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Abstract. Background:. Breast cancer is ranked among the most prevalent malignancies in the Chinese female population. However, comprehensive reports detailing the latest epidemiological data and attributable disease burden have not been extensively documented. Methods:. In 2018, high-quality cancer surveillance data were recorded in 700 population-based cancer registries in China. We extracted data on female breast cancers (International Classification of Diseases, Tenth Revision [ICD-10]: C50) and estimated the incidence and mortality in 2022 according to the baseline data and corresponding trends from 2010 to 2018. Pathological types were classified according to the ICD for Oncology, 3rd Edition codes. Disability-adjusted life years (DALYs) were calculated as the sum of the years of life lost (YLLs) and years lived with disability (YLDs). Results:. In 2022, approximately 357,200 new female breast cancer cases and 75,000 deaths occurred in China, accounting for 15.59% and 7.94% of total new cancer cases and deaths, respectively. The age-standardized incidence rate (ASIR) was 33.04 per 100,000. When analyzed by pathological type, the ASIRs for papillary neoplasms, invasive breast carcinoma, rare and salivary gland-type tumors, and other types were 1.13, 29.79, 0.24, and 1.88 per 100,000, respectively. The age-standardized mortality rate (ASMR) was 6.10 per 100,000. A total of 2,628,000 DALYs were found to be attributable to female breast cancer in China, comprising 2,278,300 YLLs and 349,700 YLDs. The ASIR, ASMR, and age-standardized rate (ASR) for DALYs in urban areas were consistently higher than those in rural areas. We observed a four-fold increase in the ASIR and ASR for DALYs and an eight-fold increase in the ASMR among females over 55 years compared with those aged under 55 years. Conclusion:. These data provide invaluable insights into the latest epidemiology of female breast cancer in China and highlight the urgency for disease prevention and control strategy formulation.

Abstract Background Breast cancer (BC) is the leading cause of morbidity and the second leading cause of death among female malignant tumors. Although available drugs have been approved for the corresponding breast cancer subtypes (ER-positive, HER2+) currently, there are still no effective targeted drugs or treatment strategies for metastatic breast cancer or triple-negative breast cancer that lack targets. Therefore, it is urgent to discover new potential targets. ERCC6L is an essential protein involved in chromosome separation during cell mitosis. However, the effect of ERCC6L on the tumorigenesis and progression of breast cancer is unclear. Methods and results Here, we found that ERCC6L was highly expressed in breast cancer, especially in TNBC, which was closely related to poor outcomes of patients. An ERCC6L conditional knockout mouse model was first established in this study, and the results confirmed that ERCC6L was required for the development of the mammary gland and the tumorigenesis and progression of mammary gland cancers. In in vitro cell culture, ERCC6L acted as a tumor promoter in the malignant progression of breast cancer cells. Overexpression of ERCC6L promoted cell proliferation, migration and invasion, while knockdown of ERCC6L caused the opposite results. Mechanistically, ERCC6L accelerated the cell cycle by regulating the G2/M checkpoint signalling pathway. Additionally, we demonstrated that there is an interaction between ERCC6L and KIF4A, both of which are closely related factors in mitosis and are involved in the malignant progression of breast cancer. Conclusions We first demonstrated that ERCC6L deficiency can significantly inhibit the occurrence and development of mammary gland tumors. ERCC6L was found to accelerate the cell cycle by regulating the p53/p21/CDK1/Cyclin B and PLK/CDC25C/CDK1/Cyclin B signalling pathways, thereby promoting the malignant progression of breast cancer cell lines. There was a direct interaction between KIF4A and ERCC6L, and both are closely associated with mitosis and contribute to growth and metastasis of breast tumor. To sum up, our results suggest that ERCC6L may be used as a promising target for the treatment of BC.

Abstract. Background:. Metastasis is the main cause of tumor-associated death and mainly responsible for treatment failure of breast cancer. Autophagy accelerates tumor metastasis. In our work, we aimed to investigate the possibility of microRNAs (miRNAs) which participate in the regulation of autophagy to inhibit tumor metastasis. Methods:. MiRNA array and comprehensive analysis were performed to identify miRNAs which participated in the regulation of autophagy to inhibit tumor metastasis. The expression levels of miR-3653 in breast cancer tissues and cells were detected by quantitative real-time polymerase chain reaction. In vivo and in vitro assays were conducted to determine the function of miR-3653. The target genes of miR-3653 were detected by a dual luciferase reporter activity assay and Western blot. The relationship between miR-3653 and epithelial-mesenchymal transition (EMT) was assessed by Western blot. Student's t-test was used to analyze the difference between any two groups, and the difference among multiple groups was analyzed with one-way analysis of variance and a Bonferroni post hoc test. Results:. miR-3653 was downregulated in breast cancer cells with high metastatic ability, and high expression of miR-3653 blocked autophagic flux in breast cancer cells. Clinically, low expression of miR-3653 in breast cancer tissues (0.054 ± 0.013 vs. 0.131 ± 0.028, t = 2.475, P = 0.014) was positively correlated with lymph node metastasis (0.015 ± 0.004 vs. 0.078 ± 0.020, t = 2.319, P = 0.023) and poor prognosis (P

Abstract Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4+ and CD8+ T cells. Co-culturing CD4+ with autologous CD8+ T cells from ART-suppressed HIV+ donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8+ T cells. This trispecific antibody mediates CD4+ and CD8+ T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection.

Abstract Background Early detection is critical for improving the survival of breast cancer (BC) patients. Exhaled breath testing as a non-invasive technique might help to improve BC detection. However, the breath test accuracy for BC diagnosis is unclear. Methods This multi-center cohort study consecutively recruited 5047 women from four areas of China who underwent BC screening. Breath samples were collected through standardized breath collection procedures. Volatile organic compound (VOC) markers were identified from a high-throughput breathomics analysis by the high-pressure photon ionization–time-of-flight mass spectrometry (HPPI-TOFMS). Diagnostic models were constructed using the random forest algorithm in the discovery cohort and tested in three external validation cohorts. Results A total of 465 (9.21%) participants were identified with BC. Ten optimal VOC markers were identified to distinguish the breath samples of BC patients from those of non-cancer women. A diagnostic model (BreathBC) consisting of 10 optimal VOC markers showed an area under the curve (AUC) of 0.87 in external validation cohorts. BreathBC-Plus, which combined 10 VOC markers with risk factors, achieved better performance (AUC = 0.94 in the external validation cohorts), superior to that of mammography and ultrasound. Overall, the BreathBC-Plus detection rates were 96.97% for ductal carcinoma in situ, 85.06%, 90.00%, 88.24%, and 100% for stages I, II, III, and IV BC, respectively, with a specificity of 87.70% in the external validation cohorts. Conclusions This is the largest study on breath tests to date. Considering the easy-to-perform procedure and high accuracy, these findings exemplify the potential applicability of breath tests in BC screening.

Objectives: This study aimed to identify plasma proteins that are associated with and causative of breast cancer through Proteome and Transcriptome-wide association studies combining Mendelian Randomization.Methods: Utilizing high-throughput datasets, we designed a two-phase analytical framework aimed at identifying novel plasma proteins that are both associated with and causative of breast cancer. Initially, we conducted Proteome/Transcriptome-wide association studies (P/TWAS) to identify plasma proteins with significant associations. Subsequently, Mendelian Randomization was employed to ascertain the causation. The validity and robustness of our findings were further reinforced through external validation and various sensitivity analyses, including Bayesian colocalization, Steiger filtering, heterogeneity and pleiotropy. Additionally, we performed functional enrichment analysis of the identified proteins to better understand their roles in breast cancer and to assess their potential as druggable targets.Results: We identified 5 plasma proteins demonstrating strong associations and causative links with breast cancer. Specifically, PEX14 (OR = 1.201, p = 0.016) and CTSF (OR = 1.114, p < 0.001) both displayed positive and causal association with breast cancer. In contrast, SNUPN (OR = 0.905, p < 0.001), CSK (OR = 0.962, p = 0.038), and PARK7 (OR = 0.954, p < 0.001) were negatively associated with the disease. For the ER-positive subtype, 3 plasma proteins were identified, with CSK and CTSF exhibiting consistent trends, while GDI2 (OR = 0.920, p < 0.001) was distinct to this subtype. In ER-negative subtype, PEX14 (OR = 1.645, p < 0.001) stood out as the sole protein, even showing a stronger causal effect compared to breast cancer. These associations were robustly supported by colocalization and sensitivity analyses.Conclusion: Integrating multiple data dimensions, our study successfully pinpointed plasma proteins significantly associated with and causative of breast cancer, offering valuable insights for future research and potential new biomarkers and therapeutic targets.

Mass spectrometry-based thermal stability assays (MS-TSA) are a promising approach to characterize protein-ligand interaction, and several strategies have been recently developed to improve their performance. Here, the authors combine three recent strategies to qualitatively and quantitatively improve aspects of MS-TSA.

Abstract Background Breast cancer (BC) metastasis is the leading cause of poor prognosis and therapeutic failure. However, the mechanisms underlying cancer metastasis are far from clear. Methods We screened candidate genes related to metastasis through genome-wide CRISPR screening and high-throughput sequencing of patients with metastatic BC, followed by a panel of metastatic model assays. The effects of tetratricopeptide repeat domain 17 (TTC17) on migration, invasion, and colony formation ability together with the responses to anticancer drugs were investigated in vitro and in vivo. The mechanism mediated by TTC17 was determined by RNA sequencing, Western blotting, immunohistochemistry, and immunofluorescence. The clinical significance of TTC17 was evaluated using BC tissue samples combined with clinicopathological data. Results We identified the loss of TTC17 as a metastasis driver in BC, and its expression was negatively correlated with malignancy and positively correlated with patient prognosis. TTC17 loss in BC cells promoted their migration, invasion, and colony formation capacity in vitro and lung metastasis in vivo. Conversely, overexpressing TTC17 suppressed these aggressive phenotypes. Mechanistically, TTC17 knockdown in BC cells resulted in the activation of the RAP1/CDC42 pathway along with a disordered cytoskeleton in BC cells, and pharmacological blockade of CDC42 abolished the potentiation of motility and invasiveness caused by TTC17 silencing. Research on BC specimens demonstrated reduced TTC17 and increased CDC42 in metastatic tumors and lymph nodes, and low TTC17 expression was linked to more aggressive clinicopathologic characteristics. Through screening the anticancer drug library, the CDC42 inhibitor rapamycin and the microtubule-stabilizing drug paclitaxel showed stronger inhibition of TTC17-silenced BC cells, which was confirmed by more favorable efficacy in BC patients and tumor-bearing mice receiving rapamycin or paclitaxel in the TTC17Low arm. Conclusions TTC17 loss is a novel factor promoting BC metastasis, that enhances migration and invasion by activating RAP1/CDC42 signaling and sensitizes BC to rapamycin and paclitaxel, which may improve stratified treatment strategies under the concept of molecular phenotyping-based precision therapy of BC.

Monitoring the temperature of the coal gangue mountains is fundamental to preventing their spontaneous combustion. However, the existing temperature monitoring systems fail to achieve stable, pollution-free temperature monitoring without affecting vegetation growth in these mountains. To address this issue, this work proposes a flexible thermoelectric device (FTD) based on a protrusion-structured liquid metal elastomer (LME). Utilizing a high-thermal-conductivity LME, the FTD adheres closely to the surface of the gravity heat pipe (GHP), ensuring compatibility between FTD and the curved surface of the GHP. Simultaneously, employing a low-thermal-conductivity elastomer helps concentrate heat onto FTD, thereby enhancing thermoelectric power generation efficiency. Additionally, the impact of the shape, size, and height of the protrusion structure at the cold end of the GHP on its efficiency was also investigated. The practical application of FTD on GHP was demonstrated.

Background and aim: Current observational studies have compared the effectiveness and safety of edoxaban with other oral anticoagulants in patients with AF, but the results are still disputed. This meta-analysis was conducted to compare the effect of edoxaban in patients with AF. Methods: We performed systematic research from the PubMed, EMBASE, and Cochrane Library databases until November 2022 to obtain relevant observational studies. Adjusted risk ratios (RRs) and 95 % confidence intervals (CIs) of the outcomes were collected and pooled by a random-effects model. This study was prospectively registered in PROSPERO (CRD42022314222). Results: A total of 17 observational studies were included in this meta-analysis. Compared with vitamin K antagonists, edoxaban was associated with lower risks of stroke or systemic embolism (RR = 0.67, 95 % CI:0.61–0.74), major bleeding (RR = 0.54, 95 % CI:0.44–0.67), and intracranial hemorrhage (RR = 0.51, 95 % CI:0.29–0.90). Compared with dabigatran or rivaroxaban, edoxaban was associated with reduced risks of stroke or systemic embolism (dabigatran [RR = 0.76, 95 % CI:0.66–0.87]; rivaroxaban [RR = 0.81, 95 % CI:0.70–0.94]) and major bleeding (dabigatran [RR = 0.82, 95 % CI:0.69–0.98]; rivaroxaban [RR = 0.81, 95 % CI:0.70–0.94]). Compared with apixaban, edoxaban was associated with a reduced risk of stroke or systemic embolism (RR = 0.87, 95 % CI:0.79–0.97), but had similar risks of bleeding events. Conclusions: Our current evidence suggested that edoxaban might have superior effectiveness and/or safety outcomes than vitamin K antagonists, dabigatran, rivaroxaban, and apixaban for stroke prevention in patients with AF.

[Objective] The spatial-temporal evolution characteristics and driving mechanism of agricultural carbon emissions in Henan Province were determined to predict the change trend of agricultural carbon emissions during the next ten years in order to formulate an agricultural carbon sequestration and emission reduction scheme, and to promote the transformation to low-carbon and green agricultural production. [Methods] We used a carbon emission equity evaluation model, GeoDetector, and the GM (1,1) model to accomplish the study objectives. [Results] ① Agricultural net carbon emissions in Henan Province declined over time during the study period, with a distribution pattern of "high in the southwest and low in the northeast" . Carbon emissions from animal husbandry accounted for a large proportion of total emissions, and carbon emissions were mainly from cattle, sheep, and pigs. Wheat, corn and vegetables contributed more to carbon absorption than other sinks. ② The ecological carrying coefficient of agricultural carbon emissions was higher in the north and south, and lower in the west. The coefficient of economic contribution was high in the southeast and low in the southwest. ③ The agricultural employee population, per capita disposable income of rural residents, agricultural machinery gross power, and fiscal expenditures on education were the key factors affecting spatial differences in agricultural carbon emissions, and interactions among these factors were strong. ④ Agricultural net carbon emissions in Henan Province will continue to decrease from 2021 to 2030. It is estimated that Henan Province will achieve the goal of agricultural carbon neutrality by 2029. [Conclusion] In the future, Henan Province should strengthen science popularization, actively promote low-carbon agricultural production technology, and increase the efficiency of comprehensive utilization of agricultural resources. Additionally, all localities should give increased attention to system integration, strengthening regional cooperation, and achieving regional integration of agricultural carbon emission reduction.

Abstract Background Concurrent chemoradiotherapy is currently the standard of care for patients with locally advanced cervical cancer. However, even with the application of modern radiotherapy techniques, a considerable number of patients still develop distant metastases. PD-L1 inhibitors show good efficacy in cervical cancer. This single-arm phase II study aims to explore the efficacy and tolerability of combining PD-L1 inhibitor with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. Methods/design The primary endpoint of the study was the objective response rate assessed according to RECIST v1.1 criteria. The inclusion criteria were previously untreated patients aged 18–75 years with stage III-IVA (FIGO 2018 staging system) locally advanced cervical cancer. During concurrent chemoradiotherapy and consolidation chemotherapy, the enrolled patients will receive toripalimab (240 mg) every 3 weeks. After consolidation chemotherapy, the enrolled patients will be treated with toripalimab (240 mg) once every 6 weeks until the whole treatment cycle reaches 1 year. Intensity modulated radiotherapy was used for external beam radiation, and high-dose rate brachytherapy was delivered under image-guidance. Weekly DDP (40 mg/m2) was given concurrently with radiotherapy while 6 cycles of consolidated chemotherapy (paclitaxel plus DDP) were given after radiotherapy every three weeks. Secondary objectives included safety and tolerability, toxicity profile, progression-free survival, and overall survival. Discussion PD-L1 inhibitor has shown good efficacy in recurrent/metastatic cervical cancer. However, there is still a lack of evidence about its combination with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. The purpose of this study is to explore the efficacy and tolerance of this combination therapy, so as to lay the foundation for the future phase III randomized study. Trial registration clinicaltrials.gov NCT05084677 . Retrospectively registered on Octorber 07, 2021.

We investigated the feasibility of the generation of synthetic CT (sCT) from CBCT images with deep learning and the dose evaluation for CBCT-guided breast cancer adaptive radiotherapy.A total of sixty-eight patients receiving radiotherapy after breast-conserving surgery were retrospectively included in this study. We compared the performance of three deep-learning methods in generating sCT from CBCT, including U-Net, Cycle generative adversarial network (CycleGAN) and pix2pix. The original treatment plan was transferred to sCT keeping the same parameters. The dosimetric evaluation was performed by a quick dose recalculation on sCT based on gamma analysis.The U-Net model obtained the lowest mean absolute error (MAE) within the body, clinical target volume (CTV) and organs at risk (OARs), with 62.53 ± 9.14 HU within the body, 35.99 ± 6.32 HU within tumor bed, and 30.15 ± 6.36 HU within CTV. In terms of dose comparison, the gamma pass rates under 3%/3 mm and 2%/2 mm criteria were 91.40 ± 3.52% and 85.95 ± 4.75% for the U-Net model, whereas 89.50 ± 3.46% and 83.65 ± 4.00% for the pix2pix model, and 89.84 ± 3.47% and 83.69 ± 4.28% for the CycleGAN model, respectively.The sCT images generated by the U-Net model can provide higher image similarity and dosimetric accuracy than those generated by the pix2pix and CycleGAN models. The approach could be used to realize accurate dose calculation for breast cancer adaptive radiotherapy based on CBCT.

Cultivated land quality (CLQ) is at the core of the trinity protection of cultivated land in China. Scientific evaluation of CLQ and identification of its obstacle factors are the foundation for the construction and improvement of the quality of cultivated land. The main objective of this study was to evaluate CLQ and identify its obstacle factors, and Quzhou County, an intensive agricultural region in the North China Plain (NCP), was selected as a case study. The evaluation index system of CLQ was constructed based on five dimensions, including climate condition, topographic characteristic, soil property, farming status, and environmental condition, by analyzing the logical evolution of elements, processes, functions, and quality of cultivated land. A methodological system based on the Weighted Summation Method (WSM) and the “1 + X” model was developed to evaluate the CLQ. Then, the obstacle diagnosis model constructed based on the Cask Law and relevant academic studies was used to identify the obstacle factors of CLQ. The results showed that the proportion of high-, medium-, and low-quality cultivated land in Quzhou County was 36.19%, 33.60%, and 30.21%, respectively, and the average grade of CLQ was 2.97, which was considered to be at a medium level. Moran’s I of global spatial autocorrelation in Quzhou County was 0.8782, indicating a significant positive autocorrelation of the cultivated land quality index (CLQI). The main obstacle factors of CLQ in Quzhou County were soil profile constitution, irrigation guarantee rate, groundwater depth, and soil microbial biomass carbon. Therefore, based on the stable and dynamic characteristics of the obstacle factors, suggestions were provided to improve the quality of cultivated land in terms of strengthening the consolidation of cultivated land, transforming the concept of agricultural fertilization, and carrying out cultivated land recuperation. This study provides a new perspective on the cognition, evaluation, and identification of obstacle factors of CLQ, and the findings of this study can provide a reference for the consolidation and improvement of CLQ in the NCP.

Background: Neuronopathic Gaucher disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in GBA and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features; however, the role of GBA in individual cell types and involvement of microglia, blood-derived macrophages, and immune infiltrates in nGD pathophysiology remains enigmatic. Methods: Here, using single-cell resolution of mouse nGD brains, lipidomics, and newly generated biomarkers, we found induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons. Results: Targeted rescue of Gba in microglia and neurons, respectively, in Gba-deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), concomitant with amelioration of neuroinflammation, reduced serum neurofilament light chain (Nf-L), and improved survival. Serum GlcSph concentration was correlated with serum Nf-L and ApoE in nGD mouse models as well as in GD patients. Gba rescue in microglia/macrophage compartment prolonged survival, which was further enhanced upon treatment with brain-permeant inhibitor of glucosylceramide synthase, effects mediated via improved glycosphingolipid homeostasis, and reversal of neuroinflammation involving activation of microglia, brain macrophages, and NK cells. Conclusions: Together, our study delineates individual cellular effects of Gba deficiency in nGD brains, highlighting the central role of neuroinflammation driven by microglia activation. Brain-permeant small-molecule inhibitor of glucosylceramide synthase reduced the accumulation of bioactive glycosphingolipids, concomitant with amelioration of neuroinflammation involving microglia, NK cells, astrocytes, and neurons. Our findings advance nGD disease biology whilst identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials, and illuminate therapeutic targets. Funding: Research grant from Sanofi; other support includes R01NS110354.

The agro-pastoral ecotone is an ecologically fragile region where drought is the main factor influencing land use and livelihoods. In this paper, we took two farmer villages and two herder villages in Ar Horqin Banner, located in the agro-pastoral ecotone of northwestern China, as the research areas, and where we conducted participatory rural appraisal and questionnaire survey to analyze the responses of land-use changes to drought and its disparate impact on the livelihoods of farmers and herders. Results show that: 1) Under drought, farmers tended to abandon rain-fed land, and herders tended to abandon grassland. 2) The livelihood activities of farmers were more stable than those of herders under drought. Farmers abandoned rain-fed farming, and herders just retained cattle rearing. The per capita net income of each farmer in Pingandi and Fenghuangling in the drought year of 2016 was only 9.27% and 12.52% lower than those in 2012, respectively, which was 132.88% and 128.25% lower than those in 2012 of each herder in Wuriduhubu and Haolibao. 3) Diversified livelihoods, especially non-agricultural ones, are the key to ensuring the sustainable livelihoods of farmers and herders. It is an effective way for farmers to encourage more labor force to emigrate to non-agricultural sectors. Regarding herders, it is urgent to develop artificial pastures and animal products processing industry with the support of government.

PurposeAccurate segmentation of gross target volume (GTV) from computed tomography (CT) images is a prerequisite in radiotherapy for nasopharyngeal carcinoma (NPC). However, this task is very challenging due to the low contrast at the boundary of the tumor and the great variety of sizes and morphologies of tumors between different stages. Meanwhile, the data source also seriously affect the results of segmentation. In this paper, we propose a novel three-dimensional (3D) automatic segmentation algorithm that adopts cascaded multiscale local enhancement of convolutional neural networks (CNNs) and conduct experiments on multi-institutional datasets to address the above problems.Materials and MethodsIn this study, we retrospectively collected CT images of 257 NPC patients to test the performance of the proposed automatic segmentation model, and conducted experiments on two additional multi-institutional datasets. Our novel segmentation framework consists of three parts. First, the segmentation framework is based on a 3D Res-UNet backbone model that has excellent segmentation performance. Then, we adopt a multiscale dilated convolution block to enhance the receptive field and focus on the target area and boundary for segmentation improvement. Finally, a central localization cascade model for local enhancement is designed to concentrate on the GTV region for fine segmentation to improve the robustness. The Dice similarity coefficient (DSC), positive predictive value (PPV), sensitivity (SEN), average symmetric surface distance (ASSD) and 95% Hausdorff distance (HD95) are utilized as qualitative evaluation criteria to estimate the performance of our automated segmentation algorithm.ResultsThe experimental results show that compared with other state-of-the-art methods, our modified version 3D Res-UNet backbone has excellent performance and achieves the best results in terms of the quantitative metrics DSC, PPR, ASSD and HD95, which reached 74.49 ± 7.81%, 79.97 ± 13.90%, 1.49 ± 0.65 mm and 5.06 ± 3.30 mm, respectively. It should be noted that the receptive field enhancement mechanism and cascade architecture can have a great impact on the stable output of automatic segmentation results with high accuracy, which is critical for an algorithm. The final DSC, SEN, ASSD and HD95 values can be increased to 76.23 ± 6.45%, 79.14 ± 12.48%, 1.39 ± 5.44mm, 4.72 ± 3.04mm. In addition, the outcomes of multi-institution experiments demonstrate that our model is robust and generalizable and can achieve good performance through transfer learning.ConclusionsThe proposed algorithm could accurately segment NPC in CT images from multi-institutional datasets and thereby may improve and facilitate clinical applications.

Liquid carbon dioxide phase transition fracturing technology (LCPTF) is an effective method to increase coal seam permeability, but there are many factors that affect the fracturing effect. Blasting pressure, vent diameter, and blasting time are important factors that affect the fracturing effect. However, very limited studies were performed in this regard. Therefore, in this paper, a multifield coupled model for fracturing coal bodies by LCPTF is established; the effect of blasting pressure, vent diameter, and blasting time on blasting effectiveness was studied; a numerical simulation study based on the seepage field and stress field is performed and verified in the field based on the specific geological conditions of Hujiahe mine. Experimental results show that the fracturing radius and the maximum displacement of coal increase with the increase of blasting pressure, and the fracturing radius is 4.875 m when the blasting pressure is 280 MPa, which is 9.6% higher than that of 200 MPa, and the effect is obvious. The fracturing effect improves with the increase of vent diameter but the effect is modest. In general, the fracturing effect increases with the increase of CO2 impact duration, and when there is no gas impact, the fracturing radius basically remains the same. The maximum displacement gradually decreases with time, and its maximum displacement of the coal body decreases by 33.69% at 200 s. After field blasting, the gas flow attenuation coefficient was reduced by up to 85.7% and the effective radius of influence was between 4 and 5 m.

In Gaucher disease (GD), genetic deficiency of acid β-glucosidase leads to accumulation of its substrate glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Lipid-laden cells, most prominently seen as macrophages engorged with GlcCer and GlcSph-laden lysosomes, trigger chronic metabolic inflammation and multisystemic phenotypes. Among the pleiotropic effects of inflammatory cascades, the induction of glucosylceramide synthase accentuates the primary metabolic defect. First-line therapies for adults with GD type 1 include Enzyme Replacement Therapy (ERT) and eliglustat Substrate Reduction Therapy (SRT). The ENCORE phase 3 clinical trial of eliglustat demonstrated non-inferiority compared to ERT. It is not known whether switching stable patients from long-term ERT to SRT results in the incremental reversal of the disease phenotype and its surrogate indicators. Herein, we report real-world experience from a single tertiary referral center of 38 adult GD type 1 patients, stable on long-term ERT (mean 13.3 years), who switched to eliglustat SRT (mean 3.1 years). After switch to SRT, there was significant reduction in spleen volume (P = 0.003) while liver volume, which was normal at baseline, remained unchanged. Platelet counts increased significantly (P = 0.026). Concomitantly, there was reduction of three validated biomarkers of Gaucher disease activity: plasma GlcSph decreased from 63.7 ng/ml (95% CI, 37.6-89.8) to 26.1 ng/ml (95% CI, 15.7-36.6) (P

PurposeWe developed a deep learning model to achieve automatic multitarget delineation on planning CT (pCT) and synthetic CT (sCT) images generated from cone-beam CT (CBCT) images. The geometric and dosimetric impact of the model was evaluated for breast cancer adaptive radiation therapy.MethodsWe retrospectively analyzed 1,127 patients treated with radiotherapy after breast-conserving surgery from two medical institutions. The CBCT images for patient setup acquired utilizing breath-hold guided by optical surface monitoring system were used to generate sCT with a generative adversarial network. Organs at risk (OARs), clinical target volume (CTV), and tumor bed (TB) were delineated automatically with a 3D U-Net model on pCT and sCT images. The geometric accuracy of the model was evaluated with metrics, including Dice similarity coefficient (DSC) and 95% Hausdorff distance (HD95). Dosimetric evaluation was performed by quick dose recalculation on sCT images relying on gamma analysis and dose-volume histogram (DVH) parameters. The relationship between ΔD95, ΔV95 and DSC-CTV was assessed to quantify the clinical impact of the geometric changes of CTV.ResultsThe ranges of DSC and HD95 were 0.73–0.97 and 2.22–9.36 mm for pCT, 0.63–0.95 and 2.30–19.57 mm for sCT from institution A, 0.70–0.97 and 2.10–11.43 mm for pCT from institution B, respectively. The quality of sCT was excellent with an average mean absolute error (MAE) of 71.58 ± 8.78 HU. The mean gamma pass rate (3%/3 mm criterion) was 91.46 ± 4.63%. DSC-CTV down to 0.65 accounted for a variation of more than 6% of V95 and 3 Gy of D95. DSC-CTV up to 0.80 accounted for a variation of less than 4% of V95 and 2 Gy of D95. The mean ΔD90/ΔD95 of CTV and TB were less than 2Gy/4Gy, 4Gy/5Gy for all the patients. The cardiac dose difference in left breast cancer cases was larger than that in right breast cancer cases.ConclusionsThe accurate multitarget delineation is achievable on pCT and sCT via deep learning. The results show that dose distribution needs to be considered to evaluate the clinical impact of geometric variations during breast cancer radiotherapy.

Rural settlements are the carrier of farmers’ life and rural industries. This paper introduces symbiosis theory to construct an analytical framework for the symbiosis between production land and living land in rural settlements, taking three villages in Shanxi, China as examples (secondary industry-led: Tian Village, tourism-led: Shuiyukou Village, multi-industry integration: Jiling Village). The results show that: (1) From 2010 to 2020, the compatibility and coupling coordination degree between production land and living land in Tian Village increased; the compatibility degree between production land and living land in Shuiyukou Village decreased slightly, and the coupling coordination increased significantly. In Jiling Village, the compatibility between production land and living land decreased, and the coupling coordination showed an increasing trend. (2) From 2010 to 2020, the degree of symbiosis between production land and living land in the three Villages both showed an increasing trend, and the growth of symbiosis degree was mainly caused by the growth of coupling coordination. (3) In 2010–2015 and 2015–2020, the symbiotic growth between production land and living land in Tian Village was driven by farmers’ demand and social economy, respectively. The dominant driving factor for Shuiyukou Village in these two periods was resource endowment. Jiling Village was driven by social economy and regional policies, respectively. This work can provide scientific support for the practical adjustment of land use structure and the reconstruction of rural settlements in China.

Abstract Background The present prospective study evaluated the safety and efficacy of the rectum following KUSHEN Ningjiaos in cervical cancer. We compared rectal wall changes during brachytherapy with or without KUSHEN Ningjiaos in cervical cancer patients and analyzed the difference in spatial dose distribution, including whole rectum-wall (R-w), anterior rectum-wall (R-a) and posterior rectum-wall (R-p). Methods and materials One hundred cervical cancer patients with and without KUSHEN Ningjiaos were treated with brachytherapy (600 cGy). The whole R-w was divided into two areas of R-a and R-p, and R-w dose surface map were constructed. The volume of each R-w was compared in patients pre- and post-KUSHEN Ningjiaos. Results When the pre- vs. post-KUSHEN groups were compared the volume of R-w increased. In the post-KUSHEN group, a significantly higher proportion of the D2cc of VR-w and VR-a compared with the pre-KUSHEN group showed that the D2ccmean increased from 532.45 cGy to 564.7 cGy and 533.51 cGy to 565.26 cGy, respectively; however, results demonstrated a decrease in the D2ccmean of R-p from 260.5 cGy to 240.0868 cGy (P

This work was to devise a comprehensive testing scheme to evaluate the geometric and dosimetric accuracy of the Edge accelerator gating with electromagnetic tracking (EMT) for its safety in clinical application. A CIRS thorax phantom was scanned with four-dimensional cone-beam CT (4D-CBCT) on an Edge accelerator while the simulated tumor was simultaneously tracked with an EMT system using Calypso. The geometric accuracy was validated by comparing the motion trajectories derived from Calypso and 4D-CBCT with the ground truth from motion control software. The two-dimensional and three-dimensional dynamic doses were measured with the Matrixx and ArcCHECK installed on a motion platform, both with and without EMT. For tumor motion with 5, 7.5 mm amplitudes, the average absolute differences of sample position between Calypso and the ground truth were 0.286±0.234 mm, 0.407±0.331 mm respectively. Dosimetric accuracy was validated with 3 mm/3% gamma criterion. The average gamma pass rates of 2D dynamic dose validation based on Matrixx were less than 46% without EMT, 97.3% using 2 mm gating limit, 96% using 3 mm gating limit and 93.4% using 5mm gating limit respectively. The mean 3D dynamic dose validation pass rates based on ArcCHECK were 65.9% without EMT, 96.2% using 3 mm gating limit, and 92.5% using 5 mm gating limit with EMT respectively. The geometric accuracy of the Calypso system in tracking the moving target area was stable at the submillimeter level. The dosimetric accuracy could be improved significantly with EMT using an appropriate gating limit.

Abstract Background Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and progression. Methods We examined the top 20 highly expressed piRNAs based on the analysis of TCGA breast cancer data in two patient cohorts to test the roles of piRNAs in breast cancer. The effects of piRNA-36,712 on the malignant phenotypes and chemosensitivity of breast cancer cells were detected in vitro and in vivo. MS2-RIP and reporter gene assays were conducted to identify the interaction and regulation among piRNA-36,712, miRNAs and SEPW1P. Kaplan-Meier estimate with log-rank test was used to compare patient survival by different piRNA-36,712 expression levels. Results We found piRNA-36,712 level was significantly lower in breast cancer than in normal breast tissues and low level was correlated with poor clinical outcome in patients. Functional studies demonstrated that piRNA-36,712 interacts with RNAs produced by SEPW1P, a retroprocessed pseudogene of SEPW1, and subsequently inhibits SEPW1 expression through competition of SEPW1 mRNA with SEPW1P RNA for microRNA-7 and microRNA-324. We also found that higher SEPW1 expression due to downregulation of piRNA-36,712 in breast cancer may suppress P53, leading to the upregulated Slug but decreased P21 and E-cadherin levels, thus promoting cancer cell proliferation, invasion and migration. Furthermore, we found that piRNA-36,712 had synergistic anticancer effects with the paclitaxel and doxorubicin, two chemotherapeutic agents for breast cancer. Conclusions These findings suggest that piRNA-36,712 is a novel tumor suppressor and may serve as a potential predictor for the prognosis of breast cancer patients.

PurposeThis retrospective study aimed to evaluate the dosimetric effects of a rectal insertion of Kushen Ningjiao on rectal protection using deformable dose accumulation and machine learning–based discriminative modelling.Materials and MethodsSixty-two patients with cervical cancer enrolled in a clinical trial, who received a Kushen Ningjiao injection of 20 g into their rectum for rectal protection via high–dose rate brachytherapy (HDR-BT, 6 Gy/f), were studied. The cumulative equivalent 2-Gy fractional rectal surface dose was deformably summed using an in-house-developed topography-preserved point-matching deformable image registration method. The cumulative three-dimensional (3D) dose was flattened and mapped to a two-dimensional (2D) plane to obtain the rectal surface dose map (RSDM). For analysis, the rectal dose (RD) was further subdivided as follows: whole, anterior, and posterior 3D-RD and 2D-RSDM. The dose–volume parameters (DVPs) were extracted from the 3D-RD, while the dose geometric parameters (DGPs) and textures were extracted from the 2D-RSDM. These features were fed into 192 classification models (built with 8 classifiers and 24 feature selection methods) for discriminating the dose distributions between pre-Kushen Ningjiao and pro-Kushen Ningjiao.ResultsThe rectal insertion of Kushen Ningjiao dialated the rectum in the ambilateral direction, with the rectal column increased from pre-KN 15 cm3 to post-KN 18 cm3 (P < 0.001). The characteristics of DGPs accounted for the largest portions of the top-ranked features. The top-ranked dosimetric features extracted from the posterior rectum were more reliable indicators of the dosimetric effects/changes introduced by the rectal insertion of Kushen Ningjiao. A significant dosimetric impact was found on the dose–volume parameters D1.0cc–D2.5cc extracted on the posterior rectal wall.ConclusionsThe rectal insertion of Kushen Ningjiao incurs significant dosimetric changes on the posterior rectal wall. Whether this effect is eventually translated into clinical gains requires further long-term follow-up and more clinical data for confirmation.

Integrated development in urban and rural areas has led to a new form of urban–rural interdependence, which promotes rural territorial functional evolution and land use changes. Rural land use transition, showing the synchronous development between cities and villages, is an important window through which to observe integrated development in urban and rural areas. We focus on uncovering the association between rural land use transition and urban–rural integration development (URID), put forward a dynamic relationship assumption between rural land use transformation and URID stages based on the transmission mechanism of urban–rural linkages, and undertake empirical analysis using the panel regression model with the data of county-level administrative units in Shandong Province, China. The results show that rural land use transition has maintained a close association with URID, and that the changes in cultivated land, forest land, and surface-water area are highly related to URID. There are different leading urban–rural linkages in rural areas around big-sized cities, mid-sized cities, and small-sized cities, which determine whether rural areas are in different URID stages of high, medium, or low levels. Further, rural areas can take different actions to promote URID at different stages through strengthening or introducing urban–rural linkages driven by economies of scale and deepening urbanization. This provides a reference for developing countries to formulate rural land use policies on achieving the goal of URID.

Antibody therapies for Alzheimer's Disease (AD) hold promise but have been limited by the inability of these proteins to migrate efficiently across the blood brain barrier (BBB). Central nervous system (CNS) gene transfer by vectors like adeno-associated virus (AAV) overcome this barrier by allowing the bodies' own cells to produce the therapeutic protein, but previous studies using this method to target amyloid-β have shown success only with truncated single chain antibodies (Abs) lacking an Fc domain. The Fc region mediates effector function and enhances antigen clearance from the brain by neonatal Fc receptor (FcRn)-mediated reverse transcytosis and is therefore desirable to include for such treatments. Here, we show that single chain Abs fused to an Fc domain retaining FcRn binding, but lacking Fc gamma receptor (FcγR) binding, termed a silent scFv-IgG, can be expressed and released into the CNS following gene transfer with AAV. While expression of canonical IgG in the brain led to signs of neurotoxicity, this modified Ab was efficiently secreted from neuronal cells and retained target specificity. Steady state levels in the brain exceeded peak levels obtained by intravenous injection of IgG. AAV-mediated expression of this scFv-IgG reduced cortical and hippocampal plaque load in a transgenic mouse model of progressive β-amyloid plaque accumulation. These findings suggest that CNS gene delivery of a silent anti-Aβ scFv-IgG was well-tolerated, durably expressed and functional in a relevant disease model, demonstrating the potential of this modality for the treatment of Alzheimer's disease.

Tumor cells display fundamental changes in metabolism and nutrient uptake in order to utilize additional nutrient sources to meet their enhanced bioenergetic requirements. Glutamine (Gln) is one such nutrient that is rapidly taken up by tumor cells to fulfill this increased metabolic demand. A vital step in the catabolism of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase (GLS). This study has identified GLS a potential therapeutic target in breast cancer, specifically in the basal subtype that exhibits a deregulated glutaminolysis pathway. Using inducible shRNA mediated gene knockdown, we discovered that loss of GLS function in triple-negative breast cancer (TNBC) cell lines with a deregulated glutaminolysis pathway led to profound tumor growth inhibition in vitro and in vivo. GLS knockdown had no effect on growth and metabolite levels in non-TNBC cell lines. We rescued the anti-tumor effect of GLS knockdown using shRNA resistant cDNAs encoding both GLS isoforms and by addition of an α-ketoglutarate (αKG) analog thus confirming the critical role of GLS in TNBC. Pharmacological inhibition of GLS with the small molecule inhibitor CB-839 reduced cell growth and led to a decrease in mammalian target of rapamycin (mTOR) activity and an increase in the stress response pathway driven by activating transcription factor 4 (ATF4). Finally, we found that GLS inhibition synergizes with mTOR inhibition, which introduces the possibility of a novel therapeutic strategy for TNBC. Our study revealed that GLS is essential for the survival of TNBC with a deregulated glutaminolysis pathway. The synergistic activity of GLS and mTOR inhibitors in TNBC cell lines suggests therapeutic potential of this combination for the treatment of vulnerable subpopulations of TNBC.

A conundrum has long lingered over association of cytosol elongation factor Tu (EF-Tu) with bacterial surface. Here we investigated it with Acinetobacter baumannii, an emerging opportunistic pathogen associated with a wide spectrum of infectious diseases. The gene for A. baumannii EF-Tu was sequenced, and recombinant EF-Tu was purified for antibody development. EF-Tu on the bacterial surface and the outer membrane vesicles (OMVs) was revealed by immune electron microscopy, and its presence in the outer membrane (OM) and the OMV subproteomes was verified by Western blotting with the EF-Tu antibodies and confirmed by proteomic analyses. EF-Tu in the OM and the OMV subproteomes bound to fibronectin as detected by Western blot and confirmed by a label-free real-time optical sensor. The sensor that originates from photonic crystal structure in a total-Internal-reflection (PC-TIR) configuration was functionalized with fibronectin for characterizing EF-Tu binding. Altogether, with a novel combination of immunological, proteomical, and biophysical assays, these results suggest association of A. baumannii EF-Tu with the bacterial cell surface, OMVs, and fibronectin.

Coal mine gangue hills have a significant impact on the ecological environment. To address this challenge, gravity heat pipes have been recognized as an effective means of controlling deep-seated temperature in coal mine gangue hills. Among various factors affecting heat transfer efficiency, the magnitude of external airflow velocity in the heat dissipation section of the heat pipe is critical. In this study, we develop a novel chimney effect model for gravity heat pipes in coal mine gangue hills. We employ the non-isothermal flow multiphysics transient solution method to analyze the single-factor effects of entrance radius, height of outlet section, and radius of outlet section on the average velocity at the chimney outlet. Furthermore, we utilize a comprehensive factorial response surface research method to fit the functional relationship between the average velocity at the chimney outlet and various chimney parameters. Notably, our study introduces the height and radius of the outlet section as constraint conditions based on field conditions. As a result, we determine the optimal chimney parameters for achieving the chimney effect in gravity heat pipes within coal gangue hills. Specifically, we set the chimney inlet radius at 1.05 m, the chimney outlet height at 0.03 m, and the chimney outlet radius at 0.145 m. Comparative analysis reveals that introducing the chimney improves the heat dissipation efficiency of the gravity heat pipe by 2.6%. Overall, our study offers innovative approaches to addressing the challenges associated with coal gangue hills and provides valuable insights into the optimization of gravity heat pipes for efficient heat dissipation. [ABSTRACT FROM AUTHOR]