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ObjectiveFast and accurate deformable image registration (DIR) that include DIR uncertainty estimation are essential for safe and reliable clinical deployment. While recent deep learning models have shown promise in predicting DIR with its uncertainty, challenges persist in proper uncertainty evaluation and hyperparameter optimization for these methods. This work aims to develop and evaluate a model that can perform fast DIR and predict its uncertainty in seconds.ApproachIn this study, we introduce a novel probabilistic multi-resolution image registration model utilizing convolutional neural networks (CNNs) to estimate a multivariate normal distributed dense displacement field (DDF) in a multimodal image registration problem. To assess the quality of the DDF distribution predicted by the model, we propose a new metric based on the Kullback-Leibler divergence. The performance of our approach was evaluated against three other DIR algorithms (VoxelMorph, Monte Carlo Drop-Out, and Monte Carlo B-splines) capable of predicting uncertainty. The evaluation of the models included not only the quality of the deformation but also the reliability of the estimated uncertainty. Our application investigated registration of a treatment planning computed tomography (CT) to follow-up cone beam CT for daily adaptive radiotherapy.Main resultsThe hyperparameter tuning of the models showed that there is a trade-off between the reliability of the estimated uncertainty and the accuracy of the deformation. In the optimal trade-off our model excelled in contour propagation and uncertainty estimation (p < 0.01) compared to existing uncertainty estimation models. We obtained an average dice similarity coefficient of 0.89 and a KL-divergence of 0.15.SignificanceBy addressing challenges in DIR uncertainty estimation and evaluation, our work showed that both the DIR and its uncertainty can be reliably predicted paving the way for safe deployment in clinical environment..

Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.

PurposeTo develop and compare tumor-control probability (TCP) models for single-fraction stereotactic radiosurgery (SRS) for brain metastasis (BMs) with and without retreatment.Methods and materialsWe developed three different schemas to model TCP of BMs treated with linear accelerator-based SRS. Dose to 99% of each planning target volume (PTV D99) and 6-month local control were fit using linear-quadratic-linear (LQ-L) models based on equivalent-dose conversions in 2 Gy (EQD2). The M1 schema had separate LQ-L TCP models for initial dose (M1-initial) and retreatment dose (M1-retreat), and the M2 schema had an LQ-L model using the sum of 50% of the initial SRS dose plus the retreatment SRS dose. The M1-initial and M1-retreat schema modeled local control after first SRS to 48 lesions (patients = 22) and second SRS to 46 lesions (patients = 21). The M0 schema included a whole data set of 349 lesions (patients = 136) receiving first SRS (no retreatment and M1-initial).ResultsLQ-L models fitted the data well (χ2 = 0.059-0.525 and P = 0.999-1.000). For M0 and M1-retreat, the fitted models EQD250 and γ50 parameters were similar. The LQ-L fitted EQD250 was ∼8.0 Gy for M0 and M1-retreat, ∼24 Gy for M1-initial, and ∼19 Gy for M2. The model fitted γ50 was 0.1 Gy for M0, M1-retreat, and M2 and 0.5 for M1-initial. For the PTV D99 of 10 and 20 Gy, the steepest to shallowest dose-response or largest change in TCP, that is, TCP20Gy - TCP10Gy, was observed in M1-initial (0.49) and M2 (0.17). M0 and M1-retreat showed a similar change in TCP of 0.21.ConclusionsThe model-fitted parameters predicted the recurrent BMs required a higher threshold dose and had a steeper dose-response for first SRS versus second SRS and M0. Alternatively, the recurrent BMs required ∼2 Gy higher predicted PTV D99 dose for first SRS to achieve the same TCP of 0.75 compared with second SRS and M0. Further investigations on larger patient cohorts are needed for validating our findings in predictive modeling of recurrent BMs.

PurposeTo suggest PTV margins for liver SBRT with different motion management strategies based on a systematic review and meta-analysis.MethodsIn accordance with Preferred-Reporting-Items-for-Systematic-Reviews-and-Meta-Analyses (PRISMA), a systematic review in PubMed, Embase and Medline databases was performed for liver tumor position variability. From an initial 533 studies published before October 2020, 36 studies were categorized as 18 free-breathing (FB; npatients = 401), 9 abdominal compression (AC; npatients = 145) and 9 breath-hold (BH; npatients = 126). A meta-analysis was performed on inter- and intra-fraction position variability to report weighted-mean with 95% confidence interval (CI95) in superior-inferior (SI), left-right (LR) and anterior-posterior (AP) directions. Furthermore, weighted-mean ITV margins were computed for FB (nstudies = 15, npatients = 373) and AC (nstudies = 6, npatients = 97) and PTV margins were computed for FB (nstudies = 6, npatients = 95), AC (nstudies = 7, npatients = 106) and BH (nstudies = 8, npatients = 133).ResultsThe FB weighted-mean intra-fraction variability, ITV margins and weighted-standard-deviation in mm were SI-9.7, CI95 = 9.3-10.1, 13.5 ± 4.9; LR-5.4, CI95 = 5.3-5.6, 7.3 ± 7.9; and AP-4.2, CI95 = 4.0-4.4, 6.3 ± 7.6. The inter-fraction-based results were SI-4.7, CI95 = 4.3-5.1, 5.7 ± 1.7; LR-1.4, CI95 = 1.1-1.6, 3.6 ± 2.7; and AP-2.8, CI95 = 2.5-3.1, 4.8 ± 2.1. For AC intra-fraction results in mm were SI-1.8, CI95 = 1.6-2.0, 2.6 ± 1.2; LR-0.7, CI95 = 0.6-0.8, 1.7 ± 1.5; and AP-0.9, CI95 = 0.8-1.0, 1.9 ± 1.7. The inter-fraction results were SI-2.6, CI95 = 2.3-3.0, 5.2 ± 2.9; LR-1.9, CI95 = 1.7-2.1, 4.0 ± 2.2; and AP-2.9, CI95 = 2.5-3.2, 5.8 ± 2.7. For BH the inter-fraction variability, and the weighted-mean PTV margins and weighted-standard-deviation in mm were SI-2.4, CI95 = 2.1-2.7, 5.6 ± 2.9; LR-1.8, CI95 = 1.3-2.2, 5.5 ± 1.7; and AP-1.4; CI95 = 1.2-1.7, 6.1 ± 2.1.ConclusionOur meta-analysis suggests a symmetric weighted-mean PTV margin of 6 mm might be appropriate for BH. For AC and FB, asymmetric PTV margins (weighted-mean margin of 4 mm (AP), 6 mm (SI/LR)) might be appropriate. For FB, if larger (>ITV margin) intra-fraction variability observed, the additional intra- and inter-fraction variability should be accounted in the PTV margin.

Aim: We present the synthesis of anti-bacterial gold nanoparticles using chitosan as a dual-functional agent. The resulting ChAuNPs were further modified with a lipopolysaccharide-targeting antibacterial peptide to aid in biocompatibility and specificity. Materials & methods: The nanoparticles' antibacterial activity against Escherichia coli was tested in the presence of a 450 nm laser. Results: Our data suggested that the peptide and laser emissions had a synergistic impact on the gold nanoparticles, resulting in strong antibacterial effects. The study shows that advanced nanomaterials, including chitosan, gold nanoparticles and lipopolysaccharide targeting peptides, can boost antibacterial functions at a low concentration of 250 μg/ml. Conclusion: The findings highlight ChAuNPs' potential as strong antibacterial agents, with targeted alterations critical for maximizing their utilization. Article highlights Use of chitosan as a dual-functional i.e. reducing and stabilizing agent for synthesizing the gold nanoparticles. Lipopolysaccharide-targeting antibacterial peptide decorated chitosan-coated gold nanoparticles (ChAuNPs) with improved biocompatibility and specificity. Advanced nanomaterials featuring chitosan, gold nanoparticles and lipopolysaccharide-targeting peptides were developed. The antibacterial effectiveness of the nanoparticles was tested against E. coli with 450 nm laser exposure. The study showed significant antimicrobial effects due to the combined action of the peptide and laser. The results highlight the potential of ChAuNPs as potent antibacterial and ROS producing agents due to its tailored modifications. The nanomaterials demonstrated enhanced antimicrobial properties at a low concentration of 250 μg/ml. The study contributes to advanced nanomaterials for antimicrobial applications, emphasizing the potential of LPS targeting ChAuNPs in fighting bacterial infections. [ABSTRACT FROM AUTHOR]

Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell–cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]