Pseudo-CT synthesis in adaptive radiotherapy based on a stacked coarse-to-fine model: Combing diffusion process and spatial-frequency convolutions.

BACKGROUND: Cone beam computed tomography (CBCT) provides critical anatomical information for adaptive radiotherapy (ART), especially for tumors in the pelvic region that undergo significant deformation. However, CBCT suffers from inaccurate Hounsfield Unit (HU) values and lower soft tissue contrast. These issues affect the accuracy of pelvic treatment plans and implementation of the treatment, hence requiring correction. PURPOSE: A novel stacked coarse-to-fine model combining Denoising Diffusion Probabilistic Model (DDPM) and spatial-frequency domain convolution modules is proposed to enhance the imaging quality of CBCT images. METHODS: The enhancement of low-quality CBCT images is divided into two stages. In the coarse stage, the improved DDPM with U-ConvNeXt architecture is used to complete the denoising task of CBCT images. In the fine stage, the deep convolutional network model jointly constructed by fast Fourier and dilated convolution modules is used to further enhance the image quality in local details and global imaging. Finally, the accurate pseudo-CT (pCT) images consistent with the size of the original data are obtained. Two hundred fifty paired CBCT-CT images from cervical and rectal cancer, combined with 200 public dataset cases, were used collectively for training, validation, and testing. RESULTS: To evaluate the anatomical consistency between pCT and real CT, we have used the mean(std) of structure similarity index measure (SSIM), peak signal to noise ratio (PSNR), and normalized cross-correlation (NCC). The numerical results for the above three metrics comparing the pCT synthesized by the proposed model against real CT for cervical cancer cases were 87.14% (2.91%), 34.02 dB (1.35 dB), and 88.01% (1.82%), respectively. For rectal cancer cases, the corresponding results were 86.06% (2.70%), 33.50 dB (1.41 dB), and 87.44% (1.95%). The paired t-test analysis between the proposed model and the comparative models (ResUnet, CycleGAN, DDPM, and DDIM) for these metrics revealed statistically significant differences (p < 0.05). The visual results also showed that the anatomical structures between the real CT and the pCT synthesized by the proposed model were closer. For the dosimetric verification, mean absolute error of dosimetry (MAEdoes) values for the maximum dose (Dmax), the minimum dose (Dmin), and the mean dose (Dmean) in the planning target volume (PTV) were analyzed, with results presented as mean (lower quartile, upper quartile). The experimental results show that the values of the above three dosimetry indexes (Dmin, Dmax, and Dmean) for the pCT images synthesized by the proposed model were 0.90% (0.48%, 1.29%), 0.82% (0.47%, 1.17%), and 0.57% (0.44%, 0.67%). Compared with 10 cases of the original CBCT image by Mann-Whitney test (p < 0.05), it also proved that pCT can significantly improve the accuracy of HU values for the dose calculation. CONCLUSION: The pCT synthesized by the proposed model outperforms the comparative models in numerical accuracy and visualization, promising for ART of pelvic cancers.

Bacillus cereus CGMCC 1.60196: a promising bacterial inoculant isolated from biological soil crusts for maize growth enhancement.

Soil microbial inoculants are widely recognized as an environmentally friendly strategy for promoting crop growth and increasing productivity. However, research on utilizing the microbial resources from desert biological soil crusts to enhance crop growth remains relatively unexplored. In the present work, a bacterial strain designated AC1-8 with high levels of amylase, protease, and cellulase activity was isolated from cyanobacterial crusts of the Tengger Desert and identified as Bacillus cereus (CGMCC 1.60196). The refinement of the fermentation parameters of B. cereus CGMCC 1.60196 determined that the most effective medium for biomass production was composed of 5 g/L glucose, 22 g/L yeast extract and 15 g/L MgSO4, and the optimal culture conditions were pH 6.0, temperature 37°C, inoculation quantity 3% and agitation speed 240 rpm. Furthermore, the utilization of B. cereus CGMCC 1.60196 has resulted in substantial improvements in various growth parameters of maize seedlings, including shoot length, shoot fresh and dry weights, root fresh and dry weights, and the contents of chlorophyll a, chlorophyll b, and total chlorophyll. The most pronounced growth promotion was observed at an application concentration of 1 × 109 CFU/m2. These results suggest that the novel B. cereus strain, isolated from cyanobacterial crusts, can be regarded as an exemplary biological agent for soil improvement, capable of enhancing soil conditions, promoting crop cultivation and supporting food production.

Long-term results of induction chemotherapy for non-operable esophageal squamous cell carcinoma followed by concurrent chemoradiotherapy: a single-centre experience.

BACKGROUND: This study aimed to investigate the long-term clinical outcomes and toxicities of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) vs. CCRT alone in patients with non-operable esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Between 2008 and 2022, 271 ESCC patients who received definitive CCRT based on intensity modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) were enrolled. Through a propensity score-matched (PSM) method, 71 patients receiving IC and CCRT were matched 1:1 to patients who received CCRT alone. The Kaplan-Meier method and Cox proportional hazards model were applied to analyze survival and prognosis. RESULTS: The IC + CCRT group had no improvement in 5-year overall survival (OS) rate, recurrence-free survival (RFS) rate, and distant metastasis-free survival (DMFS) rate (all p > 0.05) compared with the CCRT group. The 5-year OS rate (65.6% vs. 17.6% vs. 29.3%, p < 0.001), RFS rate (65.6% vs. 17.6% vs. 26.9%, p < 0.001), and DMFS rate (62.5% vs. 10.3% vs. 27.2%, p < 0.001) of the IC good responders were significantly higher than that of the IC poor responders and CCRT group. Multivariate analysis revealed that total radiotherapy time (≥ 49 days) and stage III/IV were independent predictive factors of OS, RFS, and DMFS. No significant differences were observed in the rates of grade 3-4 toxicities between both groups. CONCLUSIONS: Our results showed the addition of IC to CCRT was not superior to CCRT in unselected ESCC patients, while IC responders could benefit from this regime without an increase in toxicities.

Smart Implantable Hydrogel for Large Segmental Bone Regeneration.

Large segmental bone defects often lead to nonunion and dysfunction, posing a significant challenge for clinicians. Inspired by the intrinsic bone defect repair logic of "vascularization and then osteogenesis", this study originally reports a smart implantable hydrogel (PDS-DC) with high mechanical properties, controllable scaffold degradation, and timing drug release that can proactively match different bone healing cycles to efficiently promote bone regeneration. The main scaffold of PDS-DC consists of polyacrylamide, polydopamine, and silk fibroin, which endows it with superior interfacial adhesion, structural toughness, and mechanical stiffness. In particular, the adjustment of scaffold cross-linking agent mixing ratio can effectively regulate the in vivo degradation rate of PDS-DC and intelligently satisfy the requirements of different bone defect healing cycles. Ultimately, PDS hydrogel loaded with free desferrioxamine (DFO) and CaCO3 mineralized ZIF-90 loaded bone morphogenetic protein-2 (BMP-2) to stimulate efficient angiogenesis and osteogenesis. Notably, DFO is released rapidly by free diffusion, whereas BMP-2 is released slowly by pH-dependent layer-by-layer disintegration, resulting in a significant difference in release time, thus matching the intrinsic logic of bone defect repair. In vivo and in vitro results confirm that PDS-DC can effectively realize high-quality bone generation and intelligently regulate to adapt to different demands of bone defects.

p-STAT3-elevated E3 ubiquitin ligase DTX4 confers the stability of HBV cccDNA by ubiquitinating APOBEC3B in liver.

Background: Clinically, the persistence of HBV cccDNA is the major obstacle in anti-HBV therapy. However, the underlying mechanism of HBV cccDNA is poorly understood. The transcriptional factor STAT3 is able to activate HBV replication in liver. Approach & Results: RNA-Seq analysis demonstrated that cucurbitacin I targeting STAT3 was associated with virus replication in liver. HBV-infected human liver chimeric mouse model and HBV hydrodynamic injection mouse model were established. Then, we validated that cucurbitacin I effectively limited the stability of HBV cccDNA and HBV replication in cells, in which cucurbitacin I enhanced the sensitivity of pegylated interferon α (PEG-IFN α) against HBV via combination in vitro and in vivo. Mechanistically, we identified that cucurbitacin I increased the levels of APOBEC3B to control HBV cccDNA by inhibiting p-STAT3 in cells, resulting in the inhibition of HBV replication. Moreover, RNA-Seq data showed that E3 ubiquitin ligase DTX4 might be involved in the events. Then, we observed that HBV particles could upregulate DTX4 by increasing the levels of p-STAT3 in vitro and in vivo. The p-STAT3-elevated DTX4/male-specific lethal 2 (MSL2) independently and synergistically enhanced the stability of HBV cccDNA by facilitating the ubiquitination degradation of APOBEC3B in cells, leading to the HBV replication. Conclusions: p-STAT3-elevated DTX4 confers the stability of HBV cccDNA and HBV replication by facilitating the ubiquitination degradation of APOBEC3B. Cucurbitacin Ⅰ effectively enhances the sensitivity of PEG-IFN α in anti-HBV therapy by inhibiting the p-STAT3/DTX4/MSL2/APOBEC3B signalling. Our finding provides new insights into the mechanism of HBV cccDNA. The p-STAT3 and DTX4/MSL2 might serve as the therapeutical targets of HBV cccDNA.

The effects of exercise on microRNA expression profiling in adipose tissue macrophages of mice.

Background: Exercise is recognized for its broad health benefits, influencing various physiological processes, including the behavior of adipose tissue macrophages (ATMs). While existing studies mainly associate ATM activity with obesity and metabolic syndrome, our study explores the impact of aerobic exercise on ATM microRNA expression profiling in a non-obese context, highlighting its general health-promoting mechanisms. Methods: Sixty male C57BL/6 mice were randomly assigned to either a sedentary (S) or an exercise (E) group. The S group remained inactive, while the E group underwent a one-week treadmill adaptation, followed by an 8-week aerobic treadmill exercise protocol (60 min/day, 5 days/week, at 65%-75% VO2max). Post-training, glucose tolerance and the serum lipid levels were measured in mice subjected to both exercise and non-exercise conditions. ATMs harvested from visceral adipose tissues were analyzed and sorted using flow cytometer. To further investigate the effects of exercise in ATMs at the molecular level, miRNA microarray analysis was performed, followed by bioinformatic analysis. Results: The 8-week regimen of moderate-intensity aerobic exercise ameliorated glucolipid metabolism and fostered a dynamic shift toward an M2 macrophage phenotype in the adipose tissue, independent of obesity. A total of 62 differentially expressed miRNAs were identified in ATMs of mice post-exercise. Notably, six miRNAs (miR-212-5p, miR-511-5p, miR-7b-5p, miR-142-3p, miR-1894-3p, and miR-31-5p) as well as their target gene were consistently altered and associated with macrophage polarization and metabolic regulation. Conclusion: Our findings broaden the understanding of how exercise regulates ATM functions through significant changes in microRNA profiles, emphasizing its potential to enhance health and prevent chronic conditions. This study supports the application of aerobic exercise for its preventive effects on chronic diseases and underscores the importance of microRNA profiling in understanding the immune-modulatory impacts of exercise.

Echocardiography-Guided Radiofrequency Ablation for Cardiac Tumors.

Background: Patients with cardiac tumors may present challenges for surgical resection due to poor clinical condition. Echocardiography-guided transapical radiofrequency ablation for cardiac tumors (TARFACT) potentially offers a less invasive palliative therapy option. Objectives: This study aimed to evaluate the safety and efficacy of TARFACT. Methods: Five patients with cardiac tumors (mucinous liposarcoma, myocardial hypertrophy with inflammatory cell infiltration mass, fibrous tissue tumor hyperplasia, myocardial clear cell sarcoma, and cardiac rhabdomyoma) were included. All patients underwent TARFACT and were assessed with electrocardiogram, echocardiographic imaging, biochemical analysis, and pathological confirmation. Results: The median follow-up for all patients was 9 (range 4-12) months. Three surviving patients were alive at their last follow-up (9, 12, and 12 months, respectively), whereas 2 patients with late-stage tumors survived 6 months and 13 months after TARFACT, respectively. After TARFACT, all patients showed significant reductions in tumor size: the mean length decreased from 6.7 ± 2.0 cm to 4.7 ± 1.8 cm (P = 0.007); and the mean width decreased from 5.0 ± 2.1 cm to 2.5 ± 0.7 cm (P = 0.041). NYHA functional class also improved: median (IQR) decreased from 3.0 (1.5) to 2.0 (1.0) (P = 0.038), Peak E-wave on echocardiography showed a mean increase from 64.4 ± 15.7 cm/s to 76.6 ± 18.6 cm/s (P = 0.008), and NT-pro BNP levels had a median (IQR) reduction from 115.7 (252.1) pg/mL to 55.0 (121.6) pg/mL (P = 0.043). Conclusions: TARFACT is a novel palliative treatment option for cardiac tumors, reducing accessible tumors and improving clinical symptoms in a preliminary group of patients. (Cardiac Tumors Interventional [Radio Frequency/Laser Ablation] Therapy [CTIH]; NCT02815553).

Multifunctional aggregation network of cell nuclei segmentation aiming histopathological diagnosis assistance: A new MA-Net construction.

Automated diagnostic systems can enhance the accuracy and efficiency of pathological diagnoses, nuclear segmentation plays a crucial role in computer-aided diagnosis systems for histopathology. However, achieving accurate nuclear segmentation is challenging due to the complex background tissue structures and significant variations in cell morphology and size in pathological images. In this study, we have proposed a U-Net based deep learning model, called MA-Net(Multifunctional Aggregation Network), to accurately segmenting nuclei from H&E stained images. In contrast to previous studies that focused on improving a single module of the network, we applied feature fusion modules, attention gate units, and atrous spatial pyramid pooling to the encoder and decoder, skip connections, and bottleneck of U-Net, respectively, to enhance the network's performance in nuclear segmentation. The dice coefficient loss was used during model training to enhance the network's ability to segment small objects. We applied the proposed MA-Net to multiple public datasets, and comprehensive results showed that this method outperforms the original U-Net method and other state-of-the-art methods in nuclei segmentation tasks. The source code of our work can be found in https://github.com/LinaZhaoAIGroup/MA-Net.

A2HTL: An Automated Hybrid Transformer Based Learning for Predicting Survival of Esophageal Cancer Using CT Images.

Esophageal cancer is a common malignant tumor, precisely predicting survival of esophageal cancer is crucial for personalized treatment. However, current region of interest (ROI) based methodologies not only necessitate prior medical knowledge for tumor delineation, but may also cause the model to be overly sensitive to ROI. To address these challenges, we develop an automated Hybrid Transformer based learning that integrates a Hybrid Transformer size-aware U-Net with a ranked survival prediction network to enable automatic survival prediction for esophageal cancer. Specifically, we first incorporate the Transformer with shifted windowing multi-head self-attention mechanism (SW-MSA) into the base of the UNet encoder to capture the long-range dependency in CT images. Furthermore, to alleviate the imbalance between the ROI and the background in CT images, we devise a size-aware coefficient for the segmentation loss. Finally, we also design a ranked pair sorting loss to more comprehensively capture the ranked information inherent in CT images. We evaluate our proposed method on a dataset comprising 759 samples with esophageal cancer. Experimental results demonstrate the superior performance of our proposed method in survival prediction, even without ROI ground truth.

The causal relationship between 91 inflammatory cytokines and Gestational Diabetes Mmellitus: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Gestational Diabetes Mellitus (GDM) poses significant risks to maternal and fetal health, yet its precise etiology remains unclear. Observational studies have demonstrated a link between specific inflammatory cytokines and the occurrence of GDM, but the causal relationships remain uncertain. METHODS: Utilizing publicly accessible genetic data, we performed a bidirectional two-sample mendelian randomization (MR) analysis to elucidate the causal association between 91 inflammatory cytokines and GDM. Sensitivity analysis was carried out to evaluate the robustness, heterogeneity, and potential presence of horizontal pleiotropy within the results. RESULTS: Elevated levels of Interleukin-7 (IL7) and Neurturin (NRTN) (OR=1.104, 95 % CI=1.003-1.216, p = 0.042; OR=1.102, 95 % CI=1.023-1.187, p = 0.010), along with decreased levels of Glial cell line-derived neurotrophic factor (GDNF), Interleukin-12 subunit beta (IL12ß), and Interleukin-20 (IL20) (OR=0.911, 95 % CI=0.849-0.979, p = 0.010;OR=0.955, 95 % CI=0.916-0.996, p = 0.033; OR=0.892, 95 % CI=0.819-0.971, p = 0.008), are associated with increased GDM risk. Additionally, GDM occurrence correlates with increased Matrix metalloproteinase-10 (MMP-10) and decreased Interleukin-20 receptor subunit alpha (IL-20Rα) levels (OR=1.042, 95 % CI=1.002-1.084, p = 0.038; OR=0.949, 95 % CI=0.909-0.992, p = 0.021). Sensitivity analyses detected no significant heterogeneity or pleiotropy. CONCLUSION: This study has clarified the causal link between inflammatory cytokines and GDM, thereby enhancing our comprehension of the potential mechanisms involved in GDM pathogenesis. These findings offer new insights into the etiology, diagnosis, and therapeutic strategies for GDM.

Quantitative Three-Dimensional Imaging Analysis of HfO2 Nanoparticles in Single Cells via Deep Learning Aided X-ray Nano-Computed Tomography.

It is crucial for understanding mechanisms of drug action to quantify the three-dimensional (3D) drug distribution within a single cell at nanoscale resolution. Yet it remains a great challenge due to limited lateral resolution, detection sensitivities, and reconstruction problems. The preferable method is using X-ray nano-computed tomography (Nano-CT) to observe and analyze drug distribution within cells, but it is time-consuming, requiring specialized expertise, and often subjective, particularly with ultrasmall metal nanoparticles (NPs). Furthermore, the accuracy of batch data analysis through conventional processing methods remains uncertain. In this study, we used radioenhancer ultrasmall HfO2 nanoparticles as a model to develop a modular and automated deep learning aided Nano-CT method for the localization quantitative analysis of ultrasmall metal NPs uptake in cancer cells. We have established an ultrasmall objects segmentation method for 3D Nano-CT images in single cells, which can highly sensitively analyze minute NPs and even ultrasmall NPs in single cells. We also constructed a localization quantitative analysis method, which may accurately segment the intracellularly bioavailable particles from those of the extracellular space and intracellular components and NPs. The high bioavailability of HfO2 NPs in tumor cells from deeper penetration in tumor tissue and higher tumor intracellular uptake provide mechanistic insight into HfO2 NPs as advanced radioenhancers in the combination of quantitative subcellular image analysis with the therapeutic effects of NPs on 3D tumor spheroids and breast cancer. Our findings unveil the substantial uptake rate and subcellular quantification of HfO2 NPs by the human breast cancer cell line (MCF-7). This revelation explicates the notable efficacy and safety profile of HfO2 NPs in tumor treatment. These findings demonstrate that this 3D imaging technique promoted by the deep learning algorithm has the potential to provide localization quantitative information about the 3D distributions of specific molecules at the nanoscale level. This study provides an approach for exploring the subcellular quantitative analysis of NPs in single cells, offering a valuable quantitative imaging tool for minute amounts or ultrasmall NPs.

Effects of Different Non-Saccharomyces Strains in Simultaneous and Sequential Co-Fermentations with Saccharomyces cerevisiae on the Quality Characteristics of Kiwi Wine.

With the increasing awareness of health, more people have shown a preference for low-alcohol beverages. Seeking various methods to improve the quality of kiwi wine is now a major research interest in the wine industry. In this study, kiwi wine was fermented by Saccharomyces cerevisiae and different non-Saccharomyces strains (Torulaspora delbrueckii, Kluyveromyces thermotolerans, Pichia fermentans) in three methods (pure fermentation, simultaneous, and sequential co-fermentation). The physicochemical characteristics, color parameters, phenolic profiles, total phenolic content (TPC), antioxidant activities, organic acids, and taste sense of the different wines were evaluated to determine the effects of different yeasts and fermentation methods on the quality of the kiwi wine. Results indicated that co-fermentation reduced the contents of alcohol while enhancing the lightness of the kiwi wine. The TPC of sequential co-fermentation with K. thermotolerans/S. cerevisiae was significantly higher than that of their simultaneous co-fermentation. Compared to K. thermotolerans/S. cerevisiae, the antioxidant activities were increased by co-fermentation of T. delbrueckii/S. cerevisiae and P. fermentans/S. cerevisiae. Principal component analysis showed that kiwi wines fermented by different yeasts and inoculation methods could be separated and grouped. Correlation analysis presented positive correlations of phenolic composition, antioxidant activities, and color intensity. This study provided theoretical guidance for co-fermentation of non-Saccharomyces/S. cerevisiae and accelerated the industrialization process of kiwi wine.

Effects of Loquat Juice Addition on Sensory Characteristics and Volatile Organic Compounds of Loquat Beer.

Beer, as an ancient and widely consumed alcoholic beverage, holds a rich cultural heritage and history. In recent years, fruit beer has gained significant attention as a distinct beer type produced by incorporating fruit juice into traditional beer ingredients. This study employed headspace solid-phase microextraction-gas chromatography-mass spectrometry techniques, redundancy analysis, and orthogonal projections to latent structures discriminant analysis to analyze the sensory evaluation, physicochemical properties, organic acids, and volatile organic compounds (VOCs) of loquat beer with different proportions of loquat juice. The results shown that the addition of an appropriate amount of loquat juice (40%) enhanced the overall sensory quality of the beer; as the proportion of loquat juice increased, the contents of malic acid and tartaric acid significantly increased (p < 0.05). A total of 100 VOCs were identified, among which 23 key VOCs (VIP > 1, p < 0.05) represented the most important characteristic flavor components in loquat beer based on their odor activity value (OAV). This study holds significant importance for the value-added processing and economic development of loquat.

Association between relative fat mass and periodontitis: results from NHANES 2009-2014.

Relative fat mass (RFM) is a novel indicator for measuring body fat. This cross-section study aims to explore the association between RFM and periodontitis and to investigate possible effect modifiers in U.S. adults based on the National Health and Nutrition Examination Survey 2009-2014. The category of periodontitis was defined by the CDC/AAP. Mean clinical attachment loss and mean pocket probing depth (PPD) were calculated. The RFM formula is: 64 - (20 × height/WC) + (12 × sex), with sex coded as 1 for female and 0 for male. Natural cubic spline and weighted multivariable regression analyses were conducted to investigate the relationship between RFM and periodontal status. Subgroup and interaction analyses were also employed to assess the moderating roles of age, gender, and race. A total of 10,307 participants were included in our study. Compared to the lowest quartiles, individuals in the highest quartiles of RFM levels were more likely to have moderate/severe periodontitis (ORQ4vs1 = 1.64, 95% CI 1.30-2.06) and had a higher mean PPD (ßQ4vs1 = 0.15, 95% CI 0.09-0.22). This association was particularly stronger in populations under the age of 60, with significant interactions. Taken together, RFM is positively associated with periodontitis, particularly in those under 60 years old.

Deep learning architecture with shunted transformer and 3D deformable convolution for voxel-level dose prediction of head and neck tumors.

Intensity-modulated radiation therapy (IMRT) has been widely used in treating head and neck tumors. However, due to the complex anatomical structures in the head and neck region, it is challenging for the plan optimizer to rapidly generate clinically acceptable IMRT treatment plans. A novel deep learning multi-scale Transformer (MST) model was developed in the current study aiming to accelerate the IMRT planning for head and neck tumors while generating more precise prediction of the voxel-level dose distribution. The proposed end-to-end MST model employs the shunted Transformer to capture multi-scale features and learn a global dependency, and utilizes 3D deformable convolution bottleneck blocks to extract shape-aware feature and compensate the loss of spatial information in the patch merging layers. Moreover, data augmentation and self-knowledge distillation are used to further improve the prediction performance of the model. The MST model was trained and evaluated on the OpenKBP Challenge dataset. Its prediction accuracy was compared with three previous dose prediction models: C3D, TrDosePred, and TSNet. The predicted dose distributions of our proposed MST model in the tumor region are closest to the original clinical dose distribution. The MST model achieves the dose score of 2.23 Gy and the DVH score of 1.34 Gy on the test dataset, outperforming the other three models by 8%-17%. For clinical-related DVH dosimetric metrics, the prediction accuracy in terms of mean absolute error (MAE) is 2.04% for D 99 , 1.54% for D 95 , 1.87% for D 1 , 1.87% for D mean , 1.89% for D 0.1 c c , respectively, superior to the other three models. The quantitative results demonstrated that the proposed MST model achieved more accurate voxel-level dose prediction than the previous models for head and neck tumors. The MST model has a great potential to be applied to other disease sites to further improve the quality and efficiency of radiotherapy planning.

Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.

Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.

Precise and efficient measurement of tibial slope on magnetic resonance imaging (MRI): two novel autonomous pipelines by traditional and deep learning algorithms.

Background: The measurement of posterior tibial slopes (PTS) can aid in the screening and prevention of anterior cruciate ligament (ACL) injuries and improve the success rate of some other knee surgeries. However, the circle method for measuring PTS on magnetic resonance imaging (MRI) scans is challenging and time-consuming for most clinicians to implement in practice, despite being highly repeatable. Currently, there is no automated measurement scheme based on this method. To enhance measurement efficiency, consistency, and reduce errors resulting from manual measurements by physicians, this study proposes two novel, precise, and computationally efficient pipelines for autonomous measurement of PTS. Methods: The first pipeline employs traditional algorithms with experimental parameters to extract the tibial contour, detect adhesions, and then remove these adhesions from the extracted contour. A cyclic process is employed to adjust the parameters adaptively and generate a better binary image for the following tibial contour extraction step. The second pipeline utilizes deep learning models for classifying MRI slice images and segmenting tibial contours. The incorporation of deep learning models greatly simplifies the corresponding steps in pipeline 1. Results: To evaluate the practical performance of the proposed pipelines, doctors utilized MRI images from 20 patients. The success rates of pipeline 1 for central, medial, and lateral slices were 85%, 100%, and 90%, respectively, while pipeline 2 achieved success rates of 100%, 100%, and 95%. Compared to the 10 minutes required for manual measurement, our automated methods enable doctors to measure PTS within 10 seconds. Conclusions: These evaluation results validate that the proposed pipelines are highly reliable and effective. Employing these tools can effectively prevent medical practitioners from being burdened by monotonous and repetitive manual measurement procedures, thereby enhancing both the precision and efficiency. Additionally, this tool holds the potential to contribute to the researches regarding the significance of PTS, particularly those demanding extensive and precise PTS measurement outcomes.

High-dose hyperfractionated simultaneous integrated boost radiotherapy versus standard-dose radiotherapy for limited-stage small-cell lung cancer in China: a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: For the past 20 years, twice-daily thoracic radiotherapy with concurrent chemotherapy has been the treatment of choice for limited-stage small-cell lung cancer (LS-SCLC), which has a poor prognosis. We aimed to assess the efficacy and safety of high-dose, accelerated, hyperfractionated, twice-daily thoracic radiotherapy (54 Gy in 30 fractions) versus standard-dose radiotherapy (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. METHODS: This open-label, randomised, phase 3 trial was performed at 16 public hospitals in China. The key inclusion criteria were patients aged 18-70 years, with histologically or cytologically confirmed LS-SCLC, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and who were previously untreated or had received one course of cisplatin or carboplatin and etoposide. Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions to the gross tumour volume or VMAT with a simultaneous integrated boost of 54 Gy in 30 fractions to the gross tumour volume starting 0-42 days after the first chemotherapy course. Both groups received 10 fractions of twice-daily thoracic radiotherapy per week. The planning target volume was 45 Gy in 30 fractions in both groups. Patients with responsive disease received prophylactic cranial radiotherapy (25 Gy in 10 fractions). Randomisation was performed using a centralised interactive web response system, stratified by ECOG performance status, disease stage, previous chemotherapy course, and chemotherapy choice. The primary outcome was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This study was registered at ClinicalTrials.gov, NCT03214003. FINDINGS: From June 30, 2017, to April 6, 2021, 224 patients (102 [46%] females and 122 [54%] males; median age 64 years [IQR 58-68]) were enrolled and randomly assigned to the 54 Gy group (n=108) or 45 Gy (n=116) group. The median follow-up was 46 months (IQR 33-56). The median overall survival was significantly longer in the 54 Gy group (60·7 months [95% CI 49·2-62·0]) than in the 45 Gy group (39·5 months [27·5-51·4]; hazard ratio 0·55 [95% CI 0·37-0·72]; p=0·003). Treatment was tolerable, and the chemotherapy-related and radiotherapy-related toxicities were similar between the groups. The grade 3-4 radiotherapy toxicities were oesophagitis (14 [13%] of 108 patients in the 54 Gy group vs 14 [12%] of 116 patients in the 45 Gy group; p=0·84) and pneumonitis (five [5%] of 108 patients vs seven [6%] of 116 patients; p=0·663). Only one treatment-related death occurred in the 54 Gy group (myocardial infarction). The study was prematurely terminated by an independent data safety monitoring board on April 30, 2021, based on evidence of sufficient clinical benefit. INTERPRETATION: Compared with standard-dose thoracic radiotherapy (45 Gy), high-dose radiotherapy (54 Gy) improved overall survival without increasing toxicity in a cohort of patients aged 18-70 years with LS-SCLC. Our results support the use of twice-daily accelerated thoracic radiotherapy (54 Gy) with concurrent chemotherapy as an alternative first-line LS-SCLC treatment option. FUNDING: Chinese Society of Clinical Oncology-Linghang Cancer Research, the Wu Jieping Medical Foundation, and Clinical Research Fund For Distinguished Young Scholars of Peking University Cancer Hospital and Beijing Municipal Administration of Hospitals Incubating Program.

Prevalence of Polypharmacy in Elderly Population Worldwide: A Systematic Review and Meta-Analysis.

BACKGROUND: Polypharmacy (PP) is common in elderly population and associated with some adverse clinical outcomes and increases healthcare burdens. We performed this systemic review and meta-analysis to estimate worldwide prevalence of PP and explore associated factors in the elderly. METHODS: The PubMed, Web of Science, Cochrane Library, and Ovid EMBASE databases were searched for studies published until May 30, 2022. We included observational studies representative of general patients aged ≥60 in which PP was defined as multiple drugs ≥5. Studies were excluded if only a particular group of the elderly population (e.g., with diabetes) were included. The primary outcome was the prevalence of PP. Random-effect models were employed to estimate the overall or variable-specific pooled estimates of PP. Secondary outcomes were hyperpolypharmacy (HPP, defined as multiple drugs ≥10) and PP prevalence based on different study years, genders, locations, populations, and so forth. RESULTS: We included 122 original observational studies with an overall population of 57 328 043 individuals in the meta-analysis. The overall prevalence of PP and HPP in the elderly population worldwide was 39.1% (95% confidence interval [CI], 35.5%-42.7%) and 13.3% (95% CI, 10.4%-16.5%), respectively. The prevalence of PP in Europe, Oceania, North America, Asia, and South America was 45.8% (95% CI, 41.5%-50.2%), 45.5% (95% CI, 26.7%-64.3%), 40.8% (95% CI, 29.8%-51.6%), 29.0% (95% CI, 20.0%-38.0%), and 28.4% (95% CI, 24.0%-32.8%), respectively (p < 0.01). Multivariate meta-regressions showed geographical regions of Europe or North America, age ≥70, and residence from nursing homes were independently associated with higher PP prevalence. CONCLUSIONS: Nearly 40% of the elderly population is exposed to PP. The prevalence of PP is significantly higher in elderly individuals aged 70 or older, in developed regions and in nursing homes. It is important to focus on avoiding inappropriate PP in this population to address the growing burden of PP.

Treatment outcomes of surgery followed by short-course every other day radiotherapy in keloid.

BACKGROUND: Postoperative radiotherapy can significantly reduce keloid recurrence. However, consensus on the optimal radiotherapy dose and treatment schedule remains elusive. This study aims to evaluate the effectiveness of surgery followed by a short-course of radiotherapy administered every other day for keloid treatment. MATERIALS/METHODS: We conducted a retrospective analysis of 498 patients with keloids treated at our institution between January 2010 and December 2017. All patients underwent electron beam irradiation at a dose of 16 Gy, delivered in four fractions every other day, starting within 24 h post-surgery. The primary endpoint of the study was the local control rate. RESULTS: A total of 130 (26.5%) keloids recurred after a median follow-up of 68.1months (42.6-129.9 months). The local control rates at 1 year, 3 years and 5 years for all patients were 89.5%, 82.5% and 81%, respectively. The highest recurrence rate was observed in keloids located in the chest region (50.8%), followed by the suprapubic (47.8%), head and neck (38.8%), limbs (33.3%) and ear (14%). Both multivariate and univariate analyses identified the presence of pain and or pruritus as an independently prognostic factor for keloid recurrence (p<0.0001). The local control rates at 1-year, 3-years and 5-years for patients with or without symptom of pain or pruritus were 45% vs. 98.8%, 12.5% vs. 95.9%, and 8.8% vs. 95%, respectively (HR:37.829, 95%CI: 24.385-58.686, p<0.001). In the ear keloid subgroup, the 1-year, 3-year and 5-year local control rates for patients with pruritus were significantly lower than those without pain or pruritus (60.0% vs. 97.9%, 26.7% vs. 94.7%, 26.7% vs. 94.3%, HR:30.209, 95% CI:14.793-61.69, p<0.001). The same results were found in other location(p<0.001). During treatment and follow-up, two patients experienced infections, and one patient developed a cutaneous fibroblastoma. CONCLUSION: This study suggests that a combination of surgery followed by short-course, every-other-day radiotherapy can yield satisfactory local control rates for keloids. Pain and or pruritus symptom was an independently prognostic factors for recurrence of keloid. To further validate these results, a prospective randomized controlled trial is recommended.