Biology subjects

Haris, M.

Publications and source records attributed to Haris, M..

5 recordsLinked to original sources

bioRxiv2026

Contrast-induced changes in chemical exchange saturation transfer MRI differentiate tumor progression from pseudoprogression

Tumor pseudo-progression (PsP) refers to an initial increase in tumor size or the appearance of new lesions. These pseudo-progressive lesions are predominantly composed of infiltrative inflammatory cells, such as macrophages. This phenomenon commonly occurs in patients undergoing radiation therapy or immunotherapy and typically indicates a positive treatment response. However, it often leads to premature treatment cessation due to misinterpretation as disease progression. Non-invasive imaging biomarkers capable of distinguishing pseudo-progression from true progression would greatly aid in treatment decision-making. In our preliminary study, we explored the potential of gadoterate meglumine (Gd-DOTA, a macrocyclic Gd-contrast) in combination with amine chemical-exchange saturation transfer (amine-CEST) imaging to differentiate tumor from radiation necrosis by assessing Gd-DOTA uptake by infiltrating immune cells, such as macrophages. To evaluate whether amine-CEST, in combination with Gd-DOTA, can differentiate macrophages from cancer cells, we incubated them with Gd-DOTA for 30 minutes. Subsequently, the cells were processed, and amine-CEST imaging was performed on a 9.4 Tesla preclinical scanner. Upon treatment with Gd-DOTA, we did not observe a significant change in amine-CEST contrast in F98 cells compared with untreated cells, whereas treated macrophages exhibited a marked decrease ([~]40%) in amine-CEST signal compared with untreated macrophages. This reduction in signal was attributed to the uptake of Gd-DOTA by macrophages, which notably shortened water T1 relaxation, thereby quenching the amine-CEST signal. Conversely, cancer cells showed no appreciable change in the amine-CEST signal, indicating no Gd-DOTA uptake. Furthermore, to validate that T1 shortening influences amine-CEST signal, cancer cells were also treated with manganese chloride (MnCl2) for 30 minutes. The uptake of MnCl2 by cancer cells similarly induced T1 shortening, as observed in macrophages, resulting in a decrease in the amine-CEST signal from these cells. Next, we performed the amin-CEST imaging on F98 tumor-bearing rats and radiation necrotic rats. Post-injection with Gd-DOTA showed no appreciable change in the amine-CEST contrast in the tumor-bearing rat, whereas a significant decrease in contrast was observed in the radiation necrotic rat. This further demonstrates that no change in the amine-CEST contrast in tumor-bearing rats is due to cancer cells failing to take up Gd-DOTA. The decrease in amine-CEST contrast in radiation-treated rats reflects the uptake of Gd-DOTA by macrophages infiltrating the radiation-necrotic regions. This straightforward imaging approach holds promise for clinical translation. It offers a novel method for characterizing pseudo-progressive lesions and monitoring diverse treatment responses in cancer patients using standard clinical scanners.

cancer biology↗

bioRxiv2026

Unsupervised anomaly detection for tumor delineation in a preclinical model of glioblastoma using CEST MRI

IntroductionGlioblastoma is characterized by heterogeneous tumor characteristics and infiltrative tumor boundaries, making accurate delineation difficult with extensive manual annotations. Chemical exchange saturation transfer (CEST) is a non-invasive MRI technique used for in vivo assessment of metabolic and macromolecular information through a Z-spectrum. CEST may provide insight into metabolic changes present in early-stage disease that are not visible in routine clinical imaging, thereby improving tumor delineation. In this work, we use an unsupervised anomaly detection (UAD) strategy to learn the distribution of features present in Z-spectra of healthy tissue and capture their deviations in pathology, foregoing the need for extensive labels. The approach leverages the metabolic information provided by CEST to improve the detection and delineation of glioblastoma and inform further treatment planning. MethodsA 1D convolutional autoencoder (CAE) was implemented to reconstruct Z-spectra from individual tissue voxels. The network was trained on Z-spectra acquired at 9.4T from healthy Sprague-Dawley rats and tested on data acquired from F98 glioma-bearing rats post Gd-administration. For baseline comparisons, Isolation Forest and Local Outlier Factor, which have shown success in anomaly detection, were implemented. For the CAE, our anomaly score was determined to be the mean squared reconstruction error. To facilitate clinical translation and evaluate the robustness of our model for under sampled Z-spectra, acceleration factors of 2x and 7x were performed with two sampling schemes: uniformly skipping frequency offsets and selecting offsets based on feature importance identified by Shapley value analysis and Integrated Gradients (IG). Binarization was performed by determining an optimal anomaly threshold, followed by comparison to ground truth tumor masks. Metrics related to model performance were assessed for baseline anomaly detectors on the fully sampled dataset and for the CAE on fully and under sampled datasets. ResultsThe best baseline anomaly detector was Isolation Forest, with an ROC-AUC of 0.967 and an F1-score of 0.584. Our method, the CAE, accurately reconstructed Z-spectral features, achieving Dice scores of up to 0.72 and outperforming the baseline model with an ROC-AUC of 0.968 and F1-score of 0.642. This model performance remained robust across sampling schemes and acceleration factors, with ROC-AUCs of [~]0.96 and similar Dice scores (up to 0.7). Feature importance analysis indicated that offsets in the range of {+/-}3.0 to 5.0ppm contributed most to the anomaly score. DiscussionThis study successfully demonstrated a UAD pipeline utilizing the Z-spectrum from CEST MRI for metabolically informed tumor delineation. The framework captures biochemical deviations that may precede or extend beyond morphologic abnormalities, enabling sensitive detection of tumor regions and intra-tumoral heterogeneity that previous methods may fail to capture. The offsets from the feature analysis indicated a strong contribution from the magnetization transfer (MT) pool to the spectral deviations captured by the model, with additional contributions from relayed nuclear Overhauser effect (rNOE) and amide proton transfer (APT). Model robustness with under sampling further highlights the pipelines potential in accelerated acquisitions, thus improving clinical practicality. While there is a need for validation on larger cohorts and clinical datasets, the current results demonstrate that this label-free, Z-spectral anomaly mapping can serve as an interpretable and scalable tool for monitoring tumor heterogeneity and progression, with potential applicability to other diffuse or metabolically subtle pathologies.

cancer biology↗

bioRxiv2025

Multimodal MR Imaging for quantification of brain lipid in mice at 9.4T

BackgroundAdvanced MR imaging techniques like steady state Nuclear Overhauser enhancement (ssNOE), transient NOE (tNOE), and myelin water fraction (MWF) provide a non-invasive way to assess the biochemical and structural integrity of brain tissue. Their sensitivity to endogenous lipids and macromolecules allows for the early detection of neuropathological changes, making them valuable tools in studying brain health and disease progression. In this study, we systematically evaluate the repeatability and sensitivity of NOEMTR, tNOE, and MWF for quantifying lipid and myelin content in the brains of wild-type (WT) mice, correlating the results with immunohistochemistry (IHC). MethodsFive 6-month-old C57BL6/J mice were imaged using 3D-NOE, and four mice underwent imaging with 2D tNOE and MWF across four repeated sessions using a 9.4T Scanner. For ssNOE imaging, CEST-weighted images at 56 frequency offsets were acquired using B1rms of 1.0 T and 3s saturation duration. For tNOE, 52 offsets were acquired with a hyperbolic secant inversion pulse (bandwidth = 400Hz, duration = 44ms) and a mixing time of 200ms. For MWF, a multi-echo spin-echo (MESE) sequence was acquired with 40 evenly spaced echoes from 5.5ms to 200ms. For both ssNOE and tNOE, B0 correction was performed using WASSR. Repeatability was quantified using intra- and inter-subject coefficients of variation (COV%). Pearson correlation was performed to see the association between imaging matrices and IHC measures, Luxol fast blue (LFB) stained sections, and myelin basic protein (MBP). ResultsAll techniques demonstrated high repeatability across the whole brain (WB) and selected regions of interest (ROIs). Whole-brain intra-subject COV% for NOEMTR ranged from 1.92% to 3.40%, with corresponding inter-subject COVs of 1.50%. tNOE exhibited improved intra-subject repeatability with COVs ranging from 0.75% to 5.57%, but a reduced inter-subject COV of 2.97%. MWF imaging showed the highest stability overall, with an intra-subject COV ranging from 0.47% to 2.03% and an inter-subject COV of 0.75%. Visually, tNOE offers superior contrast in myelin-rich areas compared to NOEMTR and MWF imaging, showing greater sensitivity to myelinated regions. tNOE strongly correlates with histological markers: r = 0.83 with MBP staining and r = 0.72 with LFB staining (both p < 0.001). MWF and NOEMTR showed correlations with MBP (r = 0.63 and r = 0.57, respectively). ConclusionNOEMTR, tNOE, and MWF imaging are reliable and repeatable methods for quantifying macromolecules in the brain. Among these, tNOE emerges as the most sensitive for detecting myelin lipids as confirmed by histological validation. These findings highlight the translational potential of tNOE for studying demyelinating disorders and neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Magnetic Resonance Imaging for Improved Brain Tumor Detection

Precise demarcation of brain tumor boundaries is critical for optimizing treatment strategies and improving patient outcomes. In vivo characterization of tumor using PET/CT and MRI is clinical standard. PET/CT highlights the metabolic aspects of the tumor, while MRI provides information on functional, metabolic and structural changes. Even with technological advancements in both PET/CT and MRI, a method that can precisely delineate infiltrative tumor boundaries from normal-appearing brain regions (NABR) in vivo is still lacking. To address this limitation, we explored a relatively new MR imaging method, the Nuclear Overhauser Effect Magnetization Transfer Ratio (NOEMTR), in conjunction with a gadolinium-based contrast agent (Gd-DOTA), to precisely delineate the tumor boundaries in a rat model of infiltrative gliosarcoma. NOEMTR imaging was performed in the rat model (n=5) before and after Gd-DOTA administration. The post-Gd-DOTA NOEMTR map was subtracted from the pre-Gd-DOTA map and compared with contrast-enhanced T1-weighted images and immuno-histological findings. The resulting NOEMTR difference map clearly highlighted both the tumor core and infiltrative boundaries, which was not discernible on the post-contrast T1-weighted images. The extended tumor boundaries observed on the NOEMTR difference map corroborated with the IHC image, which confirmed the presence of infiltrative tumor cells and macrophages in these regions. Guided by the NOEMTR difference map, regions of interest (ROI) were drawn to quantify NOEMTR signal changes in the tumor core, tumor boundaries, and NABR post-Gd-DOTA. Tumor core showed a significant [~]43% reduction in NOEMTR signal (plJ=lJ0.003), while the tumor periphery exhibited a moderate reduction of [~]10%, (plJ=lJ0.045). No appreciable change in was observed in the NABR (plJ=lJ0.371). In contrast, the post contrast T1-weighted signal changes in tumor core, tumor periphery and NABR were, 33.32% (p = 0.092), 3.8% (p = 0.478), and 8.7% (p = 0.464) respectively. These findings suggest that NOEMTR imaging provides enhanced tumor contrast, particularly at the infiltrative tumor margins, where conventional contrast enhanced T1-weighted MRI may underestimate tumor extent. Histological validation confirmed the presence of infiltrative tumor cells and macrophages in the tumor periphery, as highlighted by the NOEMTR difference map. Overall, NOEMTR imaging, in combination with Gd-DOTA administration, demonstrates superior delineation of brain tumor boundaries compared to conventional MRI. As NOEMTR imaging is a fast acquisition scan (under 10 minutes) and performed on standard 3 Tesla, it can be easily integrated into clinical protocols. By improving visualization of tumor infiltration and distinguishing tumor regions from NABR, NOEMTR imaging holds promise for advancing neuro-oncological diagnostics and treatment planning.

bioengineering↗

bioRxiv2022

Hypoxic conditions promote a proliferative, poorly differentiated, and pro-secretory phenotype in COPD lung tissue progenitor cells in vitro

Chronic obstructive pulmonary disease patients experience variable symptoms dependent on the presence of an emphysematous versus a chronic bronchitis phenotype. Both presentations can be associated with lung tissue and systemic hypoxia, at its most severe leading to Cor pulmonale. Despite this, minimal attention has been given to the effects of hypoxia at the cellular disease level. We isolated and cultured progenitor cells from the distal lung tissue of a 64 year-old, male, emphysematous donor in ambient (21%) and hypoxic (2%) oxygen conditions. Proliferative capacity was determined on collagen coated culture plastic and growth-inactivated 3T3-J2 co-cultures. Epithelial (E-cadherin and pan-cytokeratin) and progenitor (TP63, cytokeratin 5) marker expression were examined. Expanded cells were differentiated at air-liquid interface and ciliated, mucous producing, and club cell populations identified. Isolated cells were positive for the epithelial, pan-cytokeratin and E-cadherin, and progenitor, TP63 and cytokeratin 5, cell markers at isolation and again at passage 5. Passage 5 expanded cells in hypoxia had increased the proportion of TP63 expressing cells by 10% from 51.6 {+/-} 1.2% to 62.6 {+/-} 2.3% (p [≤] 0.01). Proliferative capacity was greater in 3T3J2 co-cultured cells overall and in 2% oxygen this supported the emergence of a proliferation unrestricted population with a limited differentiation capacity. Cells expanded on collagen I in either oxygen underwent differentiation having been expanded with the production of ciliated cells positive for {beta}IV tubulin, and mucin 5ac, mucin 5b and CC10 positive secretory cells. Epithelial barrier formation was reduced significantly (p [≤] 0.0001) in hypoxia-expanded cells compared to normoxia. qRT-PCR showed higher expression of mucins in 2% expanded cells, significantly so with MUC5B (P [≤] 0.05) although mucin protein secretion was greater in 21% expanded cells. Concomitantly these results demonstrate that hypoxia promotes a proliferative phenotype while reducing the overall differentiation capacity of the cells. Further, the retained differentiation potential becomes skewed to a more secretory phenotype demonstrating that hypoxia may be contributing to disease symptom and severity in COPD patients.

physiology↗