Biology subjects

Shah, N. A.

Publications and source records attributed to Shah, N. A..

5 recordsLinked to original sources

bioRxiv2026

Homologous recombination deficiency prediction from whole slide images using label refinement and foundation-model benchmarking in ovarian cancer

BackgroundHomologous recombination deficiency (HRD) is clinically imperative in high-grade serous ovarian carcinoma (HGSOC), particularly because of its association with platinum sensitivity and benefit from poly(ADP-ribose) polymerase inhibitor (PARPi) therapy. However, public datasets rarely contain a complete combination of diagnostic haematoxylin and eosin (H&E) whole-slide images (WSIs), validated clinical HRD assay results, genomic scar scores, BRCA1 promoter methylation data, and treatment-response outcomes. This creates a major barrier for computational pathology studies seeking to develop clinically interpretable models of HRD or PARPi response from routine histology. ObjectiveWe performed an exploratory, leakage-controlled computational pathology benchmarking study to evaluate whether H&E WSIs from TCGA-OV contain a measurable morphology-linked signal associated with research-grade molecular HRD labels, and whether label refinement and pathology foundation-model embeddings alter predictive performance. MethodsWe assembled a frozen-primary TCGA-OV WSI cohort comprising 717 tissue-section/biospecimen slides from 316 patients. Diagnostic FFPE DX slides were excluded from model selection because of complete patient overlap with the frozen-primary cohort. Two HRD labels were evaluated: an initial mutation-only molecular label based on BRCA/HR-gene mutation evidence, and a refined methylation-enhanced molecular label that additionally incorporated BRCA1 promoter methylation. Feature extraction was performed using ResNet50, UNI, CONCH, Virchow2, Phikon-v2, and UNI2-h encoders. Patient-level attention-based multiple instance learning (ABMIL) was used with patient-as-bag modelling. Evaluation used patient-level grouped 5-fold x 5-repeat stratified cross-validation, with 25 folds total, bootstrap confidence intervals, and patient-level leakage control. ResultsThe initial mutation-only label classified 78 patients as positive and 238 as negative. The refined methylation-enhanced label recovered 33 additional positives, resulting in 111 positive and 205 negative patients. Patient-level ABMIL using UNI2-h features achieved the strongest performance for the refined label, with AUROC 0.634 (95% CI 0.571-0.698), AUPRC 0.468 (95% CI 0.390-0.562), balanced accuracy 0.597, sensitivity 0.532, specificity 0.663, F1 score 0.494, and Brier score 0.233. The calibrated threshold was 0.512, yielding TN=136, FP=69, FN=52, and TP=59. Comparative models showed lower discrimination, including UNI2-h with the initial label (AUROC 0.628), Phikon-v2 refined (0.582), Virchow2 refined (0.582), CONCH initial (0.587), ResNet50 refined (0.570), and clinical baselines (AUROC 0.54-0.57). ConclusionsTCGA-OV H&E WSIs contain a modest but reproducible morphology-linked signal associated with research-grade molecular HRD status. However, the AUROC around 0.63, absence of clinical HRD assay labels, lack of genomic scar endpoints in the implemented workflow, and absence of PARPi/platinum response targets prevent clinical interpretation. This study should be interpreted as a proof-of-concept benchmarking framework and methodological foundation for future H&E-based predictive modelling in clinically curated PARPi response cohorts.

pathology↗

bioRxiv2025

Shear Difference: Flow Type Dictates Endothelial Flow-Responsive Gene Programs in a 3D-Printed in vitro Model

BackgroundEndothelial cells (ECs) are mechanosensitive and adopt distinct phenotypes in response to hemodynamic forces. These phenotypes are rarely seen in shear-responsive signalling studies because commonly used in vitro platforms rarely reproduce the true scale of vessel geometries or physiologic waveforms. AimTo determine how the presence and temporal pattern of flow impact endothelial morphology and transcriptional activity in a 3D macrofluidic model. MethodsIdealised vessels were 3D-printed using a water-soluble polyvinyl alcohol filament and cast in polydimethylsiloxane. The polyvinyl alcohol cores were dissolved leaving a polydimethylsiloxane lumen on which HMEC-1 cells were grown and perfused for 24 h under static, continuous flow, or pulsatile flow. Cell morphology was assessed using immunofluorescence. Bulk RNA-seq was performed with Hallmark pathway enrichment using gene set enrichment analysis. ResultsRelative to static culture, continuous flow increased cell eccentricity (0.74 vs 0.48, p <0.0001) and reduced variability in cell orientation ({Delta} = -47.1{degrees}, p <0.0001). At the transcriptome level, differential gene expression was extensive (continuous vs static: 2,103 genes; pulsatile vs static: 2,643 genes; pulsatile vs continuous: 384 genes). Continuous flow favoured oxidative-metabolic and barrier-maintenance pathways. By contrast, pulsatile shear of the same mean load promoted cell-cycle/checkpoint signalling rather than oxidative-metabolic programmes. Head-to-head, pulsatile flow emphasized MYC proto-oncogene (MYC) and E2F transcription factor (E2F), whereas continuous flow preferentially engaged oxidative phosphorylation and phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase (AKT)-mechanistic target of rapamycin (MTOR) (with higher tumor protein p53and transforming growth factor-{beta} signaling). ConclusionUnder matched mean shear, pulsatile versus continuous flow drive distinct endothelial morphological and transcriptional programs, enriching pathways central to blood vessel function, remodelling, and disease. 3D macrofluidic platforms can replicate flow-specific endothelial cell mechanobiology, providing a translational tool to better understand vascular outcomes.

bioengineering↗

bioRxiv2024

Differences in Cellular mechanics and ECM dynamics shape differential development of wing and haltere in Drosophila

Diverse organ shapes and sizes arise from the complex interplay between cellular properties, mechanical forces, and gene regulation. Drosophila wing-a flat structure and the globular haltere are two homologous flight appendages emerging from a similar group of progenitor cells. The activity of a single Hox transcription factor, Ultrabithorax (Ubx), governs the development of these two distinct organs-wing and haltere with different cell and organ morphologies. Our work reported here on differential development of wing and haltere suggest that the localisation and abundance of actomyosin complexes, apical cell contractility, properties of extracellular matrix, and cell size and shape, which is a result of various cell intrinsic and extrinsic forces, plausibly influence the flat vs. globular geometry of these two organs. We followed the three-dimensional architecture of developing wing and halteres during early pupal morphogenesis, indicating the role of the above-mentioned factors in force generation and in driving differential morphogenesis, leading to different organ shapes. Loss of Ubx function led to wing cell-like cellular features in haltere discs, and corresponding changes at the level of adult organs. We also observed that RNAi-mediated downregulation of Atrophin or Pten, in the background of downregulated Expanded (or elevated Yki), gave rise to varying degrees of haltere to wing homeotic transformations at the cellular as well as adult organ levels. Finally, we provide simulated scenarios based on computational modelling that propose key ingredients required for producing wing- or haltere-like morphologies in Drosophila.

developmental biology↗

bioRxiv2021

Sugar Beet Extract Acts as a Natural Bio-Stimulant for Physio-Biochemical analysis of Hordeum Vulgare L. under Induced Salinity Stress

Change in climate of the entire globe due to elevated temperature and minimum annual rainfall in barren zone frequently leads to salinity of soil. The current study was aimed to evaluate the importance of sugar beet extract (SBE) as a bio-stimulant to improve the adverse damages of induced salinity stress (40mM) on growth, oosmolytes and antioxidant defense system of barley (Hordeum vulgare L.). Pot experiment was carried in green house under different concentrations of SBE (10%, 20%, 30%, 40%, 50%) pre-soaked seeds of Hordeum vulgare for 5 hours SBE was analyzed for glycine betaine (100mmol/kg), betalains (1.3mg/l), phenolics (1.30g/100ml), flavonoids (0.59mg/ml), carotenoids (0.23ml/100ml), vitamin E (0.002%), vitamin C (8.04g/100ml), sugar (8g/100ml), protein (1.39mg/100ml), and oxalic acid (38mg/100ml) while Ca (13.72mg/l), Mg (7.121 mg/l) and K (11.45mg/l) contents were also determined. We found significant improvement in germination parameters of Hordeum vulgare L. via SB extract on coefficient of velocity of emergence (CVE), mean emergence time (MET), germination energy (GE), timson germination index (TGI), germination rate index (GRI) and time to 50% emergence (E50) under induced salinity stress. However, photosynthetic pigments, e.g., chlorophyll and carotenoids were enhanced using 40% SB extract, soluble sugar, protein, proline, POD, MDA with 50% SB extract while SOD and H2O2 in 20% SBE, respectively. Our findings suggested that SB extract promotes both agronomical and physiological attributes, is a positive way to enhance our economy by increasing crop yields in arid and semi-arid areas along with plant tolerance to under induced salinity stress. HighlightsThe recent study is of utmost importance owing to the following reasons:[tpltrtarr] Changes in climatic condition results in salinity, droughts, floods, earthquakes, fluctuation in temperature and other environmental hazards. [tpltrtarr]Salinity stress has myriad of damaging effects on crop growth and productivity and becoming a global issue of major concern especially in the Asian countries including Pakistan. Statistical analysis showed that 6.30 million of lands is affected with salinity. [tpltrtarr]Barley (Hordeum Vulgare L.) being an important crop of economic and nutritional value has been facing salinity stress condition in Pakistan, resulting in productivity reduction and ultimately paving the way for food scarcity and crippling economy. [tpltrtarr]The sole purpose of this research article is to assess and ameliorate the physio-biochemical responses via application of sugar beet extract as bio-stimulants in Barley (Hordeum Vulgare L.) grown under induced salinity stress; in order to cope with the dire consequences of salinity stress especially in the southern areas of Pakistan being badly affected by salt stress. [tpltrtarr]Furthermore, there is a great need for adaptive measures suggested by the present research and other findings made by researchers in pursuit of tackling this alarming global menace.

plant biology↗

bioRxiv2019

Whole-Genome Association Analyses of Sleep-disordered Breathing Phenotypes in the NHLBI TOPMed Program

Sleep-disordered breathing (SDB) is a common disorder associated with significant morbidity. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program we report the first whole-genome sequence analysis of SDB. We identified 4 rare gene-based associations with SDB traits in 7,988 individuals of diverse ancestry and 4 replicated common variant associations with inclusion of additional samples (n=13,257). We identified a multi-ethnic set-based rare-variant association (p = 3.48 x 10-8) on chromosome X with ARMCX3. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Results highlighted associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis and HIF1A-mediated hypoxic response.

genetics↗