic insufficiency. C_LIO_LIHighlights the need to consider pancreatic function monitoring in kidney disease and transplant settings. C_LIO_LIOpens new research avenues into the role of primary cilia in pancreatic homeostasis and disease. C_LI

cell biology↗

bioRxiv2025

Knowledge, attitudes, and practices of para-veterinary workers about ticks and tick-borne diseases in three provinces of Pakistan

There is a high prevalence of tick infestation in Pakistani livestock, affecting more than 45% of the population of more than 200 million small and large ruminants. Most livestock farmers seek assistance from para-veterinary workers, who fall under the definition of Veterinary Paraprofessionals (VPPs), according to the World Organization for Animal Health (WOAH). There is a shortage of information concerning the awareness of these para-veterinary workers regarding tick control and management. This study aims to bridge this critical knowledge gap by conducting a cross-sectional survey that evaluates the knowledge, attitudes, and practices of para-veterinary workers about tick-borne diseases (TBDs) in Pakistan. Between March and August 2023, we conducted a web-based survey among para-veterinary workers recruited via email, text message, and face-to-face conversations. Poisson regression was used to identify factors associated with knowledge, attitude, and practice (KAP) scores related to TBDs. We received 118 responses from three provinces; only 27.9% (n = 33) responded that they had attended workshops related to ticks and TBDs. Attending workshops was associated with higher KAP scores. All section scores were correlated, and higher knowledge scores were significantly associated with lower odds of tick exposure. Our findings suggest that workshop attendance is important in increasing overall awareness and promoting better practices regarding TBDs.

scientific communication and education↗

bioRxiv2025

Identification and Implications for Tumor Heterogeneity of a DNA Methylation-Based Signature Classifying Pancreatic Ductal Adenocarcinoma Based on their Cellular Origin

BackgroundPancreatic ductal adenocarcinoma (PDAC) arises from distinct cellular origins, yet the extent to which DNA methylation patterns from normal pancreatic cells are preserved in tumor cells remains unclear. Identifying cell-of-origin signatures may enhance PDAC classification and therapeutic stratification. ObjectiveTo determine whether DNA methylation signatures in normal acinar and ductal pancreatic cells are retained in PDAC cell lines and to develop a robust classifier for distinguishing tumor origins. DesignWe performed DNA methylation profiling using the Illumina Infinium Mouse MethylationEPIC array on normal acinar and ductal cells and their PDAC derivatives in genetically engineered mouse models (GEMMs). Differential methylation analysis, and hierarchical clustering were used to identify and validate a conserved cell-of-origin DNA methylation signature. A logistic regression model was developed for classification. ResultsWe identified 178 CpG sites that remain preserved during tumorigenesis and effectively distinguished acinar- and ductal-derived PDAC cell lines. This signature was validated across independent sample sets, primary tumors, and orthotopic allografts. It successfully classified cell lines of unknown origin, including PDAC samples from KPC mice, and revealed the impact of oncogenic mutations on tumor fate. A logistic regression model supported these findings, confirming the robustness of the classification approach. Furthermore, the cell of origin influenced key PDAC characteristics, including treatment response, highlighting its potential role in molecular subtyping and patient stratification. ConclusionA preserved DNA methylation signature during pancreatic carcinogenesis distinguishes PDAC origins and influences tumor behavior. These results highlight the potential of DNA methylation profiling for tumor classification and personalized treatment strategies. They also raise important questions about the relevance of KPC mice as a preclinical model and the mechanisms driving PDAC heterogeneity. What is already known on this topicO_LIHuman PDAC exhibits significant heterogeneity, with molecular subtyping (classical vs basal-like) providing some insights into tumor behavior and clinical outcomes. C_LIO_LIMouse acinar and ductal cells can give rise to PDAC, influencing tumor characteristics and survival outcomes. C_LIO_LIDNA methylation is a powerful tool for tracing cellular identity and distinguishing cancer subtypes based on epigenetic profiles. C_LI What this study addsO_LIA cell-of-origin methylation signature is preserved during mouse carcinogenesis and across diverse experimental settings, providing a reliable tool for tumor classification. C_LIO_LIA DNA methylation-based classification system reliably distinguishes between acinar- and ductal-origin PDAC, filling a critical gap in methods to trace tumor lineage. C_LIO_LIAcinar- and ductal-derived PDACs exhibit distinct methylation patterns that correlate with differences in tumor behavior, such as chemoresistance, highlighting the biological relevance of cellular origin in PDAC. C_LIO_LIThe study provides new insights into how cell-of-origin influences PDAC heterogeneity and could lead to more precise therapeutic strategies tailored to the tumors lineage. C_LI How this study might affect research, practice or policyO_LIThis study provides a new, reliable method for classifying PDAC based on its cellular origin, which could significantly improve tumor classification in both preclinical and clinical settings, aiding in more accurate diagnoses and prognostic predictions. C_LIO_LIThe identification of distinct methylation patterns linked to tumor behavior offers valuable insights for developing personalized treatment strategies, as therapies could be tailored based on the tumors cellular origin and associated molecular characteristics. C_LIO_LIThe preservation of cell-of-origin methylation signature suggests the potential for developing a universal biomarker for PDAC classification, which could guide future clinical trials, therapeutic targeting, and patient stratification in PDAC care. C_LI

cancer biology↗

bioRxiv2022

MAP Kinase and mammalian target of rapamycin are main pathways of gallbladder carcinogenesis: Results from bioinformatic analysis of Next Generation Sequencing data from a hospital-based cohort.

BackgroundGallbladder Cancer (GBC) is one of the most common cancers of the biliary tract and the third commonest gastrointestinal (GI) malignancy worldwide. The disease is characterized by the late presentation and poor outcome despite treatment, and hence, newer therapies and targets need to be identified. MethodsThe current study investigated various functionally enriched pathways in GBC pathogenesis involving the genes identified through Next Generation Sequencing (NGS). The Pathway enrichment analysis and Gene Ontology (GO) were carried out after NGS, followed by the construction of the protein-protein interaction (PPI) network to discover associations among the genes. ResultsOf the thirty-three patients with GBC who were screened through next-generation sequencing (NGS), 27somatic mutations were identified. These mutations involved a total of 14 genes. The p53 and KRAS were commonly found to be mutated, while mutations in other genes were seen in one case each, the mean number of mutations were 1.2, and maximum mutation in a single case (eight) was seen in one case. The bioinformatics analysis identified MAP kinase, PI3K-AKT, EGF/EGFR, and Focal Adhesion PI3K-AKT-mTOR signaling pathways and cross-talk between these. ConclusionThe results suggest that the complex crosstalk between the mTOR, MAPK, and multiple interacting cell signaling cascades can promote GBC progression, and hence, mTOR - MAPK targeted treatment will be an attractive option.

cancer biology↗