Corrigendum: Targeting JUN, CEBPB and HDAC3: a novel strategy to overcome drug resistance in hypoxic glioblastoma.

[This corrects the article DOI: 10.3389/fonc.2019.00033.].

Cu-Mo Dual Sites in Cu-Doped MoSe2 for Enhanced Electrosynthesis of Urea.

The quest for sustainable urea production has directed attention toward electrocatalytic methods that bypass the energy-intensive traditional Haber-Bosch process. This study introduces an approach to urea synthesis through the coreduction of CO2 and NO3- using copper-doped molybdenum diselenide (Cu-MoSe2) with Cu-Mo dual sites as electrocatalysts. The electrocatalytic activity of the Cu-MoSe2 electrode is characterized by a urea yield rate of 1235 µg h-1 mgcat.-1 at -0.7 V versus the reversible hydrogen electrode and a maximum Faradaic efficiency of 23.43% at -0.6 V versus RHE. Besides, a continuous urea production with an enhanced average yield rate of 9145 µg h-1 mgcat.-1 can be achieved in a flow cell. These figures represent a substantial advancement over that of the baseline MoSe2 electrode. Density functional theory (DFT) calculations elucidate that Cu doping accelerates *NO2 deoxygenation and significantly decreases the energy barriers for C-N bond formation. Consequently, Cu-MoSe2 demonstrates a more favorable pathway for urea production, enhancing both the efficiency and feasibility of the process. This study offers valuable insights into electrode design and understanding of the facilitated electrochemical pathways.

Nitric Oxide Ameliorates the Effects of Hypoxia in Mice by Regulating Oxygen Transport by Hemoglobin.

Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. High Alt Med Biol. 00:00-00, 2024.-Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system in vivo remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O2 affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO2%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO2% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In ex vivo experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (-0.72 ± 0.062 vs.-0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94ß-His146ß in nitrosyl -Hb(NO-Hb), NO-HbßCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues.

Hypoxia-Induced Myocardial Hypertrophy Companies with Apoptosis Enhancement and p38-MAPK Pathway Activation.

Li, Xiaoxu, Zhijun Pu, Gang Xu, Yidong Yang, Yu Cui, Xiaoying Zhou, Chenyuan Wang, Zhifeng Zhong, Simin Zhou, Jun Yin, Fabo Shan, Chengzhong Yang, Li Jiao, Dewei Chen, and Jian Huang. Hypoxia-induced myocardial hypertrophy companies with apoptosis enhancement and p38-MAPK pathway activation. High Alt Med Biol. 00:00-00, 2024. Background: Right ventricular function and remodeling are closely associated with symptom severity and patient survival in hypoxic pulmonary hypertension. However, the detailed molecular mechanisms underlying hypoxia-induced myocardial hypertrophy remain unclear. Methods: In Sprague-Dawley rats, hemodynamics were assessed under both normoxia and hypobaric hypoxia at intervals of 7 (H7), 14 (H14), and 28 (H28) days. Morphological changes in myocardial tissue were examined using hematoxylin and eosin (HE) staining, while myocardial hypertrophy was evaluated with wheat germ agglutinin (WGA) staining. Apoptosis was determined through TUNEL assays. To further understand the mechanism of myocardial hypertrophy, RNA sequencing was conducted, with findings validated via Western blot analysis. Results: The study demonstrated increased hypoxic pulmonary hypertension and improved right ventricular diastolic and systolic function in the rat models. Significant elevations in pulmonary arterial systolic pressure (PASP), mean pulmonary arterial pressure (mPAP), right ventricular mean pressure (RVMP), and the absolute value of +dp/dtmax were observed in the H14 and H28 groups compared with controls. In addition, right ventricular systolic pressure (RVSP), -dp/dtmax, and the mean dp/dt during isovolumetric relaxation period were notably higher in the H28 group. Heart rate increased in the H14 group, whereas the time constant of right ventricular isovolumic relaxation (tau) was reduced in both H14 and H28 groups. Both the right heart hypertrophy index and the heart weight/body weight ratio (HW/BW) were elevated in the H14 and H28 groups. Myocardial cell cross-sectional area also increased, as shown by HE and WGA staining. Western blot results revealed upregulated HIF-1α levels and enhanced HIF-2α expression in the H7 group. In addition, phosphorylation of p38 and c-fos was augmented in the H28 group. The H28 group showed elevated levels of Cytochrome C (Cyto C), whereas the H14 and H28 groups exhibited increased levels of Cleaved Caspase-3 and the Bax/Bcl-2 ratio. TUNEL analysis revealed a rise in apoptosis with the extension of hypoxia duration in the right ventricle. Conclusions: The study established a link between apoptosis and p38-MAPK pathway activation in hypoxia-induced myocardial hypertrophy, suggesting their significant roles in this pathological process.

Evaluation of the effectiveness of surgical resection and ablation for the treatment of early-stage hepatocellular carcinoma: A retrospective cohort study.

BACKGROUND: The optimal treatment strategy for early-stage hepatocellular carcinoma (HCC) remains controversial, specifically in regard to surgical resection (SR) and ablation. The aim of this study was to investigate the impact of SR and ablation on recurrence and prognosis in early-stage HCC patients, to optimize treatment strategies and improve long-term survival. METHODS: A retrospective analysis was conducted on 801 patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage 0/A HCC and treated with SR or ablation between January 2015 and December 2019. The effectiveness and complications of both treatments were analyzed, and patients were followed up to measure recurrence and survival. Propensity score matching (PSM) was employed to increase comparability between the two groups. The Kaplan-Meier method was used to analyze recurrence and survival, and a Cox risk proportional hazard model was used to identify risk factors that affect recurrence and surviva. RESULTS: Before PSM, the overall survival (OS) rates were similar in both groups, with recurrence-free survival (RFS) rates better in the SR group than in the ablation group. After PSM, there was no significant difference in OS between the two groups. However, the RFS rates were significantly better in the SR group than in the ablation group. The ablation group exhibited superior outcomes compared to the SR group, with shorter treatment times, reduced bleeding, shorter hospital stays, and lower hospital costs. Concerning the location of the HCC within the liver, comparable efficacy was observed between SR and ablation for disease located in the noncentral region or left lobe. However, for HCCs located in the central region or right lobe of the liver, SR was more effective than ablation. CONCLUSIONS: This study revealed no significant difference in OS between SR and ablation for early-stage HCC, with SR providing better RFS and ablation demonstrating better safety profiles and lower hospital costs. These findings offer valuable insights for clinicians in determining optimal treatment strategies for early-stage HCC patients, particularly in terms of balancing efficacy, safety, and cost considerations.

Improvement of 2D cine image quality using 3D priors and cycle generative adversarial network for low field MRI-guided radiation therapy.

BACKGROUND: Cine magnetic resonance (MR) images have been used for real-time MR guided radiation therapy (MRgRT). However, the onboard MR systems with low-field strength face the problem of limited image quality. PURPOSE: To improve the quality of cine MR images in MRgRT using prior image information provided by the patient planning and positioning MR images. METHODS: This study employed MR images from 18 pancreatic cancer patients who received MR-guided stereotactic body radiation therapy. Planning 3D MR images were acquired during the patient simulation, and positioning 3D MR images and 2D sagittal cine MR images were acquired before and during the beam delivery, respectively. A deep learning-based framework consisting of two cycle generative adversarial networks (CycleGAN), Denoising CycleGAN and Enhancement CycleGAN, was developed to establish the mapping between the 3D and 2D MR images. The Denoising CycleGAN was trained to first denoise the cine images using the time domain cine image series, and the Enhancement CycleGAN was trained to enhance the spatial resolution and contrast by taking advantage of the prior image information from the planning and positioning images. The denoising performance was assessed by signal-to-noise ratio (SNR), structural similarity index measure, peak SNR, blind/reference-less image spatial quality evaluator (BRISQUE), natural image quality evaluator, and perception-based image quality evaluator scores. The quality enhancement performance was assessed by the BRISQUE and physician visual scores. In addition, the target contouring was evaluated on the original and processed images. RESULTS: Significant differences were found for all evaluation metrics after Denoising CycleGAN processing. The BRISQUE and visual scores were also significantly improved after sequential Denoising and Enhancement CycleGAN processing. In target contouring evaluation, Dice similarity coefficient, centroid distance, Hausdorff distance, and average surface distance values were significantly improved on the enhanced images. The whole processing time was within 20 ms for a typical input image size of 512 × 512. CONCLUSION: Taking advantage of the prior high-quality positioning and planning MR images, the deep learning-based framework enhanced the cine MR image quality significantly, leading to improved accuracy in automatic target contouring. With the merits of both high computational efficiency and considerable image quality enhancement, the proposed method may hold important clinical implication for real-time MRgRT.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients.

BACKGROUND: The clinical and histological features of chronic hepatitis B (CHB) patients who fall into the "grey zone (GZ)" and do not fit into conventional natural phases are unclear. AIM: To explore the impact of varying the threshold of alanine aminotransferase (ALT) levels in identifying significant liver injury among GZ patients. METHODS: This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy. The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines. GZ CHB patients were classified into four groups: GZ-A (HBeAg positive, normal ALT levels, and HBV DNA ≤ 107 IU/mL), GZ-B (HBeAg positive, elevated ALT levels, and HBV DNA < 104 or > 107 IU/mL), GZ-C (HBeAg negative, normal ALT levels, and HBV DNA ≥ 2000 IU/mL), and GZ-D (HBeAg negative, elevated ALT levels, and HBV DNA ≤ 2000 IU/mL). Significant hepatic injury (SHI) was defined as the presence of notable liver inflammation (≥ G2) and/or significant fibrosis (≥ S2). RESULTS: The results showed that 50.22% of patients were classified as GZ, and 63.7% of GZ patients developed SHI. The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria (35 U/L for men and 25 U/L for women) can more accurately identify patients with significant liver damage in the GZ phases. In total, the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 64.86% [(221 + 294)/794]. When we lowered the ALT treatment threshold to the new criteria (30 U/L for men and 19 U/L for women), the same outcome was revealed, and the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 75.44% [(401 + 198)/794]. Additionally, the proportion of SHI was 49.1% in patients under 30 years old and increased to 55.3% in patients over 30 years old (P = 0.136). CONCLUSION: These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

Emerging Electrocatalysts in Urea Production.

Urea synthesis from abundant CO2 and N-feedstocks via renewable electricity has attracted increasing interests, offering a promising alternative to the industrial-applied Haber-Meiser process. However, the studies toward electrochemical urea production remain scarce and appeal for more research. Herein, in this perspective, an up-to-date overview on the urea electrosynthesis is highlighted and summarized. Firstly, the reaction pathways of urea formation through various feedstocks are comprehensively discussed. Then, we focus on the strategies of materials design to improve C-N coupling efficiency by identifying the descriptor and understanding the reaction mechanism. Finally, the current challenges and disadvantages in this field are reviewed and some future development directions of electrocatalytic urea synthesis are also prospected. This Minireview aims to promote future investigations of the electrochemical urea synthesis.

The engagement of autophagy in maniac disease.

AIMS: Mania is a prevalent psychiatric disorder with undefined pathological mechanism. Here, we reviewed current knowledge indicating the potential involvement of autophagy dysregulation in mania and further discussed whether targeting autophagy could be a promising strategy for mania therapy. DISCUSSIONS: Accumulating evidence indicated the involvement of autophagy in the pathology of mania. One of the most well-accepted mechanisms underlying mania, circadian dysregulation, showed mutual interaction with autophagy dysfunction. In addition, several first-line drugs for mania therapy were found to regulate neuronal autophagy. Besides, deficiencies in mitochondrial quality control, neurotransmission, and ion channel, which showed causal links to mania, were intimately associated with autophagy dysfunction. CONCLUSIONS: Although more efforts should be made to either identify the key pathology of mania, the current evidence supported that autophagy dysregulation may act as a possible mechanism involved in the onset of mania-like symptoms. It is therefore a potential strategy to treat manic disorder by correting autophagy.

Dosimetry impact of distinct gating strategies in cine MR image-guided breath-hold pancreatic cancer radiotherapy.

PURPOSE: To investigate the dosimetry effects of different gating strategies in cine magnetic resonance imaging (MRI)-guided breath-hold pancreatic cancer radiotherapy. METHODS: Two cine MRI-based gating strategies were investigated： a tumor contour-based gating strategy at a gating threshold of 0-5% and a tumor displacement-based gating strategy at a gating threshold of 3-5 mm. The cine MRI videos were obtained from 17 pancreatic cancer patients who received MRI-guided radiation therapy. We calculated the tumor displacement in each cine MR frame that satisfied the gating threshold and obtained the proportion of frames with different displacements. We generated IMRT and VMAT plans using a 33 Gy prescription, and motion plans were generated by adding up all isocenter-shift plans corresponding to different tumor displacements. The dose parameters of GTV, PTV, and organs at risk (OAR) were compared between the original and motion plans. RESULTS: In both gating strategies, the difference was significant in PTV coverage but not in GTV coverage between the original and motion plans. OAR dose parameters deteriorate with increasing gating threshold. The beam duty cycle increased from 19.5±14.3% (median 18.0%) to 60.8±15.6% (61.1%) for gating thresholds from 0% to 5% in tumor contour-based gating and from 51.7±11.5% (49.7%) to 67.3±12.4% (67.1%) for gating thresholds from 3 to 5 mm in tumor displacement-based gating. CONCLUSION: In tumor contour-based gating strategy, the dose delivery accuracy deteriorates while the dose delivery efficiency improves with increasing gating thresholds. To ensure treatment efficiency, the gating threshold might be no less than 3%. A threshold up to 5% may be acceptable in terms of the GTV coverage. The displacement-based gating strategy may serve as a potential alternative to the tumor contour based gating strategy, in which the gating threshold of approximately 4 mm might be a good choice for reasonably balancing the dose delivery accuracy and efficiency.

A GPU-accelerated Monte Carlo dose computation engine for small animal radiotherapy.

BACKGROUND: Accurate dose computation is critical in precision small animal radiotherapy. The Monte Carlo simulation method is the gold standard for radiation dose computation but has not been widely implemented in practice due to its low computation efficiency. PURPOSE: This study aims to develop a GPU-accelerated radiation dose engine (GARDEN) based on the Monte Carlo simulation method for fast and accurate dose computation. METHODS: In the GARDEN simulation, Compton scattering, Rayleigh scattering, and photoelectric effect were considered. The Woodcock tracking algorithm and GPU-specific acceleration techniques were used to obtain a high computational efficiency. Benchmark studies against both Geant4 simulations and experimental measurements were performed for various phantoms and beams. Finally, a conformal arc treatment plan was designed for a lung tumor to further evaluate the accuracy and efficiency in small animal radiotherapy. RESULT: The engine attained a speed-up of 1232 times in a homogeneous water phantom and 935 times in a water-bone-lung heterogeneous phantom when compared with Geant4. Both the depth-dose curves and cross-sectional dose profiles for various radiation field sizes showed a great match between measurements and the GARDEN calculations. For in vivo dose validation, the differences between calculations and measurements in the mouse thorax and abdomen were 2.50% ± 1.50% and 1.56% ± 1.40%, respectively. The computation time for an arc treatment plan delivered from 36 angles was 2 s at a <1% uncertainty level using an NVIDIA GeForce RTX 2060 SUPER GPU. When compared with Geant4, the 3D gamma comparison passing rate was 98.7% at 2%/0.3 mm criteria. CONCLUSION: GARDEN can perform fast and accurate dose computations in heterogeneous tissue environments and is expected to play a vital role in image-guided precision small animal radiotherapy.

Peripheral immune characteristics of hepatitis B virus-related hepatocellular carcinoma.

Background: Liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. As a chronic liver disease, many studies have shown that the immune response plays a key role in the progression of liver cancer. Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for HCC, accounting for 50%-80% of HCC cases worldwide, and little is known about the immune status of HBV associated hepatocellular carcinoma (HBV-HCC), therefore, we aimed to explore the changes in peripheral immunity in patients with HBV-HCC. Methods: In this study, patients with HBV-HCC (n=26), patients with hepatitis B-related cirrhosis (HBV-LC) (n=31) and healthy volunteers (n=49) were included. The lymphocytes and their subpopulation phenotypes in peripheral blood were characterized. In addition, we explored the effect of viral replication on peripheral immunity in patients with HCC and analyzed the circulating immunophenotypic characteristics at different stages of HCC with flow cytometry. Results: Firstly, our results showed that the percentages of total αß T cells in the peripheral blood of HBV-HCC patients was significantly decreased compared to healthy subjects. Secondly, we found that naïve CD4+ T cells in HBV-HCC patients were significantly reduced, terminally differentiated CD8+ T cells, homing memory CD8+ T cells and Th2 cells were increased in peripheral circulation in HBV-HCC patients. Moreover, in the peripheral blood of HBV-HCC patients, expression of TIGIT on CD4+ T cells and PD-1 on the surface of Vδ 1 T cells was increased. In addition, we found that sustained viral replication resulted in up-regulation of TIM3 expression on CD4+ T cells, and TIM3+ γδ T cells increased in peripheral circulation in patients with advanced HBV-HCC. Conclusion: Our study showed that circulating lymphocytes in HBV-HCC patients exhibited features of immune exhaustion, especially in HCC patients with persistent viral replication and in patients with intermediate and advanced HBV-HCC, including decreased frequency of T cells and elevated expression of inhibitory receptors including TIGIT and TIM3 on CD4+ T cells and γδ T cells. Meanwhile, our research suggests that the combination of CD3+ T cell and CD8+HLADR+CD38+ T cell may be a potential diagnostic indicator for HBV-HCC. These findings could help us to better understand the immune characteristics of HBV-HCC and explore the immune mechanisms and immunotherapy strategies for HBV-HCC.

Carbon-Anchored Molybdenum Oxide Nanoclusters as Efficient Catalysts for the Electrosynthesis of Ammonia and Urea.

The electrochemical NO3 - reduction and its coupling with CO2 can provide novel and clean routes to synthesize NH3 and urea, respectively. However, their practical application is still impeded by the lack of efficient catalysts with desirable Faradaic efficiency (FE) and yield rate. Herein, we report the synthesis of molybdenum oxide nanoclusters anchored on carbon black (MoOx /C) as electrocatalyst. It affords an outstanding FE of 98.14 % and NH3 yield rate of 91.63 mg h-1 mgcat. -1 in NO3 - reduction. Besides, the highest FE of 27.7 % with a maximum urea yield rate of 1431.5 µg h-1 mgcat. -1 toward urea is also achieved. The formation of electron-rich MoOx nanoclusters with highly unsaturated metal sites in the MoOx /C heterostructure is beneficial for enhanced catalytic performance. Studies on the mechanism reveal that the stabilization of *NO and *CO2 NOOH intermediates are critical for the NH3 and urea synthesis, respectively.

Assessing the allocation of attention during visual search using digit-tracking, a calibration-free alternative to eye tracking.

Digit-tracking, a simple, calibration-free technique, has proven to be a good alternative to eye tracking in vision science. Participants view stimuli superimposed by Gaussian blur on a touchscreen interface and slide a finger across the display to locally sharpen an area the size of the foveal region just at the finger's position. Finger movements are recorded as an indicator of eye movements and attentional focus. Because of its simplicity and portability, this system has many potential applications in basic and applied research. Here we used digit-tracking to investigate visual search and replicated several known effects observed using different types of search arrays. Exploration patterns measured with digit-tracking during visual search of natural scenes were comparable to those previously reported for eye-tracking and constrained by similar saliency. Therefore, our results provide further evidence for the validity and relevance of digit-tracking for basic and applied research on vision and attention.

A partial convolution generative adversarial network for lesion synthesis and enhanced liver tumor segmentation.

Lesion segmentation is critical for clinicians to accurately stage the disease and determine treatment strategy. Deep learning based automatic segmentation can improve both the segmentation efficiency and accuracy. However, training a robust deep learning segmentation model requires sufficient training examples with sufficient diversity in lesion location and lesion size. This study is to develop a deep learning framework for generation of synthetic lesions with various locations and sizes that can be included in the training dataset to enhance the lesion segmentation performance. The lesion synthesis network is a modified generative adversarial network (GAN). Specifically, we innovated a partial convolution strategy to construct a U-Net-like generator. The discriminator is designed using Wasserstein GAN with gradient penalty and spectral normalization. A mask generation method based on principal component analysis (PCA) was developed to model various lesion shapes. The generated masks are then converted into liver lesions through a lesion synthesis network. The lesion synthesis framework was evaluated for lesion textures, and the synthetic lesions were used to train a lesion segmentation network to further validate the effectiveness of the lesion synthesis framework. All the networks are trained and tested on the LITS public dataset. Our experiments demonstrate that the synthetic lesions generated by our approach have very similar distributions for the two parameters, GLCM-energy and GLCM-correlation. Including the synthetic lesions in the segmentation network improved the segmentation dice performance from 67.3% to 71.4%. Meanwhile, the precision and sensitivity for lesion segmentation were improved from 74.6% to 76.0% and 66.1% to 70.9%, respectively. The proposed lesion synthesis approach outperforms the other two existing approaches. Including the synthetic lesion data into the training dataset significantly improves the segmentation performance.

A practical and robust method for beam blocker-based cone beam CT scatter correction.

Objective. In the traditional beam-blocker based cone beam CT (CBCT) scatter correction, the scatter measured in the region shaded by lead strips was multiplied by a correction factor to directly represent the scatter in the unblocked region. The correction factor optimization is a tedious process and lacks an objective stop criterion. To skip the optimization process, an indirect scatter estimation method was developed and validated in phantom imaging.Approach.A beam-blocker made of lead strips was mounted between the x-ray source and object for scatter estimation. The primary signal between lead strips in the blocked region was first calculated by subtracting the measured scatter, and then used to calculate the scatter signal in the unblocked region corresponding to the same attenuation path. The calculated scatter signal was smoothed via local filtration and used to correct the measured projection in the unblocked region. Finally, the CBCT was reconstructed via Feldkamp-Davis-Kress algorithm. A Catphan and a head phantom were used to verify the performance of the proposed method in both full- and half-blocker scenarios, and with and without a bow-tie filter.Main Results. For scans without the bow-tie filter, the CT number error was reduced to 3.97±2.27 and 5.51±3.90 HU in the full- and half-blocker scenarios, respectively, for the Catphan, and to 4.01±2.18 and 7.97 ± 4.05 HU for the head phantom. When the bow-tie filter was applied, the CT number error was reduced to 2.29±1.42 and 6.72±0.77 HU in the full- and half-blocker scenarios, respectively, for the Catphan, and 2.35±1.25 and 4.96 ± 1.89 HU for the head phantom.Significance. The proposed method effectively avoids the influence of the inserted beam blocker itself on the scatter intensity estimation, and proves a more practical and robust way for the beam-blocker based scatter correction in CBCT scanning.

Accurate and Early Metastases Diagnosis in Live Animals With Multimodal X-ray and Optical Imaging.

PURPOSE: In vivo optical imaging systems are essential to track disease progression and evaluate therapeutic efficacy in animal studies. However, current approaches are limited by their inability to accurately capture 3-dimensional (3-D) image information. To overcome this hindrance, we adopted x-ray computed tomography (CT) as a prior for 3-D optical image reconstruction and further challenged the multimodal imaging performance with a metastasis model. METHODS AND MATERIALS: The iSMAART system, an integrated small animal research platform, features coregistered high-quality quantitative optical tomography and CT. In the synergistic dual-modality imaging, CT provides both 3-D anatomy information and animal structure mesh for optical tomography reconstruction, which is performed using bioluminescence projections acquired from 4 orthogonal angles. The multimodal imaging system was challenged with a prostate cancer metastasis model, and a double-blind histopathology diagnosis was obtained to validate the imaging results. RESULTS: The iSMAART located, visualized, and quantified early tumor metastases at the millimeter scale, and can accurately track deep tumors as small as 1.5 mm in live animals. Tumors metastasized into the liver, diaphragm, and tibia in 4 mice were all successfully diagnosed by the integrated tomographic imaging. CONCLUSIONS: Instead of roughly comparing surface-light intensities, as traditionally performed in 2-dimensional optical imaging, iSMAART provides accurate tumor imaging and quantitative assessment capabilities with integrated CT and optical tomography for cancer metastasis research. With the powerful 3-D optical/CT imaging capability, iSMAART has the potential to tackle more complex research needs with higher targeting accuracy.

TAM-targeted reeducation for enhanced cancer immunotherapy: Mechanism and recent progress.

Tumor-associated macrophage (TAM) as an important component of tumor microenvironment (TME) are closely related with the occurrence, development, and metastasis of malignant tumors. TAMs are generally identified as two distinct functional populations in TME, i.e., inflammatory/anti-tumorigenic (M1) and regenerative/pro-tumorigenic (M2) phenotype. Evidence suggests that occupation of the TME by M2-TAMs is closely related to the inactivation of anti-tumor immune cells such as T cells in TME. Recently, efforts have been made to reeducate TAMs from M2- to M1- phenotype to enhance cancer immunotherapy, and great progress has been made in realizing efficient modulation of TAMs using nanomedicines. To help readers better understand this emerging field, the potential TAM reeducation targets for potentiating cancer immunotherapy and the underlying mechanisms are summarized in this review. Moreover, the most recent advances in utilizing nanomedicine for the TAM immunomodulation for augmented cancer immunotherapy are introduced. Finally, we conclude with our perspectives on the future development in this field.

Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-κBp65/HK2 signalling.

BACKGROUND: Aerobic glycolysis has been recognized as one of the growth-promoting metabolic alterations of cancer cells. Emerging evidence indicates that nuclear factor κB (NF-κB) plays significant roles in metabolic adaptation in normal cells and cancer cells. However, whether and how NF-κB regulates metabolic reprogramming in hepatocellular carcinoma (HCC), specifically hepatitis B virus X protein (HBx)-initiated HCC, has not been determined. METHODS: A dataset of the HCC cohort from the TCGA database was used to analyse the expression of NF-κB family members. Expression of NF-κBp65 and phosphorylation of NF-κBp65 (p-p65) were detected in liver tissues from HBV-related HCC patients and normal controls. A newly established HBx+/+/NF-κBp65f/f and HBx+/+/NF-κBp65Δhepa spontaneous HCC mouse model was used to investigate the effects of NF-κBp65 on HBx-initiated hepatocarcinogenesis. Whether and how NF-κBp65 is involved in aerobic glycolysis induced by HBx in hepatocellular carcinogenesis were analysed in vitro and in vivo. RESULTS: NF-κBp65 was upregulated in HBV-related HCC, and HBx induced NF-κBp65 upregulation and phosphorylation in vivo and in vitro. Hepatocyte-specific NF-κBp65 deficiency remarkably decreased HBx-initiated spontaneous HCC incidence in HBx-TG mice. Mechanistically, HBx induced aerobic glycolysis by activating NF-κBp65/hexokinase 2 (HK2) signalling in spontaneous hepatocarcinogenesis, and overproduced lactate significantly promoted HCC cell pernicious proliferation via the PI3K (phosphatidylinositide 3-kinase)/Akt pathway in hepatocarcinogenesis. CONCLUSION: The data elucidate that NF-κBp65 plays a pivotal role in HBx-initiated spontaneous HCC, which depends on hyperactive NF-κBp65/HK2-mediated aerobic glycolysis to activate PI3K/Akt signalling. Thus, phosphorylation of NF-κBp65 will be a potential therapeutic target for HBV-related HCC.

Development of an unsupervised cycle contrastive unpaired translation network for MRI-to-CT synthesis.

PURPOSE: The purpose of this work is to develop and evaluate a novel cycle-contrastive unpaired translation network (cycleCUT) for synthetic computed tomography (sCT) generation from T1-weighted magnetic resonance images (MRI). METHODS: The cycleCUT proposed in this work integrated the contrastive learning module from contrastive unpaired translation network (CUT) into the cycle-consistent generative adversarial network (cycleGAN) framework to effectively achieve unsupervised CT synthesis from MRI. The diagnostic MRI and radiotherapy planning CT images of 24 brain cancer patients were obtained and reshuffled to train the network. For comparison, the traditional cycleGAN and CUT were also implemented. The sCT images were then imported into a treatment planning system to verify their feasibility for radiotherapy planning. The mean absolute error (MAE), peak signal-to-noise ratio (PSNR), and structural similarity index (SSIM) between the sCT and the corresponding real CT images were calculated. Gamma analysis between sCT- and CT-based dose distributions was also conducted. RESULTS: Quantitative evaluation of an independent test set of six patients showed that the average MAE was 69.62 ± 5.68 Hounsfield Units (HU) for the proposed cycleCUT, significantly (p-value < 0.05) lower than that for cycleGAN (77.02 ± 6.00 HU) and CUT (78.05 ± 8.29). The average PSNR was 28.73 ± 0.46 decibels (dB) for cycleCUT, significantly larger than that for cycleGAN (27.96 ± 0.49 dB) and CUT (27.95 ± 0.69 dB). The average SSIM for cycleCUT (0.918 ± 0.012) was also significantly higher than that for cycleGAN (0.906 ± 0.012) and CUT (0.903 ± 0.015). Regarding gamma analysis, cycleCUT achieved the highest passing rate (97.95 ± 1.24% at the 2%/2 mm criteria and 10% dose threshold) but was not significantly different from the others. CONCLUSION: The proposed cycleCUT could be effectively trained using unaligned image data, and could generate better sCT images than cycleGAN and CUT in terms of HU number accuracy and fine structural details.