Biology subjects

Gad, A.

Publications and source records attributed to Gad, A..

3 recordsLinked to original sources

bioRxiv2025

FOXJ1 mediates taxane resistance through regulation of microtubule dynamics

Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. We generated an in vivo model of docetaxel resistance using castration-resistant patient-derived xenografts and found increased expression of genes that drive development of multiciliated cells, including FOXJ1 and its effector genes, many of which regulate ciliary microtubules (MTs). Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients that will not benefit from taxane treatment. Statement of SignificanceThe early use of docetaxel in combination with androgen receptor targeted therapy can enhance survival in a subset of PC. This study indicates that increased FOXJ1 is predictive of tumors that will not benefit from docetaxel, and that agents targeting FOXJ1 or downstream effectors may enhance taxane responses and improve patient outcomes.

cancer biology↗

bioRxiv2025

Gradient scheme optimization for PRESS-localized edited MRS using weighted pathway suppression

This study aimed to design and implement an optimized gradient scheme for PRESS-localized edited magnetic resonance spectroscopy (MRS) to enhance suppression of out-of-voxel (OOV) artifacts. These artifacts, which originate from insufficient crushing of unwanted coherence transfer pathways (CTPs), are particularly challenging in editing schemes for metabolites like gamma-aminobutyric acid and glutathione. To address this, a volume-based likelihood model was developed to guide gradient scheme optimization, prioritizing suppression of CTPs based on likelihood. A volume-based likelihood model for CTP weighting was integrated into a Dephasing optimization through coherence order pathway selection (DOTCOPS) gradient optimization. Using a genetic algorithm with a new dual-penalty cost function, gradient schemes were optimized to maximize pathway-specific suppression. Hardware and sequence constraints, maximum gradient amplitudes and delay durations respectively, informed the optimization. Validation of the optimized scheme was performed with simulations by calculating the k-space crushing efficiency analytically with k-space trajectory. and in vivo using an edited MRS sequence in three brain regions (posterior cingulate cortex PCC, thalamus, and medial prefrontal cortex (mPFC)), with particular focus on OOV artifact reduction and spectral quality improvements. A three-way Analysis of Variance was used to assess the significance level of OOV artifact reduction. The optimized gradient scheme demonstrated improved k-space crushing efficiency (by an average of 197%). OOV artifacts were reduced in all brain regions, particularly in highly OOV-susceptible regions (thalamus and mPFC). Improvements were most notable around 4.3 ppm with significant OOV artifact amplitude reductions (p < 0.001). By using a volume-based likelihood model for CTP prioritization, the optimized DOTCOPS scheme ensures robust and region-agnostic performance in reducing OOV artifacts.

neuroscience↗

bioRxiv2025

Identifying out-of-voxel echoes in edited MRS with phase cycle inversion

1.PurposeTo identify the origin of out-of-voxel (OOV) signals based on the coherence transfer pathway (CTP) formalism using signal phase conferred by the acquisition phase cycling scheme. Knowing the CTP driving OOV artifacts enables optimization of crusher gradients to improve their suppression without additional data acquisition. Theory and MethodsA phase cycle systematically changes the phase of RF pulses across the transients of an experiment, encoding phase shifts into the data that can be used to suppress unwanted CTPs. We present a new approach, phase cycle inversion (PCI), which removes the receiver phase originally applied to the stored transients, replacing it with new receiver phases, matching the phase evolutions associated with each unwanted CTP, to identify the OOV signals. We demonstrated the efficacy of PCI using the MEGA-edited PRESS sequence in simulations, phantom and in vivo experiments. Based on these findings, the crusher gradient scheme was optimized. ResultsThe simulation results demonstrated that PCI can fully separate signals originating from different CTPs using a complete phase cycling scheme. PCI effectively identified the CTP responsible for OOV signals in phantom experiments and in vivo, though with reduced specificity in vivo due to phase instabilities. Re-optimization of the gradient scheme based on the identified OOV-associated CTP to suppress these signals, resulted in cleaner spectra in six volunteers. ConclusionPCI can be broadly applied across pulse sequences and voxel locations, making it a flexible and generalizable approach for diagnosing the CTP origin of OOV signals.

neuroscience↗