Biology subjects

Goodwin, J.

Publications and source records attributed to Goodwin, J..

8 recordsLinked to original sources

bioRxiv2026

Automated Segmentation of Prostatic Gold Fiducial Markers for MR-Only Radiotherapy Planning Using Multi-Modal Consensus Deep Learning

PurposeTo develop and evaluate a multi-model consensus deep learning approach for automated gold fiducial marker (FM) segmentation in T1-weighted prostate MRI. Materials and MethodsIn this retrospective study, T1-weighted MRI and CT-derived reference standard segmentations were collected from 127 prostate cancer patients (all male; mean age, 70 years {+/-} 7 [standard deviation]; age range, 50-88 years; collected between October 2020 and January 2026) who each had three implanted gold FMs. A 3D U-Net was trained on 93 subjects using four random seeds to produce an ensemble. At inference, marker-class probability maps were averaged across models and the top three connected components selected. Performance was evaluated on 34 temporally held-out subjects (9 tuning, 25 test) using marker-level sensitivity and precision with exact (Clopper-Pearson) 95% confidence intervals (CIs). A model count ablation study was performed. The pipeline was deployed for on-scanner processing on Siemens MRI systems via the OpenRecon framework and as a browser-based application using WebAssembly, executing entirely client-side. ResultsThe four-model consensus achieved 96% (70 of 73) sensitivity and 95% (70 of 74) precision on 25 test subjects, with 29 of 34 (85%) subjects achieving perfect marker detection. Single models had a mean sensitivity of 84% (SD, 9%), improving to 96% with four-model consensus (SD, <1%). ConclusionMulti-model consensus deep learning substantially improved FM segmentation reliability over individual models, achieving high sensitivity and precision using only routinely acquired T1-weighted MRI.

bioinformatics↗

bioRxiv2025

Palbociclib CDK4/6- and Crizotinib MET/ALK/ROS1-inhibitors Synergize to Enhance Senescence and Immune Recognition in Melanoma Cells Independently of BRAF/NRAS Status

"Pro-senescence therapy", which triggers both permanent cell cycle arrest and an immune response, has been proposed as a strategy for cancer treatment, but is still controversial. To assess this strategy in melanoma, we performed a high throughput microscopy-based senescence screen utilizing a panel of melanoma cell lines with different driver mutations and a collection of clinical and experimental drugs. We found that vemurafenib and trametinib, which inhibit BRAFV600E and MEK1/2, respectively, induced senescence in some but not all BRAF-mutant cell lines. In contrast, palbociclib, BKM-120 and crizotinib, which inhibit CDK4/6, PI3K, and MET/ALK/ROS1, respectively, triggered senescence in most cell lines, irrespective of BRAF/NRAS mutation status, and overcame intrinsic and acquired vemurafenib resistance. The combination of palbociclib and crizotinib synergized to further enhance the senescence response in all cell lines irrespective of BRAF/NRAS mutation status, increased the expression of SASP factors, such as IL-1 and {beta}, and HLA class I and other markers for recognition by NK and T cells. Further, this combination caused a significant increase in CD8+ T cells and pro-inflammatory macrophages in the tumor microenvironment and a marked reduction of mouse melanoma tumor growth that was dependent on CD8+ T cells, suggesting increased immune surveillance. Our findings suggest that pro-senescence therapy based on concomitant inhibition of both CDK4/6 and MET/ALK/ROS1 could be developed further as an alternative treatment strategy for melanoma. Significance: Pro-senescence therapy based on combined targeting of CDK4/6 with palbociclib and MET/ALK/ROS1 with crizotinib inhibits melanoma tumor growth through anti-tumor immune response activation, providing an alternative treatment strategy for melanoma.

cancer biology↗

bioRxiv2023

Deep-Learning-Enabled Differentiation between Intraprostatic Gold Fiducial Markers and Calcification in Quantitative Susceptibility Mapping

PurposeInterest is growing in MR-only radiotherapy (RT) planning for prostate cancer (PCa) due to the potential reductions in cost and patient exposure to radiation, and a more streamlined work-flow and patient imaging pathway. However, in MRI, the gold fiducial markers (FMs) used for target localization appear as signal voids, complicating differentiation from other void sources such as calcifications and bleeds. This work investigates using Quantitative Susceptibility Mapping (QSM), an MRI phase post-processing technique, to aid in the differentiation task. It also presents deep learning models that capture nuanced information and automate the segmentation task, facilitating a streamlined approach to MR-only RT. MethodsCT and MRI, including GRE and T1-weighted imaging, were acquired from 26 PCa patients, each with three implanted gold FMs. GRE data were post-processed into QSM, T 2*, and R2* maps using QSMxTs body imaging pipeline. Statistical analyses were conducted to investigate the quantitative differentiation of FMs and calcification in each contrast. 3D U-Nets were developed using fastMONAI to automate the segmentation task using various combinations of MR-derived contrasts, with a model trained on CT used as a baseline. Models were evaluated using precision and recall calculated using a leave-one-out cross-validation scheme. ResultsSignificant differences were observed between FM and calcification regions in CT, QSM and T 2*, though overlap was observed in QSM and T 2*. The baseline CT U-Net achieved an FM-level precision of {approx} 98% and perfect recall. The best-performing QSM-based model achieved precision and recall of 80% and 90%, respectively, while conventional MRI had values below 70% and 80%, respectively. The QSM-based model produced segmentations with good agreement with the ground truth, including a challenging FM that coincided with a bleed. ConclusionThe model performance highlights the value of using QSM over indirect measures in MRI, such as signal voids in magnitude-based contrasts. The results also indicate that a U-Net can capture more information about the presentation of FMs and other sources than would be possible using susceptibility quantification alone, which may be less reliable due to the diverse presentation of sources across a patient population. In our study, QSM was a reliable discriminator of FMs and other sources in the prostate, facilitating an accurate and streamlined approach to MR-only RT.

pathology↗

bioRxiv2023

Loss of endothelial glucocorticoid receptor accelerates organ fibrosis in db/db mice

Endothelial cells play a key role in maintaining homeostasis and are deranged in many disease processes, including fibrotic conditions. Absence of the endothelial glucocorticoid receptor (GR) has been shown to accelerate diabetic kidney fibrosis in part through up regulation of Wnt signaling. The db/db mouse model is a model of spontaneous type 2 diabetes that has been noted to develop fibrosis in multiple organs over time, including the kidneys. This study aimed to determine the effect of loss of endothelial GR on organ fibrosis in the db/db model. Db/Db mice lacking endothelial GR showed more severe fibrosis in multiple organs compared to endothelial GR-replete db/db mice. Organ fibrosis could be substantially improved either through administration of a Wnt inhibitor or metformin. IL-6 is a key cytokine driving the fibrosis phenotype and is mechanistically linked to Wnt signaling. The db/db model is an important tool to study mechanisms of fibrosis and its phenotype in the absence of endothelial GR highlights the synergistic effects of Wnt signaling and inflammation in the pathogenesis or organ fibrosis.

physiology↗

bioRxiv2021

QSMxT: Robust Masking and Artefact Reduction for Quantitative Susceptibility Mapping

PurposeQuantitative Susceptibility Mapping (QSM) is a post-processing technique applied to gradient-echo phase data. QSM algorithms require a signal mask to delineate regions with reliable phase signal for subsequent susceptibility estimation. Existing masking techniques used in QSM have limitations that introduce artefacts, exclude anatomical detail, and rely on parameter tuning and anatomical priors that narrow their application. Here, a robust masking and reconstruction procedure is presented to overcome these limitations and enable automated QSM processing for a wide range of use-cases implemented in an open-source software framework: QSMxT. MethodsA robust masking technique that automatically separates reliable from less reliable phase regions was developed and combined with a two-pass reconstruction procedure that operates on the separated sources before combination, extracting more information while reducing the influence of artefacts. ResultCompared with standard masking and reconstruction procedures, the two-pass inversion reduces streaking artefacts caused by unreliable phase and high dynamic ranges of susceptibility sources. QSMxT is robust across a range of datasets at 3 T in healthy volunteers and phantoms, at 7 T in tumour patients, and in the QSM challenge 2.0 simulated brain dataset, with significant artefact and error reductions, greater anatomical detail, and minimal parameter tuning. ConclusionQSMxT generates masks for QSM that separate reliable from less reliable phase regions, enables a more accurate QSM reconstruction that mitigates artefacts, operates without anatomical priors, and requires minimal parameter tuning. QSMxT makes QSM processing more accessible, reliable and reproducible.

neuroscience↗

bioRxiv2021

GABARAP membrane conjugation sequesters the FLCN-FNIP tumor suppressor complex to activate TFEB and lysosomal biogenesis

Adaptive changes in lysosomal capacity are driven by the transcription factors TFEB and TFE3 in response to increased autophagic flux and endolysosomal stress, yet the molecular details of their activation are unclear. LC3 and GABARAP members of the ATG8 protein family are required for selective autophagy and sensing perturbation within the endolysosomal system. Here we show that during single membrane ATG8 conjugation (SMAC), Parkin-dependent mitophagy, and Salmonella-induced xenophagy, the membrane conjugation of GABARAP, but not LC3, is required for activation of TFEB/TFE3 to control lysosomal homeostasis and capacity. GABARAP directly binds to a novel LC3-interacting motif (LIR) in the FLCN/FNIP tumor suppressor complex with picomolar affinity and regulates its relocalization to these GABARAP-conjugated membrane compartments. This disrupts the regulation of RagC/D by the FLCN/FNIP GAP complex, resulting in impaired mTOR-dependent phosphorylation of TFEB without changing mTOR activity towards other substrates. Thus, the GABARAP-FLCN/FNIP-TFEB axis serves as a universal molecular sensor that coordinates lysosomal homeostasis with perturbations and cargo flux within the autophagy-lysosomal network.

cell biology↗

bioRxiv2020

Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

Endothelial cells play a key role in the regulation of disease and other developmental processes. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells by autocrine effects or of neighboring cell types by paracrine effects, and in both cases contribute to organ fibrosis. However, regulatory control of endothelial cell homeostasis, is not well studied. Diabetes induced renal fibrosis in endothelial GR knock out mice (GRfl/fl;Tie 1 Cre; GRECKO) but not in control mice (GRfl/fl); hypercholesterolemia further enhanced severe renal fibrosis in diabetic GRECKO; Apoe-/- (DKO) but not in diabetic littermates (GRfl/fl; Apoe-/-). The fibrogenic phenotype in the kidneys of diabetic GRECKO and diabetic DKO were associated with aberrant cytokine and chemokine reprogramming. Canonical Wnt signaling was identified as new target for the action of endothelial GR. Wnt inhibiton improved kidney fibrosis by mitigating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transitions (EMT). Similarly, activation of fatty acid oxidation also suppressed kidney fibrosis. Conditioned media from endothelial cells from diabetic GRECKO stimulated Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic core molecule in diabetes.

cell biology↗

bioRxiv2019

Differentiating electrophysiological indices of internal and external performance monitoring: Relationship with perfectionism and locus of control

The impact of individual differences on performance monitoring and psychopathology is a question of active debate. Personality traits associated with psychopathology may be related to poor internal performance monitoring (as measured by the error-related negativity [ERN]) but intact external performance monitoring (as measured by the reward positivity [RewP]), suggesting that there are underlying neural differences between internal and external performance monitoring processes. We tested the relationships between individual difference measures of perfectionism, locus of control, and ERN, Pe, and RewP component difference amplitude in a healthy undergraduate sample. A total of 128 participants (69 female, M(SD)age= 20.6(2.0) years) completed two tasks: a modified version of the Eriksen Flanker and a doors gambling task along with the Frost Multidimensional Perfectionism scale, the Rotter Locus of Control scale, and the Levenson Multidimensional Locus of Control scale to quantify perfectionism and locus of control traits, respectively. Linear regressions adjusting for age and gender showed that neither {Delta}ERN nor {Delta}RewP amplitude were significantly moderated by perfectionism or locus of control scores. Findings suggest that, in psychiatrically-healthy individuals, there is not a strong link between perfectionism, locus of control, and ERN or RewP amplitude. Future research on individual difference measures in people with psychopathology may provide further insight into how these personality traits affect performance monitoring.

neuroscience↗