Biology subjects

Verma, P.

Publications and source records attributed to Verma, P..

At least 19 recordsLinked to original sources

bioRxiv2026

MICROSTRUCTURAL ORGANIZATION OF CORTICO-SUBCORTICAL FUNCTIONAL CONVERGENCE

The human subcortex integrates information from distributed cortical regions through functionally organized cortico-subcortical systems. Using the publicly available MICA-MICs multimodal MRI dataset of 50 healthy adults, we characterized the microstructural organization of functionally converging cortical regions. First, using resting-state fMRI., we identified cortical regions converging on subcortical targets, including thalamic, basal ganglia, and subcortical limbic structures. Then, using depth-resolved quantitative T1 profiles, we constructed a convergence-restricted microstructural profile covariance matrix, followed by diffusion-map embedding. The first microstructural gradient predominantly differentiated primary and association cortex, whereas the second gradient showed target-related differentiation beyond differences in primary versus association cortex. Cytoarchitectural analysis further revealed target-related differences in cortical composition. Together, these findings reveal complementary dimensions of cortico-subcortical functional organization, spanning broad cortical hierarchy, target-related microstructural differentiation, and cytoarchitectural composition.

neuroscience↗

bioRxiv2026

Structural Insights and Inhibitor Discovery for Kyasanur Forest Disease Virus NS5 Methyltransferase

Kyasanur Forest Disease Virus (KFDV) NS5 methyltransferase (MTase) protein is the essential enzyme that is involved in the cap methylation of viral RNA, viral replication, and immune evasion, and therefore it is an important protein of interest for antiviral research and drug design. In the present work, we successfully resolved the three-dimensional crystal structures of KFDV NS5 MTase co-crystallised with SAH and GTP at resolutions of 2.2 [A] and 2.6 [A], respectively. In previous studies, HC (Herbacetin) and CAPE (Caffeic acid phenethyl ester) have shown inhibitory activity against SAM-dependent viral MTase. To evaluate the inhibitory potential of HC and CAPE against KFDV NS5 MTase, we have performed isothermal titration calorimetry (ITC) and tryptophan fluorescence spectroscopy (TFS) to validate protein interaction with target compounds. MTase inhibition assay was performed using capillary electrophoresis (CE) assays. Additionally, fluorescence polarisation (FP) confirmed RNA binding inhibition by CAPE and HC. Together, these experiments suggest that HC and CAPE are promising inhibitors against KFDV NS5 MTase and could potentially act as lead compounds to design broad-spectrum anti-Orthoflavivirus drugs.

molecular biology↗

bioRxiv2026

High-speed atomic force-Raman microscopy

A comprehensive understanding of the mechanisms underlying biological systems requires correlative analysis of multiple complementary molecular properties through multidimensional measurements. High-speed atomic force microscopy (HS-AFM) is a powerful tool for elucidating biomolecular structural dynamics at the single-molecule level with high spatiotemporal resolution. However, structural information alone is often insufficient for fully understanding the biological function mechanisms. Here, we report high-speed atomic force-Raman microscopy (HS-AFRM), which enables multimodal measurements combining video-rate structural imaging with chemical-bond analysis. Raman spectroscopy is a powerful, non-invasive technique that probes molecular vibrations to provide chemical information. We achieved several key technical developments that facilitated the seamless integration of HS-AFM and micro-Raman spectroscopy, allowing reliable correlative measurements of structural and chemical information. We validated the versatility of the developed system using representative samples, including two-dimensional materials and a protein. Furthermore, we demonstrate probing of changes in the surrounding environment, which are inaccessible by HS-AFM alone. Multimodal measurements incorporating fluorescence spectroscopy were also demonstrated as an additional practical extension. This multimodal approach substantially enhances the analytical capability of HS-AFM, providing a powerful platform for revealing correlated structural and chemical properties across diverse research fields.

biophysics↗

bioRxiv2026

A Guided AI Framework for Customizable and Efficient Harmonisation to the OMOP Common Data Model

Getting clinical data from different sources to "talk" to each other within the OMOP Common Data Model (CDM) is arguably the most tedious part of multi-center research. While this integration is essential, the transformation process is frequently a manual grind, requiring a rare overlap of deep clinical knowledge and technical expertise. In this paper, we present a framework designed to alleviate some of the burden on the researcher by automating data harmonization through two distinct steps: structural schema mapping and terminological standardization. For the structural piece, we moved away from "black box" logic in favor of a stateful workflow managed by large language models (LLMs) and directed acyclic graphs. By profiling EHR data at the source, our system generates context-aware dictionaries that offer ranked mapping suggestionsalongside confidence scores. While our benchmarking showed a 97.5% agreement rate at the schema level and an 84% agreement rate at the value level when compared with human experts, the system appears most effective when treated as a "co-pilot" rather than a total replacement for human oversight. To handle value-level standardization, we implemented a hybrid search strategy that pairs the semantic depth of SapBERT embeddings with the literal precision of fuzzy string matching. By using FAISS for rapid similarity retrieval, the engine attempts to resolve messy or "noisy" clinical descriptionsto standard OMOP concepts. This approach seems particularly promising for handling the non- standardized labels that often plague smaller, local datasets. Ultimately, our results suggest that this guided approach can shift the timeline for OHDSI-compliant warehousing from weeks of manual curation to a more manageable and scalable pipeline, potentially lowering the barrier to entry for smaller research teams.

bioinformatics↗

bioRxiv2026

PEXMap: A proteogenomic method for exon and isoform level mapping of mass spectrometry derived peptides

Alternative splicing (AS) expands transcriptome and proteome diversity by differentially combining exons or their splice variants. Although RNA-seq studies have uncovered transcriptomic variability, understanding the corresponding protein-level diversity remains limited. Mass spectrometry-based proteomics provides protein-level insights through MS/MS peptide annotations, which are mostly linked to gene/transcript or UniProt identifiers. However, tracing them to specific isoforms remains challenging due to the lack of exon mapping or inconsistent annotations. We developed PEXMap (PeptideEXonMapper), a k-mer-based proteogenomic framework that systematically maps MS/MS peptides to genes, transcripts, exons, or exon-exon junctions by exact matching of unique 8-mers derived from MS/MS peptides to those in reference databases from exon-resolved isoforms. Comparing PEXMap mappings of human proteome from PeptideAtlas showed annotation concordance with it. Applying PEXMap to liver and pancreas proteomes, we identified tissue-specific isoform expression and, similarly, annotated the cancer proteome. PEXMap reliable mappings could provide insights into role of AS in shaping proteomes across tissues and disease states. Source code is publicly available for download at GitHub: https://github.com/deepanshicbg/PEXMap and supported on Linux.

systems biology↗

bioRxiv2026

Imbalance of Ciliary Programs Drives Fibroblast Differentiation and Fibrotic Signaling in Systemic Sclerosis

Systemic sclerosis (SSc) is a chronic fibrotic disease characterized by accumulation of activated profibrotic myofibroblasts in multiple organs. The mechanisms triggering pathogenic fibroblast to myofibroblast reprogramming in SSc, and maintaining the activated myofibroblast state, are not well known. Recent studies show that primary cilia (PC), solitary sensory organelles that integrate diverse chemical and mechanical signaling pathways, may regulate fibroblast fates. Here, using an orthogonal multimodal strategy spanning human cohorts, single-cell trajectories, and targeted perturbation models, we identify a fundamental imbalance in cilia-program dynamics as a unifying driver of fibrotic activation in SSc. Meta-analysis of skin biopsies integrating eight microarray datasets and two independent scRNA-seq cohorts, revealed a conserved 15-gene cilia signature that is altered in SSc. Single-cell trajectory mapping resolved a principal progenitor[->] secretory-like [->] myofibroblast differentiation axis, where SSc fibroblasts displayed spatially dysregulated ciliary programs that established a prolonged, disassembly-dominant "cilia-off" state. Notably, this ciliary imbalance appeared to emerge before the transition to fibrotic gene programs, positioning cilia disruption as an initiating, not secondary, event in fibroblast programming. Consistent with these transcriptomic findings, PC length was significantly reduced in SSc skin and cultured fibroblasts. Mechanistically, genetic and pharmacological perturbation studies demonstrated that cilia disruption is sufficient to drive fibrotic programs. These data establish a reciprocal regulatory framework in which shortened cilia promote sustained activation of TGF-{beta}-Hippo feed-forward signaling, driving fibroblast-to-myofibroblast transition and amplifying fibrotic responses. Together, these findings position the imbalance between ciliary assembly and disassembly as a central determinant of fibrotic fibroblast fate in SSc. Moreover, they indicate that therapeutically stabilizing primary cilia, "ciliotherapy", can reset pathological fibroblast trajectories and represents a promising antifibrotic strategy for SSc and other fibrotic conditions. TeaserDisrupted Primary Cilia Drives Pathophysiology of Systemic Sclerosis.

cell biology↗

bioRxiv2026

Targeting activated IL-23 signaling in Scleroderma by tildrakizumab

The pathogenesis of systemic sclerosis (SSc) involves immune system dysregulation and progressive multi-organ fibrosis. Aberrant interleukin-23 (IL-23) function is linked to many inflammatory conditions. Tildrakizumab, a humanized monoclonal antibody that binds to the p19 subunit of IL-23 to block its interaction with the IL-23 receptor, is FDA-approved for treating psoriasis. IL-23 levels are increased in SSc patients with lung involvement, but the pathogenic role of IL-23 in SSc fibrosis remains unclear. We examined IL-23 expression in SSc skin biopsies and assessed the effects of IL-23 inhibition in an in vivo fibrosis model. We found increased IL-23 expression in SSc compared to healthy skin biopsies. Pharmacological blockade of IL-23 signaling using tildrakizumab reversed experimental skin and lung fibrosis. Our findings support a pathogenic role of IL-23 in SSc and suggest that tildrakizumab could be a novel antifibrotic treatment strategy for SSc and related fibrotic disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/701821v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@777c8aorg.highwire.dtl.DTLVardef@9163f5org.highwire.dtl.DTLVardef@1399a54org.highwire.dtl.DTLVardef@c30ec2_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Selective identification of the herb Picrorhiza kurroa and probiotic Lactobacillus fermentum as a synbiotic with fermentation-enhanced physicochemical, biological, and metabolomic properties

PurposeAlthough secondary metabolites of medicinal plants can modulate the gut microbiota, their prebiotic and synbiotic potential is not fully explored. This study aimed to identify novel medicinal plant-probiotic combination(s) that show prebiotic and synbiotic effects through mutual synergism and reciprocal interactions. MethodsTen Himalayan region medicinal plants were screened for their selective prebiotic efficacy by studying in vitro proliferation of three species of lactic acid bacteria (LAB) and concurrent suppression of E. coli. The top-performing plants were evaluated for synergism with LAB through fermentation of pure extracts, followed by physicochemical, biological, and metabolomic profiling. ResultsAmong the ten plant species, Picrorhiza kurroa (PK) and Adhatoda vasica (AV) exhibited promising prebiotic attributes with PAS scores of 0.50 and 0.44, respectively, while Lactobacillus fermentum (LF) emerged as the most compatible probiotic strain. Unlike AV, fermentation of PK with LF demonstrated superior probiotic growth (2.2-fold increase), elevated total flavonoids (21.6% increase), and improved antioxidant capacity (24.02% increase) compared to unfermented PK. Fermented PK significantly enhanced cytoprotective effects and mitigated oxidative (ROS levels/lipid peroxidation) and inflammatory damage (NO/IL-6 levels) in macrophages and muscle cells exposed to separate exogenous stressors (LPS and H2O2). Elemental (ICP-OES) and metabolomic analysis (LC-MS/UHPLC) revealed that LF metabolised major elements of PK (Ca/Fe/K/Na/Cu) and induced biotransformation of large secondary metabolites, including the characteristic iridoid glycosides of PK, into smaller, more abundant metabolites. ConclusionsPK-LF combination is identified as a synbiotic, and its fermented product is a superior bioactive product that can be developed into innovative nutraceuticals or herbal formulations.

biochemistry↗

bioRxiv2025

A target product profile for a rapid diagnostic test to monitor mosquito gene drive presence and frequency

Malaria remains a major global health challenge, with over 263 million cases and nearly 600,000 deaths reported in 2023, the majority in sub-Saharan Africa. While conventional interventions such as insecticide-treated nets, indoor residual spraying and antimalarial drugs have reduced transmission, progress has stalled due to the limitations of these interventions and the emergence of resistance. Gene drive-modified mosquitoes represent a promising, potentially transformative vector control strategy, capable of spreading malaria-refractory traits or suppressing mosquito populations. Successful field deployment will depend upon monitoring systems to track the presence and frequency of gene drive constructs as they spread and persist. Current molecular surveillance techniques, though effective, are resource-intensive and reliant on laboratory infrastructure and technical competencies. Here, we make the case for a near-universal and low-cost rapid diagnostic test (RDT) designed to detect gene drive mosquitoes in the field, to complement existing surveillance infrastructure. Two use cases are outlined: i) to detect the presence of the drive construct in a new population, and ii) to provide an estimate of drive frequency prior to more accurate laboratory-based measurements. We provide a target product profile for the RDT outlining minimally essential and ideal characteristics, including test procedures, sensitivity, specificity, usability by a range of stakeholders in field settings, and compatibility with pooled testing of mosquito samples. An RDT for gene drive construct detection would support community access and participation in monitoring, enhance regulatory oversight, and promote transparency in field trials, thereby facilitating responsible deployment of gene drive-based malaria interventions.

genetics↗

bioRxiv2025

Y-linked editors for invasive rodent control

Invasive rodents are major contributors to biodiversity loss, particularly on islands where native species have evolved in their absence, rendering them vulnerable to predation. Genetic biocontrol offers a promising suite of species-specific technologies that may contribute to rodent suppression and elimination. Here, we evaluate the potential of Y-linked genome editors (YLEs), which contain a nuclease that disrupts a female-essential fertility or viability gene, to suppress or eliminate a mouse population on a small, isolated island. We benchmark YLEs against other self-limiting genetic biocontrol tools, such as sterile male releases, and self-sustaining tools, such as population suppression gene drives and Y-linked X chromosome-shredders. We use the MouseGD simulation framework to model the inheritance patterns of these systems in the context of rodent life history, calculating elimination probabilities, times to elimination and other outcomes for a range of construct designs, fitness costs and release schemes. We find that YLEs are more efficient than other self-limiting tools, and are capable of achieving rodent elimination within a short timeframe for modest release sizes. For a mouse population size of 10,000, elimination is predicted within five years for releases of 350 males per month, and within ten years for releases of 150 males per month. This scale of production is well within existing capabilities, potentially enabling suppression to encompass a larger spatial scale. We found that elimination could be achieved for YLEs targeting both haploinsufficient and haplosufficient target genes; but for a more restrictive parameter space for the haplosufficient case. Gene drives were predicted to achieve suppression and elimination for smaller release sizes; but also to spread to non-target populations. In contrast, YLEs do not bias inheritance and hence display minimal spillover. Altogether, these characteristics present YLEs as a promising, ecologically-manageable biocontrol tool for elimination of invasive rodents and conservation of native species.

ecology↗

bioRxiv2025

Targeting ALC1 can safely expand the therapeutic utility of PARP inhibitors across high-grade serous ovarian cancers

Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for homologous recombination-deficient (HRD) high-grade serous ovarian cancers (HGSOCs), but their long-term effectiveness is limited by the emergence of resistance and hematological toxicity. Moreover, PARPi are largely ineffective in HR-proficient HGSOCs, particularly tumors with CCNE1 amplification, which exhibit marked therapeutic resistance and currently lack effective treatment options. Loss of a chromatin remodeling enzyme, Amplified in Liver Cancer 1 (ALC1), has been shown to enhance PARPi sensitivity. However, the clinical contexts in which ALC1 targeting will be clinically meaningful remain elusive. Here we demonstrate that ALC1 loss enhances PARPi sensitivity across HRD and CCNE1-amplified serous ovarian cancer lines, xenograft and patient-derived cells. ALC1 depletion can overcome clinically relevant mechanisms of PARPi resistance while having minimal effects in BRCA-wild-type or heterozygous non-cancerous cells. Consistent with this therapeutic safety, PARPi sensitivity upon ALC1 loss can be reliably predicted by the endogenous levels of phospho-T21 RPA2, a marker for replication stress which is typically higher in ovarian cancer cells compared to their normal counterparts. Together, our studies define the clinical contexts in which the therapeutic utility of PARPi can be expanded by targeting ALC1, whose inhibitors are currently in Phase I clinical trials.

cancer biology↗

bioRxiv2025

Targeting RAD52 overcomes PARP inhibitor resistance in preclinical Brca2-deficient ovarian cancer model

AbstractBRCA-mutated ovarian cancer commonly develops resistance to poly (ADP-ribose) polymerase (PARP) inhibitors. Here, we investigated the DNA repair protein RAD52 as a potential target to overcome resistance. In analysis of The Cancer Genome Atlas datasets and immunohistochemistry of tissue microarrays, elevated RAD52 expression correlated with poor overall survival in patients with high-grade serous ovarian cancers. We tested two PARP inhibitor-resistant Brca2-deficient mouse ovarian cancer models, ID8-OR and HGS2-OR. HGS2- OR cells had higher RAD52 expression than parental lines. Rad52 knockout or knockdown restored PARP inhibitor sensitivity in both models. In syngeneic mice, ID8-OR cells in which Rad52 was knocked out yielded lower tumor burden and longer overall survival than control cells. Rad52 depletion impaired single-strand annealing and homologous recombination and led to accumulation of DNA double-strand breaks after PARP inhibitor treatment. RNA sequencing demonstrated that PARP inhibitor treatment induced Polq expression in Brca2- and Rad52-deficient cells, suggesting a switch to microhomology-mediated end joining. Finally, the RAD52 inhibitor D-I03 synergized with a PARP inhibitor to reduce cell viability and tumor burden and prolong survival. Collectively, our findings establish RAD52 as a promising therapeutic target to overcome PARP inhibitor resistance in BRCA2-mutated ovarian cancer and offer mechanistic insights to inform future clinical strategies.

cancer biology↗

bioRxiv2025

Targeting the COP9 signalosome overcomes platinum resistance in ovarian cancer through two distinct genome stability mechanisms

Tubo-ovarian high-grade serous carcinoma (HGSC) is a leading cause of gynecologic cancer mortality, largely due to the emergence of platinum resistance, which serves as the mainstay of chemotherapy. Here, we identify COPS5 as a therapeutic target and use an available small molecule inhibitor to overcome platinum resistance. A genetic screen for platinum-induced DNA damage in a platinum resistant ovarian cancer model identified COPS5 and COPS6, two components of the COP9 signalosome. Consistently, high COPS5 expression correlated with poor clinical outcomes in patients with HGSC. In both in vitro and in vivo experiments, COPS5 depletion sensitized ovarian cancer cells to carboplatin. A small molecule COPS5 inhibitor, CSN5i-3, synergized with carboplatin in homologous recombination-deficient and -proficient cells. This combination was also effective in xenografts and in a syngeneic mouse model of carboplatin-resistant HGSC. Importantly, we demonstrate that CSN5i-3 is selective for cancer cells, with patient-derived HGSC cells exhibiting up to 50-fold greater sensitivity to CSN5i-3 than benign cells. Finally, we show that genetic or small molecule inhibition of COPS5 impaired both nucleotide excision repair (NER) and interstrand crosslink (ICL) repair, leading to increased DNA platinum adducts. Mechanistically, this was due to increased ubiquitination and degradation of DNA-specific DNA binding protein 1 (DDB1) and other key NER and ICL repair proteins, consistent with the role of COPS5 in the regulation of these factors. Our findings highlight the importance of NER and ICL regulation in chemotherapy response and indicate that targeting COPS5 can enhance the efficacy of platinum-based chemotherapy in HGSC. One Sentence SummaryCOPS5 depletion or inhibition using a small molecule COPS5 inhibitor CSN5i-3 sensitizes high-grade serous carcinoma to platinum chemotherapy through downregulation of nucleotide excision repair and interstrand crosslink repair.

cancer biology↗

bioRxiv2025

A brain-specific microRNA, miR-1000, regulates lipid homeostasis via Neuropeptide-like precursor 1 in Drosophila melanogaster

Metabolism requires precise gene regulation to balance energy intake and expenditure for an organisms well-being, with misregulation often leading to metabolic syndromes. This study reveals that the brain-specific microRNA miR-1000 regulates fat storage by controlling the expression of a neuropeptide gene, Nplp1. Loss of miR-1000 increases Nplp1 expression, leading to higher body weight, increased fat storage, improved survival under food deprivation conditions, and a reduced overall lifespan in Drosophila. We further show that miR-1000 promotes fat storage upon feeding by regulating TAG synthesis and storage in lipid droplets, thereby playing a crucial role in metabolic regulation.

neuroscience↗

bioRxiv2025

Neural mechanisms of training in Brain-Computer Interface: ABiophysical modeling approach

Brain-Computer Interface (BCI) is a system that translates neural activity into commands, allowing direct communication between the brain and external devices. Despite its clinical application, BCI systems are unable to robustly capture subjects intent due to a limited understanding of the neural mechanisms underlying BCI control. To address this issue, we introduce a biophysical linear neural mass model to investigate the associated neural mechanisms of motor imagery-based BCI experiments by modulating the scale-free spectral characteristics of afferent inputs. We tailor this motor imagery neural mass model (mi-NMM) to simulate both motor imagery task and resting state, and apply this approach to a cohort of 19 healthy subjects trained over four sessions where magnetoencephalography (MEG) and electroencephalography (EEG) signals were simultaneously recorded. Task-dependent modulation of scale-free cortical dynamics reveals training-induced excitatory-inhibitory reconfiguration in BCI training. The intra-regional neural connectivity strengths and time scales of the modeled excitatory and inhibitory neural mass populations capture changes in neural activity across conditions and sessions. Those changes appear in important areas of the sensorimotor cortex, relevant for motor imagery tasks. We observed these effects in both EEG and MEG modalities. These findings provide insights into the underlying neural mechanisms in a motor imagery task in BCI, paving the way to tailored BCI training protocols. Significance StatementBrain-computer interface (BCI) holds great promise in allowing direct communication between the brain and external devices, yet many users struggle to learn it reliably, largely because the neural mechanisms underlying BCI training remain poorly understood - thus lack of biologically grounded training protocols. This study introduces a biophysically grounded modeling framework that links large-scale brain dynamics to learning during motor imagery based BCI training. By explicitly modeling task-dependent cortical background input, we reveal how excitatory-inhibitory population dynamics reorganize with training, shifting from widespread cortical to targeted sensorimotor recruitment. Our results, replicated across EEG and MEG, identify excitatory population time scales as a robust neural marker of motor imagery learning. These findings provide mechanistic insight into BCI learning and offer principled targets for designing individualized BCI training protocols.

neuroscience↗

bioRxiv2025

A systems biology investigation to identify potential bi-omarkers in leprosy-affected host cells.

M. leprae adapts to the host cell environment and disrupts protein-protein interactions inside the host cell for its own survival and proliferation. This study is attempts to comprehend these host-pathogen interactions at the systems level. We utilised RNA-Seq data set of leprosy-resistant and leprosy-susceptible armadillos and investigated how five different human signaling pathways get hijacked by M. leprae. We also identified the corresponding human homolog proteins. By applying graph theory on these protein networks, we predicted 25 proteins which play important role in these pathways related to leprosy pathogenesis and/progression. The study is also supported by wet lab experiments identifying 69 proteins in armadillos upon leprosy progression after experimental infection which get differentially expressed. Our study found that 69.5% of these experimentally identified proteins are part of either M. leprae-affected signaling pathways or possibly contribute to leprosy pathogenesis based on their GO terms. This study identified three human proteins: LC3-II, PI3K and IDO1 which have been implicated in M. leprae pathogenesis in other studies also leprosy patients. Thus, upon further experimentally validation, such markers can be potentially useful to diagnose leprosy in patients at an early stage .

systems biology↗

bioRxiv2025

NF-κB mediates transactivation of HNRNPD, resulting in PTEN destabilization and constitutive activation of the PI3K-AKT pathway in oral cancer cells

Heterogeneous Ribonucleoprotein D (hnRNPD), an RNA binding protein transcriptionally upregulated by NF-{kappa}B transcription factor, is associated with poor outcome of Oral Squamous Cell Carcinoma (OSCC). However, the role of hnRNPD in OSCC remains elusive. This study reveals that hnRNPD positively affects the proliferation, migration, invasion, and survival of OSCC cells. Transcriptome profiling in hnRNPD knockout cells identified significant upregulation of PTEN and inhibition of the PI3K/AKT/mTOR axis. HnRNPD mediates the destabilization of PTEN mRNA by binding to the class II AU-Rich Element (ARE) in 3UTR of PTEN. The expression of hnRNPD and PTEN are strongly negatively correlated in OSCC tissue specimens, further corroborating hnRNPD-mediated PTEN destabilization. The hnRNPD knockout inhibited autophagy, evident by an accumulation of autophagic vesicles and decreased autophagic flux. Mechanistically, the hnRNPD knockout reduced the expression of NF-{kappa}B, eventually downregulating its transcriptional target LC3b, a key mediator of autophagy. SA-{beta}-Galactosidase staining in hnRNPD KO cells conclusively demonstrated the onset of cellular senescence. The present study demonstrates hnRNPD-driven positive modulation of autophagy via NF-{kappa}B, independent of the PI3K/AKT/mTOR axis, highlighting it as a novel therapeutic target for treating oral cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/631360v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@11f6844org.highwire.dtl.DTLVardef@f65124org.highwire.dtl.DTLVardef@1492571org.highwire.dtl.DTLVardef@13931dd_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHnRNPD mediates oral cancer cell proliferation, migration, invasion, and survival. C_LIO_LIHnRNPD acts as a novel regulator of the PI3K/AKT/mTOR axis by destabilization of PTEN. C_LIO_LINF-{kappa}B/RelA downregulated on knockout of HNRNPD, inhibiting autophagy through downregulating its transcriptional target LCB-II. C_LIO_LIHnRNPD mediates cellular senescence in oral cancer cells. C_LI

cancer biology↗

bioRxiv2024

Replication stress marker phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination-proficient ovarian cancer

BackgroundOvarian cancer treatment includes cytoreductive surgery, platinum-based chemotherapy, and often poly (ADP-ribose) polymerase (PARP) inhibitors. Homologous recombination (HR)-deficiency is a well-established predictor of therapy sensitivity. However, over 50% of HR-proficient tumors also exhibit sensitivity to standard-of-care treatments. Currently, there are no biomarkers to identify which HR-proficient tumors will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. MethodsWe evaluated phospho-RPA2-T21 (pRPA2) foci via immunofluorescence as a potential biomarker of replication stress in formalin-fixed, paraffin-embedded tumor samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort: n = 31, validation cohort: n = 244) or PARP inhibitors (n = 87). Recurrent tumors (n = 37) were also analyzed. pRPA2 scores were calculated using automated imaging analysis. Samples were defined as pRPA2-High if > 16% of cells had [≥] 2 pRPA2 foci. ResultsIn the discovery cohort, HR-proficient, pRPA2-High tumors demonstrated significantly higher rates of pathologic complete response to platinum chemotherapy than HR-proficient, pRPA2-Low tumors. In the validation cohort, patients with HR-proficient, pRPA2-High tumors had significantly longer survival after platinum treatment than those with HR-proficient, pRPA2-Low tumors. Additionally, the pRPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent tumor samples. ConclusionOur study underscores the importance of considering replication stress markers alongside HR status in therapeutic planning. Our work suggest that this assay could be used throughout a patients treatment course to expand the number of patients receiving effective therapy while reducing unnecessary toxicity.

cancer biology↗