bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.04.21.053736

T2 heterogeneity provides a sensitive measure of early tumor response to radiotherapy

Tomaszewski, M. R.·Dominguez Viqueira, W.·Ortiz, A.·Shi, Y.·Costello, J. R.·Enderling, H.·Rosenberg, S. A.·Gillies, R. J.
View original source ↗Export metadata ↓

Abstract

PurposeExternal beam radiotherapy (XRT) is a widely used cancer treatment, yet responses vary dramatically between patients. These differences are not accounted for in clinical practice, in part due to a lack of sensitive biomarkers of early response. In this work, we test the hypothesis that quantification of intratumor heterogeneity is a sensitive and robust biomarker of early response to XRT. A novel Magnetic Resonance Imaging (MRI) approach is proposed, utilizing histogram analysis of clinically-used T2 relaxation measurements to assess early changes in the tumor heterogeneity following irradiation in murine models of pancreatic cancer, indicative of radiotherapy response. Methods and MaterialsDynamic Magnetic Resonance T2 relaxation imaging was performed every 72h following 10 Gy dose XRT in two murine models of pancreatic cancer. Proposed biomarker of radiotherapy response was compared with tumor growth kinetics, and biological validation was performed through quantitative histology analysis. ResultsQuantification of tumor T2 interquartile range (IQR) as a measure of histogram width showed excellent sensitivity for detection of XRT-induced tumor changes as early as 72h after treatment, outperforming whole tumor T2 and Diffusion weighted MRI metrics. This response was observed both in quantitative T2 maps and in T2-weighted images that are routine in clinical practice. Histological comparison revealed the T2 IQR provides a measure of spatial heterogeneity in tumor cell density, related to radiation-induced necrosis. The early IQR changes were found to presage subsequent tumor volume changes in two distinct pancreatic models, suggesting promise for treatment response prediction. The metric showed excellent test-retest robustness. ConclusionsOur preclinical findings indicate that spatial heterogeneity analysis of T2 MRI can provide a sensitive and readily translatable method for early radiotherapy response assessment in pancreatic cancer. We propose that this will be useful in adaptive radiotherapy, specifically in MRI-guided treatment paradigms.

Explore related subjects

biophysicsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Tomaszewski, M. R., Dominguez Viqueira, W., Ortiz, A., Shi, Y., Costello, J. R., Enderling, H., Rosenberg, S. A., Gillies, R. J.. 2020-04-23. T2 heterogeneity provides a sensitive measure of early tumor response to radiotherapy. https://doi.org/10.1101/2020.04.21.053736

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Frequency-Dependent Structural Responses of Amyloid-β Fibrils to Terahertz Pulses: A Nonequilibrium Molecular Dynamics Study

The abnormal aggregation of amyloid proteins into fibrils is closely associated with several neurodegenerative diseases, highlighting the importance of developing effective strategies to modulate fibril structural stability. Here, we employed nonequilibrium molecular dynamics(NEMD) simulations to examine the effects of intense terahertz-to-mid-infrared pulses on three amyloid fibrils (2LMP, 2MXU, and 5OQV), focusing on the combined effects of pulse frequency and electric-field strength. Frequency scans from 0.5 to 60 THz in 0.5 THz steps revealed frequency-dependent losses of {beta}-sheet content, with several common response patterns in these fibrils. Comparisons at 2, 23, 33, and 50 THz showed that pulse-induced changes in secondary structure differed from those in high-temperature controls. Hydrogen-bond analysis showed that total hydrogen-bond counts could partially recover even as interchain hydrogen bonds continued to decrease, with distinct responses among representative chain pairs. We therefore propose a two-threshold electric-field framework for fibril disruption: Eth1 describes the onset of structural perturbation, whereas Eth2 indicates persistent structural loss after the pulse. This framework offers a testable approach for characterizing amyloid structural responses to external fields, although the underlying energy-coupling mechanisms, quantitative thresholds, and long-term recovery require further validation. These findings may provide a theoretical basis for exploring external-field-based strategies to modulate protein aggregation.

biophysics↗
bioRxiv2026

Organised streaming of cerebrospinal fluid in the human third ventricle

Quasi-periodic pressure pulses associated with cardiac and respiratory activity generate reciprocating cerebrospinal fluid (CSF) motion in the human ventricles. Regular waves dominated by the cardiac cycle are overlaid with cycles of low-frequency respiratory waves, the latter to become stronger in forced breathing or even dominated by large successive flushes in NREM sleep. The present study investigates how such waves contribute to residual streaming within the human ventricles. Transient CFD simulations were performed in the third ventricle at varying parameters of frequency, stroke volume and wave-form asymmetry. Increasing the aqueduct peak Reynolds-number, either by small stroke volume and high frequency or large stroke volume at low frequency, transfers the flow from a reversible flow pattern to the formation of clear preferential pathways, alternating between the in- and outflow cycle. The resulting permanent streaming flux across the aqueduct relative to the mean oscillatory flow-rate, i.e. the dimensionless streaming ratio SR follows a rational saturation relation, SR [~] ReAq,peak/(C + ReAq,peak), demonstrating that increasing the peak aqueduct Reynolds number yields diminishing returns and bounds the relative contribution of residual inter-ventricular streaming. These findings demonstrate differences in hydrodynamic organisation in the third ventricle and highlight the importance of this organisation for intraventricular fluid exchange.

biophysics↗
bioRxiv2026

Amyloid stability and condensate material properties independently govern the hnRNPA2 condensate to fibril transition

hnRNPA2 is a component of cellular membraneless organelles many of which contain RNA and RNA-binding proteins (RBPs). RBPs frequently contain low-complexity domains (LCDs) that can also assemble into amyloid fibrils. Fibrils isolated from patients with frontotemporal lobar degeneration contain ordered segments of these LCDs and disease-associated mutations can enhance the homotypic interactions that promote aggregation. Although previous studies have largely examined the condensate-to-fibril transition by altering condensate stability, how amyloid structure governs this process remains poorly understood. Here, we show that the hnRNPA2 LCD forms a reproducible fibril fold and by combining structure-guided thermodynamic profiling, peptide design, mutagenesis and in vitro characterization under conditions with (two-phase) and without (one-phase) condensates, we define the molecular determinants of its assembly. We identify an aromatic triad within the fibril core that controls fibril formation kinetics and thermodynamic stability. Mutational analysis further reveals that condensate stability and fibril stability are largely independent. Finally, microrheology linked reduced condensate viscosity to faster fibril formation, supporting a role for condensate material properties in regulating aggregation kinetics. Together, these findings support a model in which the condensate-to-fibril transition is governed by the interplay between a disordered ''fuzzy coat'' and a fibril-forming aromatic triad within hnRNPA2. This work provides a structural framework for understanding how condensates can transition into amyloid assemblies.

biophysics↗