Comparison of the Accuracy of a Deep Learning Method for Lesion Detection in PET/CT and PET/MRI Images.

PURPOSE: Develop a universal lesion recognition algorithm for PET/CT and PET/MRI, validate it, and explore factors affecting performance. PROCEDURES: The 2022 AutoPet Challenge's 1014 PET/CT dataset was used to train the lesion detection model based on 2D and 3D fractional-residual (F-Res) models. To extend this to PET/MRI, a network for converting MR images to synthetic CT (sCT) was developed, using 41 sets of whole-body MR and corresponding CT data. 38 patients' PET/CT and PET/MRI data were used to verify the universal lesion recognition algorithm. Image quality was assessed using signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Total lesion glycolysis (TLG), metabolic tumor volume (MTV), and lesion count were calculated from the resultant lesion masks. Experienced physicians reviewed and corrected the model's outputs, establishing the ground truth. The performance of the lesion detection deep-learning model on different PET images was assessed by detection accuracy, precision, recall, and dice coefficients. Data with a detection accuracy score (DAS) less than 1 was used for analysis of outliers. RESULTS: Compared to PET/CT, PET/MRI scans had a significantly longer delay time (135 ± 45 min vs 61 ± 12 min) and lower SNR (6.17 ± 1.11 vs 9.27 ± 2.77). However, CNR values were similar (7.37 ± 5.40 vs 5.86 ± 6.69). PET/MRI detected more lesions (with a mean difference of -3.184). TLG and MTV showed no significant differences between PET/CT and PET/MRI (TLG: 119.18 ± 203.15 vs 123.57 ± 151.58, p = 0.41; MTV: 36.58 ± 57.00 vs 39.16 ± 48.34, p = 0.33). A total of 12 PET/CT and 14 PET/MRI datasets were included in the analysis of outliers. Outlier analysis revealed PET/CT anomalies in intestines, ureters, and muscles, while PET/MRI anomalies were in intestines, testicles, and low tracer uptake regions, with false positives in ureters (PET/CT) and intestines/testicles (PET/MRI). CONCLUSION: The deep learning lesion detection model performs well with both PET/CT and PET/MRI. SNR, CNR and reconstruction parameters minimally impact recognition accuracy, but delay time post-injection is significant.

Robust residual-guided iterative reconstruction for sparse-view CT in small animal imaging.

Objective. We introduce a robust image reconstruction algorithm named residual-guided Golub-Kahan iterative reconstruction technique (RGIRT) designed for sparse-view computed tomography (CT), which aims at high-fidelity image reconstruction from a limited number of projection views.Approach. RGIRT utilizes an inner-outer dual iteration framework, with a flexible least square QR (FLSQR) algorithm implemented in the inner iteration and a restarted iterative scheme applied in the outer iteration. The inner FLSQR employs a flexible Golub-Kahan bidiagonalization method to reduce the size of the inverse problem, and a weighted generalized cross-validation method to adaptively estimate the regularization hyper-parameter. The inner iteration efficiently yields the intermediate reconstruction result, while the outer iteration minimizes the residual and refines the solution by using the result obtained from the inner iteration.Main results. The reconstruction performance of RGIRT is evaluated and compared to other reference methods (FBPConvNet, SART-TV, and FLSQR) using projection data from both numerical phantoms and real experimental Micro-CT data. The experimental findings, from testing various numbers of projection views and different noise levels, underscore the robustness of RGIRT. Meanwhile, theoretical analysis confirms the convergence of residual for our approach.Significance. We propose a robust iterative reconstruction algorithm for x-ray CT scans with sparse views, thereby shortening scanning time and mitigating excessive ionizing radiation exposure to small animals.

Markerless head motion tracking and event-by-event correction in brain PET.

Objective.Head motion correction (MC) is an essential process in brain positron emission tomography (PET) imaging. We have used the Polaris Vicra, an optical hardware-based motion tracking (HMT) device, for PET head MC. However, this requires attachment of a marker to the subject's head. Markerless HMT (MLMT) methods are more convenient for clinical translation than HMT with external markers. In this study, we validated the United Imaging Healthcare motion tracking (UMT) MLMT system using phantom and human point source studies, and tested its effectiveness on eight18F-FPEB and four11C-LSN3172176 human studies, with frame-based region of interest (ROI) analysis. We also proposed an evaluation metric, registration quality (RQ), and compared it to a data-driven evaluation method, motion-corrected centroid-of-distribution (MCCOD).Approach.UMT utilized a stereovision camera with infrared structured light to capture the subject's real-time 3D facial surface. Each point cloud, acquired at up to 30 Hz, was registered to the reference cloud using a rigid-body iterative closest point registration algorithm.Main results.In the phantom point source study, UMT exhibited superior reconstruction results than the Vicra with higher spatial resolution (0.35 ± 0.27 mm) and smaller residual displacements (0.12 ± 0.10 mm). In the human point source study, UMT achieved comparable performance as Vicra on spatial resolution with lower noise. Moreover, UMT achieved comparable ROI values as Vicra for all the human studies, with negligible mean standard uptake value differences, while no MC results showed significant negative bias. TheRQevaluation metric demonstrated the effectiveness of UMT and yielded comparable results to MCCOD.Significance.We performed an initial validation of a commercial MLMT system against the Vicra. Generally, UMT achieved comparable motion-tracking results in all studies and the effectiveness of UMT-based MC was demonstrated.

AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer.

Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations are the characters of castration-resistant prostate cancer (CRPC). UHRF1 as a key epigenetic regulator, plays a critical role in prostate cancer (PCa) development, and its expression is positively correlated with the degree of malignancy. In this present study we investigated the potential regulatory mechanism of AKT1 on UHRF1, and further validated the in vitro and in vivo anticancer efficacy of AKT phosphorylation inhibitor MK2206 in combination with abiraterone. Both UHRF1 and p-AKT aberrantly overexpressed in the abiraterone-resistant PCa cells. Further studies revealed that AKT1 protein interacts with UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr-210. MK2206 induced UHRF1 protein degradation by inhibiting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinase USP7, while promoted the interaction between UHRF1 and E3 ubiquitin protein ligase BTRC. MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by decreasing UHRF1 protein level, and reversed the phenotype of NEPC, evently induced cellular senescence and cell apoptosis. Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3K/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3K/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.

High-resolution multi-shot diffusion-weighted MRI combining markerless prospective motion correction and locally low-rank constrained reconstruction.

PURPOSE: Subject head motion is a major challenge in DWI, leading to image blurring, signal losses, and biases in the estimated diffusion parameters. Here, we investigate a combined application of prospective motion correction and spatial-angular locally low-rank constrained reconstruction to obtain robust, multi-shot, high-resolution diffusion-weighted MRI under substantial motion. METHODS: Single-shot EPI with retrospective motion correction can mitigate motion artifacts and resolve any mismatching of gradient encoding orientations; however, it is limited by low spatial resolution and image distortions. Multi-shot acquisition strategies could achieve higher resolution and image fidelity but increase the vulnerability to motion artifacts and phase variations related to cardiac pulsations from shot to shot. We use prospective motion correction with optical markerless motion tracking to remove artifacts and reduce image blurring due to bulk motion, combined with locally low-rank regularization to correct for remaining artifacts due to shot-to-shot phase variations. RESULTS: The approach was evaluated on healthy adult volunteers at 3 Tesla under different motion patterns. In multi-shot DWI, image blurring due to motion with 20 mm translations and 30° rotations was successfully removed by prospective motion correction, and aliasing artifacts caused by shot-to-shot phase variations were addressed by locally low-rank regularization. The ability of prospective motion correction to preserve the orientational information in DTI without requiring a reorientation of the b-matrix is highlighted. CONCLUSION: The described technique is proved to hold valuable potential for mapping brain diffusivity and connectivity at high resolution for studies in subjects/cohorts where motion is common, including neonates, pediatrics, and patients with neurological disorders.

PET Imaging of Leg Arteries for Determining the Input Function in PET/MRI Brain Studies Using a Compact, MRI-compatible PET System.

In this study, we used a compact, high-resolution, and MRI-compatible PET camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers.

Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation-mediated CDC6 protein degradation.

Radiotherapy (RT) is a conventional cancer therapeutic modality. However, cancer cells tend to develop radioresistance after a period of treatment. Diagnostic markers and therapeutic targets for radiosensitivity are severely lacking. Our recently published studies demonstrated that the cell division cycle (CDC6) is a critical molecule contributing to radioresistance, and maybe a potential therapeutic target to overcome radioresistance. In the present study, we for the first time reported that Norcantharidin (NCTD), a demethylated form of cantharidin, re-sensitized radioresistant cancer cells to overcome radioresistance, and synergistically promoted irradiation (IR)-induced cell killing and apoptosis by inducing CDC6 protein degradation. Mechanistically, NCTD induced CDC6 protein degradation through the ubiquitin-proteasome pathways. By using small interfering RNA (siRNA) interference or small compound inhibitors, we further determined that NCTD induced CDC6 protein degradation through a neddylation-dependent pathway, but not through Huwe1, Cyclin F, and APC/C-mediated ubiquitin-proteasome pathways. We screened the six most relevant Cullin subunits (CUL1, 2, 3, 4A, 4B, and 5) using siRNAs. The knockdown of Cullin1 but not the other five cullins remarkably elevated CDC6 protein levels. NCTD promoted the binding of Cullin1 to CDC6, thereby promoting CDC6 protein degradation through a Cullin1 neddylation-mediated ubiquitin-proteasome pathway. NCTD can be used in combination with radiotherapy to achieve better anticancer efficacy, or work as a radiosensitizer to overcome cancer radioresistance.

A Path to Qualification of PET/MRI Scanners for Multicenter Brain Imaging Studies: Evaluation of MRI-Based Attenuation Correction Methods Using a Patient Phantom.

PET/MRI scanners cannot be qualified in the manner adopted for hybrid PET/CT devices. The main hurdle with qualification in PET/MRI is that attenuation correction (AC) cannot be adequately measured in conventional PET phantoms because of the difficulty in converting the MR images of the physical structures (e.g., plastic) into electron density maps. Over the last decade, a plethora of novel MRI-based algorithms has been developed to more accurately derive the attenuation properties of the human head, including the skull. Although promising, none of these techniques has yet emerged as an optimal and universally adopted strategy for AC in PET/MRI. In this work, we propose a path for PET/MRI qualification for multicenter brain imaging studies. Specifically, our solution is to separate the head AC from the other factors that affect PET data quantification and use a patient as a phantom to assess the former. The emission data collected on the integrated PET/MRI scanner to be qualified should be reconstructed using both MRI- and CT-based AC methods, and whole-brain qualitative and quantitative (both voxelwise and regional) analyses should be performed. The MRI-based approach will be considered satisfactory if the PET quantification bias is within the acceptance criteria specified here. We have implemented this approach successfully across 2 PET/MRI scanner manufacturers at 2 sites.

UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications.

The UHRF1 and CDC6, oncogenes play critical roles in therapeutic resistance. In the present study, we found that UHRF1 mediates androgen receptor (AR)-regulated CDC6 transcription in prostate cancer cells. In prostate cancer tissues and cell lines, levels of UHRF1 and CDC6 were simultaneously upregulated, and this was associated with worse survival. UHRF1 silencing significantly promoted the cytotoxicity and anti-prostate cancer efficacy of bicalutamide in mouse xenografts by inhibiting CDC6 gene expression. UHRF1 promoted AR-regulated CDC6 transcription by binding to the CCAAT motif near the androgen response element (ARE) in the CDC6 promoter. We further found that UHRF1 promoted androgen-dependent chromatin occupancy of AR protein by recruiting the H3K9me2/3-specific demethyltransferase KDM4C and modifying the intense heterochromatin status. Altogether, we found for the first time that UHRF1 promotes AR-regulated CDC6 transcription through a novel chromatin modification mechanism and contributes to anti-AR drug resistance in prostate cancer. Targeting AR and UHRF1 simultaneously may be a novel and promising therapeutic modality for prostate cancer.

Design and system evaluation of a dual-panel portable PET (DP-PET).

BACKGROUND: Integrated whole-body PET/MR technology continues to mature and is now extensively used in clinical settings. However, due to the special design architecture, integrated whole-body PET/MR comes with a few inherent limitations. Firstly, whole-body PET/MR lacks sensitivity and resolution for focused organs. Secondly, broader clinical access of integrated PET/MR has been significantly restricted due to its prohibitively high cost. The MR-compatible PET insert is an independent and removable PET scanner which can be placed within an MRI bore. However, the mobility and configurability of all existing MR-compatible PET insert prototypes remain limited. METHODS: An MR-compatible portable PET insert prototype, dual-panel portable PET (DP-PET), has been developed for simultaneous PET/MR imaging. Using SiPM, digital readout electronics, novel carbon fiber shielding, phase-change cooling, and MRI compatible battery power, DP-PET was designed to achieve high-sensitivity and high-resolution with compatibility with a clinical 3-T MRI scanner. A GPU-based reconstruction method with resolution modeling (RM) has been developed for the DP-PET reconstruction. We evaluated the system performance on PET resolution, sensitivity, image quality, and the PET/MR interference. RESULTS: The initial results reveal that the DP-PET prototype worked as expected in the MRI bore and caused minimal compromise to the MRI image quality. The PET performance was measured to show a spatial resolution ≤ 2.5 mm (parallel to the detector panels), maximum sensitivity = 3.6% at the center of FOV, and energy resolution = 12.43%. MR pulsing introduces less than 2% variation to the PET performance measurement results. CONCLUSIONS: We developed a MR-compatible PET insert prototype and performed several studies to begin to characterize the performance of the proposed DP-PET. The results showed that the proposed DP-PET performed well in the MRI bore and would cause little influence on the MRI images. The Derenzo phantom test showed that the proposed reconstruction method could obtain high-quality images using DP-PET.

NEMA NU2-2012 performance measurements of the United Imaging uPMR790: an integrated PET/MR system.

PURPOSE: In this paper, we aimed to evaluate the positron emission tomography (PET) performance of, to the best of our knowledge, the third commercially available whole-body integrated PET/magnetic resonance (MR) system. METHODS: The PET system performance was measured following the NEMA standards with and without simultaneous MR operation. PET spatial resolution, sensitivity, scatter fraction, count-rate performance, accuracy of count losses and random corrections, image quality, and time-of-flight (TOF) resolution were quantitatively evaluated. Clinical scans were acquired at the PET/MR system and compared with images acquired at a PET/CT with the same digital detector technology. RESULTS: Measurement results of essential PET performance were reported in the form of MR idle (MR pulsing). The axial, radial, and tangential spatial resolutions were measured as 2.72 mm (2.73 mm), 2.86 mm (2.85 mm), and 2.81 mm (2.82 mm) FWHM, respectively, at 1 cm radial offset. The NECR peak was measured as 129.2 kcps (129.5 kcps) at 14.7 kBq mL-1 (14.2 kBq mL-1). The scatter fraction at NECR peak was 37.9% (36.5%), and the maximum slice error below NECR was 4.1% (4.5%). Contrast recovery coefficients ranged from 51.8% (52.3%) for 10 mm hot sphere to 87.3% (87.2%) for 37 mm cold sphere. TOF resolution at 5.3 kBq mL-1 was measured at 535 ps (540 ps). With point source, TOF was measured to be 474 ps (485 ps). Clinical scans revealed similar image quality from the PET/MR and the comparative PET/CT system. CONCLUSION: The PET performance of the newly introduced integrated PET/MR system is not significantly affected by the simultaneous operation of an MR sequence (2-point DIXON sequence). Measurement results demonstrate comparable performance with other state-of-the-art PET/MR systems. The clinical benefits of high spatial resolution and long axial coverage remain to be further evaluated in specific clinical imaging applications.

Validation of MR-Based Attenuation Correction of a Newly Released Whole-Body Simultaneous PET/MR System.

The aim of this study was to validate quantitative performance of a newly released simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) scanner, by using MR-based attenuation correction (MRAC), both in phantom study and in patient study. PET/MRI image uniformities of a phantom under different hardware configurations were tested and compared. Thirty patients were examined with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET/computed tomography (CT) and subsequent PET/MRI. PET images from PET/MRI were corrected with MRAC (PETMR), CT-based attenuation maps (µ-maps, PETCT), and segmented CT µ-maps (PETCTSeg) derived from PET/CT. Standardized uptake values (SUVs) were compared among the 3 sets of PET in main organs (bone, liver and lung) and in 52 FDG-avid lesions, including soft-tissue lesions and bone lesions. The result showed that PET imaging uniformities of PET/MRI under different configurations were good (<8.8%). The SUV differences among the 3 sets of PET varied with organs and lesion types. In detail, the mean relative differences of SUV between PETMR and PETCT were as follows: -18.8%, bone (SUVmean); -8.0%, liver (SUVmean); -12.2%, lung (SUVmean); -18.1%, bone lesions (SUVmean); -13.3%, bone lesions (SUVmax); -8.2%, soft-tissue lesions (SUVmean); and -7.3%, soft-tissue lesions (SUVmax). The mean relative differences between PETMR and PETCTSeg were as follows: -19.0%, bone (SUVmean); -3.5%, liver (SUVmean); -3.3%, lung (SUVmean); -19.3%, bone lesions (SUVmean); -17.5%, bone lesions (SUVmax); -5.5%, soft-tissue lesions (SUVmean); and -4.4%, soft-tissue lesions (SUVmax). The differences of SUV between PETMR and PETCT were larger than those between PETMR and PETCTSeg, in both soft tissue and soft-tissue lesions (P < 0.001), but not in bone or bone lesions. In conclusion, MRAC in the newly released PET/MR system is accurate in most tissues, with SUV deviations being generally less than 10%, compared to PET/CT. In bone, however, underestimations can be substantial, which may be partially attributed to segmentation of the MR-based µ-maps.

[Timing calibration comparison research of integrated TOF-PET/MR].

Integrated TOF-PET/MR is a multimodal imaging system which can acquire high-quality magnetic resonance (MR) and positron emission tomography (PET) images at the same time, and it has time of flight (TOF) function. The TOF-PET system usually features better image quality compared to traditional PET because it is capable of localizing the lesion on the line of response where annihilation takes place. TOF technology measures the time difference between the detectors on which the two 180-degrees-seperated photons generated from positron annihilation are received. Since every individual crystal might be prone to its timing bias, timing calibration is needed for a TOF-PET system to work properly. Three approaches of timing calibration are introduced in this article. The first one named as fan-beam method is an iterative method that measures the bias of the Gaussian distribution of timing offset created from a fan-beam area constructed using geometric techniques. The second one is to find solutions of the overdetermination equations set using L1 norm minimization and is called L1-norm method. The last one called L2-norm method is to build histogram of the TOF and find the peak, and uses L2 norm minimization to get the result. This article focuses on the comparison of the amount of the data and the calculation time needed by each of the three methods. To avoid location error of the cylinder radioactive source during data collection, we developed a location calibration algorithm which could calculate accurate position of the source and reduce image artifacts. The experiment results indicate that the three approaches introduced in this article could enhance the qualities of PET images and standardized uptake values of cancer regions, so the timing calibration of integrated TOF-PET/MR system was realized. The fan-beam method has the best image quality, especially in small lesions. In integrated TOF-PET/MR timing calibration, we recommend using fan-beam method.

USP7 is a novel Deubiquitinase sustaining PLK1 protein stability and regulating chromosome alignment in mitosis.

BACKGROUND: The deubiquitinase USP7 has been identified as an oncogene with key roles in tumorigenesis and therapeutic resistance for a series of cancer types. Recently small molecular inhibitors have been developed to target USP7. However, the anticancer mechanism of USP7 inhibitors is still elusive. METHODS: Cell viability or clonogenicity was tested by violet crystal assay. Cell apoptosis or cell cycle was analyzed by flow cytometry, and chromosome misalignment was observed by a fluorescent microscopy. The protein interaction of PLK1 and USP7 was detected by tandem affinity purification and high throughput proteomics, and further confirmed by co-immunoprecipitation, GST pull-down and protein co-localization. The correlation between USP7 level of tumor tissues and taxane-resistance was evaluated. RESULTS: Pharmacological USP7 inhibition by P5091 retarded cell proliferation and induced cell apoptosis. Further studies showed that P5091 induced cell cycle arrest at G2/M phase, and particularly induced chromosome misalignment, indicating the key roles of USP7 in mitosis. USP7 protein was detected in the PLK1-interacted protein complex. USP7 interacts with PLK1 protein through its PBD domain by catalytic activity. USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway. By overexpressing PLK1, USP7 that had been depleted by RNAi ceased to induce chromosome misalignment in mitosis and again supported cell proliferation and cell survival. Both USP7 and PLK1 were overexpressed in taxane-resistant cancer cells, and negatively correlated with the MP scores in tumor tissues. Either USP7 or PLK1 knockdown by RNAi significantly sensitized taxane-resistant cells to taxane cell killing. CONCLUSION: This is the first report that PLK1 is a novel substrate of USP7 deubiquitinase, and that USP7 sustained the protein stability of PLK1. USP7 inhibition induces cell apoptosis and cell cycle G2/M arrest, and overcomes taxane resistance by inducing the protein degradation of PLK1, resulting in chromosome misalignment in mitosis.

Impact of patient comfort on diagnostic image quality during PET/MR exam: A quantitative survey study for clinical workflow management.

BACKGROUND: PET/MR is transferring from a powerful scientific research tool to an imaging modality in clinical routine practice. Whole body PET/MR screening usually takes 30-50 minutes to finish, during which a few factors might induce patient discomfort and further cause degraded image quality. The aim of this report is to investigate the patients' perception of the imaging procedure and its correlation with image quality. METHODS: One hundred and twenty patients (63 males and 57 females, average age = 51.3 years, range 22-70 years) who had been diagnosed with cancer or had previous history of cancer were recruited and scanned with a simultaneous PET/MR system. A questionnaire was given to all patients retrospectively after the PET/MR scan, which has nine questions to assess patients' feeling of the scan on a Likert scale scoring system (1-5, 1 as most satisfied). All PET/MR images were also visually examined by two experts independently to evaluate the quality of the images. Six body locations were assessed and each location was evaluated also with a Likert scale scoring system (1-5, 5 as the best quality). Mann-Whitney U-test was used for statistical analysis to check if there is significant correlation between image quality and patient perceptions. RESULTS: With a total of 120 patients, 118 questionnaires were filled and returned for analysis. The patients' characteristics were summarized in Table 4. The statistics of the patients' perception in the questionnaire were illustrated in Tables 5-7. Statistical significant correlations were found between MR image quality and patients' characteristics/perception. CONCLUSION: Our results show that PET/MR scanning is generally safe and comfortable for most of the patients. Statistical analysis does not support the hypothesis that bad patient's perception leads to degraded image quality.

Radiation-promoted CDC6 protein stability contributes to radioresistance by regulating senescence and epithelial to mesenchymal transition.

Ionizing radiation (IR) is a conventional cancer therapeutic, to which cancer cells develop radioresistance with exposure. The residual cancer cells after radiation treatment also have increased metastatic potential. The mechanisms by which cancer cells develop radioresistance and gain metastatic potential are still unknown. In this study acute IR exposure induced cancer cell senescence and apoptosis, but after long-term IR exposure, cancer cells exhibited radioresistance. The proliferation of radioresistant cells was retarded, and most cells were arrested in G0/G1 phase. The radioresistant cells simultaneously showed resistance to further IR-induced apoptosis, premature senescence, and epithelial to mesenchymal transformation (EMT). Acute IR exposure steadily elevated CDC6 protein levels due to the attenuation of ubiquitination, while CDC6 overexpression was observed in the radioresistant cells because the insufficiency of CDC6 phosphorylation blocked protein translocation from nucleus to cytoplasm, resulting in subcellular protein accumulation when the cells were arrested in G0/G1 phase. CDC6 ectopic overexpression in CNE2 cells resulted in apoptosis resistance, G0/G1 cell cycle arrest, premature senescence, and EMT, similar to the characteristics of radioresistant CNE2-R cells. Targeting CDC6 with siRNA promoted IR-induced senescence, sensitized cancer cells to IR-induced apoptosis, and reversed EMT. Furthermore, CDC6 depletion synergistically repressed the growth of CNE2-R xenografts when combined with IR. The study describes for the first time cell models for IR-induced senescence, apoptosis resistance, and EMT, three major mechanisms by which radioresistance develops. CDC6 is a novel radioresistance switch regulating senescence, apoptosis, and EMT. These studies suggest that CDC6highKI67low represents a new diagnostic marker of radiosensitivity, and CDC6 represents a new therapeutic target for cancer radiosensitization.

PARP inhibitor veliparib and HDAC inhibitor SAHA synergistically co-target the UHRF1/BRCA1 DNA damage repair complex in prostate cancer cells.

BACKGROUND: The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. METHODS: Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with γH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of γH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. RESULTS: PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co-treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts. CONCLUSIONS: Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials.

FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness.

Therapy-induced expansion of cancer stem cells (CSCs) has been identified as one of the most critical factors contributing to therapeutic resistance, but the mechanisms of this adaptation are not fully understood. UHRF1 is a key epigenetic regulator responsible for therapeutic resistance, and controls the self-renewal of stem cells. In the present study, taxane-resistant cancer cells were established and stem-like cancer cells were expanded. UHRF1 was overexpressed in the taxane-resistant cancer cells, which maintained CSC characteristics. UHRF1 depletion overcame taxane resistance in vitro and in vivo. Additionally, FOXM1 has been reported to play a role in therapeutic resistance and the self-renewal of CSCs. FOXM1 and UHRF1 are highly correlated in prostate cancer tissues and cells, FOXM1 regulates CSCs by regulating uhrf1 gene transcription in an E2F-independent manner, and FOXM1 protein directly binds to the FKH motifs at the uhrf1 gene promoter. This present study clarified a novel mechanism by which FOXM1 controls CSCs and taxane resistance through a UHRF1-mediated signaling pathway, and validated FOXM1 and UHRF1 as two potential therapeutic targets to overcome taxane resistance.

The state of instrumentation for combined positron emission tomography and magnetic resonance imaging.

Efforts at developing instrumentation for combined positron emission tomography and magnetic resonance imaging have gained considerable momentum in recent years, propelled in particular by new photosensor technologies. Small preclinical prototype systems developed in academia have been scaled up to full-scale small-animal imagers, and commercial whole-body clinical positron emission tomography-magnetic resonance imaging systems are now available. A wide variety of architectures are reviewed, from sequential to simultaneous and preclinical to clinical. Whereas scintillators retain their role for gamma-ray conversion, light guides, photosensors, and electronic readout methods vary widely. Common themes relating to the technical challenges are presented, including electromagnetic interference and shielding. Technological directions that will likely gain in importance in the future are discussed, such as the ability to measure time of flight and depth of interaction.