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Osteoarthritis (OA) is considered a metabolic disorder. This study investigated the effect of resveratrol (RES) on cholesterol accumulation in osteoarthritic articular cartilage via the silent information regulator 1 (SIRT1)/forkhead transcription factor (FoxO1) pathway. Interleukin (IL)-1β-treated chondrocytes that mimic OA chondrocytes were used in in vitro experiments. The optimal RES concentration was selected based on the results of chondrocyte proliferation in the Cell Counting Kit-8 assay. Western blotting, immunofluorescence, and reverse transcription-quantitative polymerase chain reaction were performed. For the animal experiments, mice were randomly divided into the RES group (n=15), medial meniscus destabilization group (n=15), and sham group (n=15), and each group received the same dose of RES or saline. Articular cartilage tissue was obtained eight weeks after surgery for relevant histological analysis. Clinical tissue test results suggest that downregulation of the SIRT1/FoxO1 pathway is associated with cholesterol buildup in OA chondrocytes. For the in vitro studies, RES increased the expression of SIRT1 and phosphorylation of FoxO1 in IL-1β-treated chondrocytes, promoted the expression of cholesterol efflux factor liver X receptor alpha (LXRα), and inhibited the expression of cholesterol synthesis-associated factor sterol-regulatory element binding proteins 2 (SREBP2). This reduced IL-1β-induced chondrocytes cholesterol accumulation. SIRT1 inhibition prevented the RES-mediated reduction in cholesterol buildup. Inhibiting FoxO1 but not SIRT1 reduced FoxO1 phosphorylation and increased cholesterol buildup in cultured chondrocytes. Additionally, in vivo experiments have shown that RES can alleviate cholesterol buildup and pathological changes in OA cartilage. Our findings suggest that RES regulates cholesterol buildup in osteoarthritic articular cartilage via the SIRT1/FoxO1 pathway, thereby improving the progression of OA.

The presence of sand in submarine heavy oil pipelines may bring a series of problems to the pipelines and offshore processing platforms. As for the sedimentation of sands contained in the heavy oil transported by submarine pipelines, the feasibility of simulating the solid-liquid two-phase flow pattern and the sedimentation laws of sands with the OLGA software was studied, and with the submarine pipelines of an oil field as the study object, a model was established reasonably based on the actual data. On this basis, the influence of the size, volume fraction, repose angle and density of sands on the critical settling velocity and the maximum settling location in the pipelines was analyzed. The results indicate that: The critical settling velocity decreases at first and then increases with the increasing of the sand size. The critical settling velocity varies little at low sand volume fraction, while it is of positive correlation with the volume fraction and density, of sands when it is high. Further, the maximum settling location was negatively correlated with sand particle size and density but positively correlated with the repose angle. When the volume fraction of sands is less than 1%, the change of the maximum settling location is not obvious, but the influence of high sand volume fraction on the maximum settling location cannot be ignored. Generally, the study results are expected to provide reference for the reduction of safety risks of heavy oil transportation in submarine pipelines.

Abstract Background Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first‐line treatment of Chinese patients with advanced or recurrent non‐squamous non‐small cell lung cancer (NSCLC). Methods Stage IIIB‐IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4‐6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression‐free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). Results Between December 15th, 2017, and May 15th, 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th, 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1‐6) and median duration of treatment of 3.0 (range 0.0‐5.1) months. ORR of response‐evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80‐1.04, within the prespecified equivalence margin of 0.75‐1.33). Up to May 15th, 2020, with a median follow‐up of 13.6 (range 0.8‐28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1‐year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. Conclusions LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non‐squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non‐squamous NSCLC patients in the first‐line setting.

BackgroundTo evaluate longitudinal changes of concurrent chemoradiotherapy (CCRT) related lymphopenia and its association with survival in locally advanced non-small cell lung cancer (LA-NSCLC) patients.MethodsTotal lymphocyte count (TLC) at baseline, weekly intervals during CCRT and monthly intervals up to 12 months after CCRT were documented. The Common Terminology Criteria for Adverse Events version 5.0 was used to grade the severity of lymphopenia. Cox regression analysis was performed to evaluate the association between overall survival (OS) and CCRT related lymphopenia at different timepoints. Logistic regression model was used to determine the clinical factors associated with TLC level.Results381 LA-NSCLC patients treated with definitive CCRT without consolidation therapy (NCT02573506/NCT02577341) between 2011 to 2020 were analyzed. With a median follow-up of 45.8 months, the median OS was 41.0 months for all patients. Univariable analysis demonstrated that the 3 weeks during CCRT Grade (G) 4 lymphopenia (P=0.018), 2 months after CCRT G1-4 lymphopenia (P=0.004), 6 months after CCRT (6m-post-CCRT) G1-4 lymphopenia (P=0.001), and TLC nadir (P=0.020) were significantly associated with poorer OS. Multivariable analysis suggested that 6m-post-CCRT G1-4 lymphopenia (HR 2.614; P=0.041) were one of the independent predictors of OS. Further analysis inferred that radiation dose (OR: 1.328; P=0.005), GTV volume (OR: 1.004; P=0.036), and baseline TLC (OR: 0.288; P=0.001) were associated with 6m-post-CCRT lymphopenia.ConclusionThe persistent lymphopenia at 6 months after CCRT was an independent prognostic factor of OS in LA-NSCLC patients. Higher radiation dose, larger gross tumor volume and lower baseline TLC were significantly related to 6m-post-CCRT lymphopenia.

BackgroundWe aimed to evaluate the efficacy and feasibility of concurrent weekly docetaxel-nedaplatin and hypo-fractionated radiotherapy (hypo-RT) in atypical histologic subtypes of primary and metastatic mediastinal malignancies.MethodsFifty-four patients diagnosed with atypical primary or metastatic mediastinal malignancies were retrospectively reviewed. 30 patients received concurrent weekly docetaxel and nedaplatin and hypo-RT (CChRT group) and 24 patients had hypo-RT alone (hRT group). Overall response rate (ORR), in-field locoregional progression-free survival (LPFS) and toxicities were analyzed. The radiobiological effect was evaluated by the LQRGC/TCP model, incorporating four “R”s of radiobiology, Gompertzian tumor growth and radio-sensitizing effect of chemotherapeutic agent. The biologically effective doses (BEDs) were calculated.ResultsThe median follow-up time was 29.2 months for all patients. The ORR was 86.7% in CChRT group, compared with 62.5% in hRT group (p=0.033). The 2-year in-field LPFS of CChRT and hRT group was 73.4% and 47.3%, respectively (p=0.003). There was no significant difference of any >=Grade 3 toxicities between the two groups (p=0.754). The mean total dose and mean BED by the LQRGC/TCP model in CChRT group were 58.2Gy and 72.34Gy, versus 52.6Gy and 67.25Gy in hRT group.ConclusionsConcurrent weekly docetaxel-nedaplatin and hypo-RT achieved promising in-field LPFS and tolerable toxicities compared with hypo-RT alone in different histologic subtypes of primary and metastatic mediastinal malignancies.

Abstract Many wooden Chinese historic buildings are destroyed due to the ravages of frequent fire disasters. The fire risk of historic buildings are highly enlarged since a long-time weathered wooden structures in the natural environment. The clean fire-extinguishing technology using fluorinated chemical gases to put out a historic building fire rapidly at the initial stage is highly recommended and widely used. However, the gaseous hydrogen fluoride (HF) yielded during the fire suppression process could be a potential method to result in secondary damage due to its corrosiveness. Nowadays, experiments were employed to clarify the effect of fire suppression on the surface of historic wooden buildings. Five traditional fluorinated chemical gases, H-37, FK-5-1-12, H-1323, H-2402, and H-1301, are used to suppress a fixed flame. The wooden samples, including a Dao Talisman board, a painting paper, and wooden chips, are placed in a chamber. Wooden chips consist of traditional and weathered samples (acting as the Chinese historic buildings). The concentration of gaseous products yielded from fire suppression are monitored by a gas-FTIR from ABB, and the surface analysis is conducted by a Quanta FEG SEM–EDX from FEI. It is observed that flame enhancement happens at the early stage of fire suppression and varies with fire agents. The amount of F-deposited on the wooden surface is positively correlated with a total amount of gaseous HF. The color change mechanism of the wooden surface is comprehensive, although the amount of HF is a leading factor. The influence of HF on color change depends on the amount of both gaseous H2O and HF. It is concluded that the value of L* of the traditional chip is much easier to be reduced comparing with weathered samples with the same wood grain. The reduction of $${\mathrm{b}}^{*}$$ b ∗ value of weathered samples is much larger than the traditional ones. It suggests the weathered chips show a color shift toward blue because of fire suppression. The present study hopes to provide a basic acknowledgment for the comprehensive understanding of secondary damage caused by fire suppression.

Abstract Background Proton beam therapy (PBT) is a new-emerging cancer treatment in China but its treatment costs are high and not yet covered by Chinese public medical insurance. The advanced form of PBT, intensity-modulated proton radiation therapy (IMPT), has been confirmed to reduce normal tissue complication probability (NTCP) as compared to conventional intensity-modulated photon-radiation therapy (IMRT) in patients with oropharyngeal cancer (OPC). Herein, we evaluated the cost-effectiveness and applicability of IMPT versus IMRT for OPC patients in China, aiming at guiding the proper use of PBT. Methods A 7-state Markov model was designed for analysis. Base-case evaluation was performed on a 56-year-old (median age of OPC in China) patient under the assumption that IMPT could provide a 25% NTCP-reduction in long-term symptomatic dysphagia and xerostomia. Model robustness was examined using probabilistic sensitivity analysis, cohort analysis, and tornado diagram. One-way sensitivity analyses were conducted to identify the cost-effective scenarios. IMPT was considered as cost-effective if the incremental cost-effectiveness ratio (ICER) was below the societal willingness-to-pay (WTP) threshold. Results Compared with IMRT, IMPT provided an extra 0.205 quality-adjusted life-year (QALY) at an additional cost of 34,926.6 US dollars ($), and had an ICER of $170,082.4/ QALY for the base case. At the current WTP of China ($33,558 / QALY) and a current IMPT treatment costs of $50,000, IMPT should provide a minimum NTCP-reduction of 47.5, 50.8, 55.6, 63.3 and 77.2% to be considered cost-effective for patient age levels of 10, 20, 30, 40 and 50-year-old, respectively. For patients at the median age level, reducing the current IMPT costs ($50,000) to a $30,000 level would make the minimum NTCP-reduction threshold for “cost-effective” decrease from 91.4 to 44.6%, at the current WTP of China (from 69.0 to 33.5%, at a WTP of $50,000 / QALY; and from 39.7 to 19.1%, at a WTP of $100,000 / QALY). Conclusions Cost-effective scenarios of PBT exist in Chinese OPC patients at the current WTP of China. Considering a potential upcoming increase in PBT use in China, such cost-effective scenarios may further expand if a decrease of proton treatment costs occurs or an increase of WTP level.

The benefit of induction chemotherapy before definitive chemoradiotherapy (CRT) for patients with esophageal cancer is still uncertain. The results of this phase II randomized trial show that the addition of induction chemotherapy to CRT does not improve the response rate or survival of patients with unresectable esophageal squamous cell carcinoma.

BackgroundIncidental exposure of the heart to ionizing irradiation is associated with an increased risk of ischemic heart disease and subsequent fatality in patients with breast cancer after radiotherapy. Proton beam therapy can limit the heart dose in breast irradiation to a negligible level. However, compared with conventional photon modality, proton breast irradiation is more expensive. In this study, we performed cost-effectiveness analyses to identify the type of patients who would be more suitable for protons.MethodsA Markov decision model was designed to evaluate the cost-effectiveness of protons vs. photons in reducing the risk of irradiation-related ischemic heart disease. A baseline evaluation was performed on a 50-year-old woman patient without the preexisting cardiac risk factor. Furthermore, risk-stratification analyses for photon mean heart dose and preexisting cardiac risk were conducted on 40-, 50-, and 60-year-old women patients under different proton cost and willingness-to-pay (WTP) settings.ResultsUsing the baseline settings, the incremental effectiveness (protons vs. photons) increased from 0.043 quality-adjusted life-year (QALY) to 0.964 QALY when preexisting cardiac risk increased to 10 times its baseline level. At a proton cost of 50,000 US dollars ($), protons could be cost-effective for ≤ 60-year-old patients with diabetes and ≤50-year-old patients with grade II–III hypertension at the WTP of China ($37,653/QALY); for ≤ 60-year-old patients with diabetes and ≤ 50-year-old patients with grade II–III hypertension or ≥ 2 major cardiac risk factors at a WTP of $50,000/QALY; and for ≤ 60-year-old patients with diabetes, grade II–III hypertension or ≥ 2 major cardiac risk factors and ≤ 50-year-old patients with total cholesterol ≥ 240 mg/dL at a WTP of $100,000/QALY.ConclusionPatients' preexisting cardiac risk status was a key factor affecting the cardiac benefits gained from protons and should therefore be a major consideration for the clinical decision of using protons; cost-effective scenarios of protons exist in those patients with high risk of developing cardiac diseases.

PurposeTo evaluate the association of gut microbiome signature and disease progression in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) by fecal metagenome analysis.MethodsMetagenome-wide association studies on baseline fecal samples from 18 LA-NSCLC patients before CCRT and 13 controls from healthy first-degree relatives were performed. Among the 18 LA-NSCLC patients, six patients were defined as the long progression-free survival (long-PFS) group (PFS≥11 months) while another 12 were in the short-PFS group (PFS

Background: Recent studies have demonstrated benefits from adjuvant tyrosine-kinase inhibitors (TKIs) compared with chemotherapy in non-small cell lung cancer. We launched a multi-center retrospective study to evaluate the efficacy and toxicity of adjuvant TKIs with or without chemotherapy in epidermal growth factor receptor (EGFR)-mutant stage III-pN2 lung adenocarcinoma. Methods: Two hundred and seventy-four consecutive cases with stage III-pN2 lung adenocarcinoma and complete resection have been investigated. Clinic-pathologic characteristics, adjuvant treatments, long-term survivals, and toxicities were documented. Risk factors of distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were evaluated. Results: There were 52 (19.0%) patients treated with adjuvant TKIs alone, 199 (72.6%) with adjuvant chemotherapy alone, and 23 (8.4%) with both. After a median follow-up time of 29 months, the two-year DMFS, DFS, and OS was 61.2%, 54.1%, and 91.2%, respectively. According to univariable analyses, the risk factors were lymphovascular invasion (p < 0.001), extranodal extension (p = 0.005), and adjuvant systemic therapy (p = 0.006) for DMFS, EGFR mutation type (p = 0.025), lymphovascular invasion (p = 0.013), extranodal extension (p = 0.004), and adjuvant systemic therapy (p < 0.001) for DFS, and EGFR mutation type (p < 0.001) for OS. Multivariable analyses indicated that the independent prognostic factors were adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, Harzard ratio (HR) = 0.40; p = 0.036; TKIs vs. chemotherapy, HR = 0.38; p = 0.004), lymphovascular invasion (yes vs. no, HR = 2.22; p = 0.001) for DMFS, and adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, HR = 0.42; p = 0.034; TKIs vs. chemotherapy, HR = 0.33; p < 0.001) for DFS. No significant difference was found in the incidence of Grade 3–4 toxicities between groups (p = 0.445). Conclusions: Adjuvant TKIs might be a beneficial choice compared with adjuvant chemotherapy or combination systemic treatments.

Abstract Background Cholangiocarcinoma is a highly malignant cancer with very dismal prognosis. Perihilar cholangiocarcinoma(pCCA) accounts for more than 50% of all cholangiocarcinoma and is well-characterized for its low rate of radical resection. Effects of radiotherapy and chemotherapy of pCCA are very limited. Methods Here we screened potential biomarkers of pCCA with transcriptome sequencing and evaluated the prognostic significance of HMGA1 in a large cohort pCCA consisting of 106 patients. With bioinformatics and in vitro/vivo experiments, we showed that HMGA1 induced tumor cell stemness and epithelial-mesenchymal-transition (EMT), and thus facilitated proliferation, migration and invasion by promoting TRIP13 transcription. Moreover, TRIP13 was also an unfavorable prognostic biomarker of pCCA, and double high expression of HMGA1/TRIP13 could predict prognosis more sensitively. TRIP13 promoted pCCA progression by suppressing FBXW7 transcription and stabilizing c-Myc. c-Myc in turn induced the transcription and expression of both HMGA1 and TRIP13, indicating that HMGA-TRIP13 axis facilitated pCCA stemness and EMT in a positive feedback pathway. Conclusions HMGA1 and TRIP13 were unfavorable prognostic biomarkers of pCCA. HMGA1 enhanced pCCA proliferation, migration, invasion, stemness and EMT, by inducing TRIP13 expression, suppressing FBXW7 expression and stabilizing c-Myc. Moreover, c-Myc can induce the transcription of HMGA1 and TRIP13, suggesting that HMGA-TRIP13 axis promoted EMT and stemness in a positive feedback pathway dependent on c-Myc.

The classical theory predicts that a geostrophically balanced mesoscale eddy can cause a sea surface temperature (SST) anomaly related to Ekman pumping. Previous studies show that an eddy-induced SST anomaly can result in a sea surface latent heat flux (LH) anomaly at a maximum magnitude of ∼O(10) Wm–2, decaying radially outward from the center to the margin. In this study, we investigate the LH anomalies associated with submesoscale processes within a cyclonic eddy for the first time using recent satellite-ship-coordinated air-sea observations in the South China Sea. Unbalanced submesoscale features can be identified as submesoscale SST fronts. Along the ship track, the SST strikingly decreases by 0.5°C within a horizontal distance of ∼1.5 km and increases quickly by 0.9°C with a spatial interval of ∼3.6 km. The along-track SST is decomposed into three parts: large-scale south-north fronts and anomalies induced by mesoscale and submesoscale motions. Our analysis shows that the amplitude of the LH anomaly induced by the mesoscale SST anomaly is 12.3 Wm–2, while it is 14.3 Wm–2 by unbalanced submesoscale motions. The mean (maximum) spatial gradient of the submesoscale LH anomalies is 1.7 (75.7) Wm–2km–1, which is approximately 1.5 times those (1.2 and 59.9 Wm–2km–1) in association with mesoscale eddies. The spectra of LH and SST anomalies show similar peaks at ∼15 km before sloping down with a power law between k–2 and k–3, indicating the underlying relationship between the LH variance and submesoscale processes.

Abstract Purpose The gross tumor volume (GTV) could be an independent prognostic factor for unresectable locally advanced non-small cell lung cancer (LANSCLC). We aimed to develop and validate a novel integrated GTV-TNM stratification system to supplement LANSCLC sub-staging in patients treated with concurrent chemoradiotherapy (CCRT). Methods We performed a retrospective review of 340 patients with unresectable LANSCLC receiving definitive CCRT. All included patients were divided into two randomized cohorts. Then the Kaplan–Meier method and Cox regression were calculated to access the prognostic value of the integrated GTV-TNM stratification system, which was further validated by the area under the receiver operating characteristic curve (AUC) score and F1-score. Results The optimal outcome-based GTV cut-off values (70 and 180 cm3) of the modeling cohort were used to determine each patient’s integrated GTV-TNM stratum in the whole cohort. Our results indicated that a lower integrated GTV-TNM stratum could had better overall survival and progression-free survival (all P

Abstract Background This study aimed to quantify the dosimetric differences between the planned and delivered dose to tumor and normal organs in locally advanced non-small cell lung cancer (LANSCLC) treated with hypofractionated radiotherapy (HRT), and to explore the necessity and identify optimal candidates for adaptive radiotherapy (ART). Methods Twenty-seven patients with stage III NSCLC were enrolled. Planned radiation dose was 51Gy in 17 fractions with cone-beam CT (CBCT) acquired at each fraction. Virtual CT was generated by deformable image registration (DIR) of the planning CT to CBCT for dose calculation and accumulation. Dosimetric parameters were compared between original and accumulated plans using Wilcoxon signed rank test. Correlations between dosimetric differences and clinical variables were analyzed using Mann-Whitney U test or Chi-square test. Results Patients had varied gross tumor volume (GTV) reduction by HRT (median reduction rate 11.1%, range − 2.9-44.0%). The V51 of planning target volume for GTV (PTV-GTV) was similar between original and accumulated plans (mean, 88.2% vs. 87.6%, p = 0.452). Only 11.1% of patients had above 5% relative decrease in V51 of PTV-GTV in accumulated plans. Compared to the original plan, limited increase (median relative increase

Abstract Background Cost-effectiveness is a pivotal consideration for clinical decision making of high-tech cancer treatment in developing countries. Intensity-modulated proton radiation therapy (IMPT, the advanced form of proton beam therapy) has been found to improve the prognosis of the patients with paranasal sinus and nasal cavity cancers compared with intensity-modulated photon-radiation therapy (IMRT). However, the cost-effectiveness of IMPT has not yet been fully evaluated. This study aimed at evaluating the cost-effectiveness of IMPT versus IMRT for treatment decision making of paranasal sinus and nasal cavity cancers in Chinese settings. Methods A 3-state Markov model was designed for cost-effectiveness analysis. A base case evaluation was performed on a patient of 47-year-old (median age of patients with paranasal sinus and nasal cavity cancers in China). Model robustness was examined by probabilistic sensitivity analysis, Markov cohort analysis and Tornado diagram. Cost-effective scenarios of IMPT were further identified by one-way sensitivity analyses and stratified analyses were performed for different age levels. The outcome measure of the model was the incremental cost-effectiveness ratio (ICER). A strategy was defined as cost-effective if the ICER was below the societal willingness-to-pay (WTP) threshold of China (30,828 US dollars ($) / quality-adjusted life year (QALY)). Results IMPT was identified as being cost-effective for the base case at the WTP of China, providing an extra 1.65 QALYs at an additional cost of $38,928.7 compared with IMRT, and had an ICER of $23,611.2 / QALY. Of note, cost-effective scenarios of IMPT only existed in the following independent conditions: probability of IMPT eradicating cancer ≥0.867; probability of IMRT eradicating cancer ≤0.764; or cost of IMPT ≤ $52,163.9. Stratified analyses for different age levels demonstrated that IMPT was more cost-effective in younger patients than older patients, and was cost-effective only in patients ≤56-year-old. Conclusions Despite initially regarded as bearing high treatment cost, IMPT could still be cost-effective for patients with paranasal sinus and nasal cavity cancers in China. The tumor control superiority of IMPT over IMRT and the patient’s age should be the principal considerations for clinical decision of prescribing this new irradiation technique.

Abstract Background To investigate the loco-regional progression-free survival (LPFS) of intensity-modulated radiotherapy (IMRT) with different fraction sizes for locally advanced non-small-cell lung cancer (LANSCLC), and to apply a new radiobiological model for tumor control probability (TCP). Methods One hundred and three LANSCLC patients treated with concurrent radiochemotherapy were retrospectively analyzed. Factors potentially predictive of LPFS were assessed in the univariate and multivariate analysis. Patients were divided into group A (2.0 ≤ fraction size

Depth image-based rendering (DIBR) is an important technology in the process of 2D-to-3D conversion. It uses texture images and related depth maps to render virtual views. While there are still some challenging problems in the current DIBR systems, such as disocclusion occurrences. Inpainting methods based on deep learning have recently shown significant improvements and generated plausible images. However, most of these methods may not deal well with the disocclusion holes in the synthesized views, because on the one hand they only treat this issue as generative inpainting after 3D warping, rather than following the full DIBR processing procedures. While on the other hand the distributions of holes on the virtual views are always around the transition regions of foreground and background, which makes them more difficult to distinguish without special constraints. Motivated by these observations, this paper proposes a novel learning-based method for stereoscopic view synthesis, in which the disocclusion regions are restored by a progressive structure reconstruction strategy instead of direct texture inpainting. Additionally, some special cues in the synthesized scenes are further exploited as constraints for the network to alleviate hallucinated structure mixtures among different layers. Extensive empirical evaluations and comparisons validate the strengths of the proposed approach and demonstrate that the model is more suitable for stereoscopic synthesis in the 2D-to-3D conversion applications.

Under climate change, the sea surface temperature and salinity change greatly, which poses a considerable threat to sustainable food security. Sea surface temperature and salinity (SST/SSS) are selected to examine the annual output of swimming crab in 24 cities along the eastern China. The Copula-based function was used to construct the probability distribution model of the swimming crab yield with SST and SSS. The pure premium rate of the swimming crab production in these 24 cities are also examined. The results show that 1) There is significant positive correlations between the yield of swimming crab with temperature and salinity over the study area. The only exception is that the correlation between yield of swimming crab and salinity is not significant in the south of study area. 2) The span of the pure insurance premium rate of swimming crab in 24 cities increases rapidly with the increase of the protection level, the maximum span up to 2.04%, and the minimum span is only 1.6%. 3) The distribution of the swimming crab insurance premium rate is various in space. The insurance premium rate of 8 cities in the south of Taizhou is low with the highest premium rate at 5.6%. The insurance premium rate of 16 cities in north of Taizhou is relatively high with the rate between 6%-22%. The research can provide a theoretical basis for the pricing of insurance products for swimming crab in 24 cities in the typical aquaculture areas in eastern China.

Currently approved therapeutical strategies for inflammatory bowel diseases (IBD) suffer from variable efficacy and association with risk of serious side effects. Therefore, efforts have been made in searching for alternative therapeutics strategies utilizing gut microbiota manipulation. In this study, we show that the probiotic strain Ligilactobacillus salivarius Li01 (Li01) and the phytochemical prebiotic resveratrol (RSV) have synergistic effect in ameliorating colitis in mice. Oral coadministration of Li01 (109 CFU/d) and RSV (1.5 g/kg/d) promoted restoration of various inflammatory injuries and gut microbiota composition, exhibiting a favorable anti-inflammatory effect in DSS-induced colitis mice. The combination treatment was associated with reductions in the levels of proinflammatory cytokines IL-1β and IL-6 and increases in the levels of the anti-inflammatory cytokine IL-17A in mouse serum. Moreover, the combination treatment was found to alter the composition and metabolism of the gut microbiota, especially influencing the production of short chain fatty acids and anti-inflammatory related molecules. The mechanism underlying the improved anti-inflammatory effect from the RSV and Li01 combination treatment was found to be associated with the environmental sensor mammalian aryl hydrocarbon receptor (AHR) and tryptophan metabolism pathway. Administration of RSV in combination with Li01 in different mouse model led to enhanced conversion of RSV into metabolites, including dihydroresveratrol (DHR), resveratrol-sulfate, and resveratrol-glucuronide. DHR was found to be the dominant metabolite of RSV in conventional and colitis mice. An increased DHR/RSV ratio was confirmed to activate AHR and contribute to an enhanced anti-inflammatory effect. DHR is considered as a potential AHR ligand. The DHR/RSV ratio also affected the serotonin pathway by controlling the expression of Tph1, SERT, and 5-HT7R leading to amelioration of colitis in mice. Our data suggest that treatment with a combination of Li01 and RSV has potential as a therapeutic strategy for IBD; further investigation of this combination in clinical settings is warranted.

Abstract Surface solar radiation (SSR), as a primary component of heat budget between land and atmosphere, controls both water and energy exchanges. However, the sub‐grid terrain radiative effect (STRE) which exerts critical influences on SSR simulation is usually extremely simplified or even ignored in most current land surface models (LSMs) due to the heavy computational burden. In this study, we developed a physically realistic and computationally efficient three dimensional (3D) STRE scheme and implemented it into the Common Land Model (CoLM) to indicate its quantitative influences on surface energy budget, land surface temperature (LST), soil temperature, and moisture simulations over the Heihe River Basin, Tibetan Plateau. Results show that the CoLM coupled with 3D‐STRE scheme shows more realistic description of SSR and improves the simulation of soil thermal and moist features at both single‐point and regional scales. Compared to the results without 3D‐STRE, the inclusion of 3D‐STRE scheme efficiently diminishes the overestimation of SSR, which leads to the root mean square error (RMSE) of LST simulation reduced by 17.1% due to significant improvements in valley areas. Adopting 3D‐STRE scheme also improves the pattern and amplitude of temporal variability of simulated soil temperature (moisture) at 37 sites with the mean Taylor score increased by 3.6–3.7% (14.0–14.3%). These results emphasize the importance of considering the 3D‐STRE scheme in LSMs and are significantly helpful to deepen our understanding of surface heat exchanges and improve the representations of land surface processes over complex terrain.

Extreme precipitation events have posed a threat to global terrestrial ecosystems in recent decades. However, the response of terrestrial ecosystems to extreme precipitation in areas with various vegetation types and complex topography remains unclear. Here, we used satellite-based solar-induced chlorophyll fluorescence measurements, a direct proxy of photosynthetic activity, to assess the response of vegetation to the record-breaking extreme precipitation event during the East Asia monsoon season in eastern China in 2020. Our results demonstrate that vegetation was adaptable to moderate increases in precipitation, but photosynthetic activity was significantly inhibited by exposure to extreme precipitation because of insufficient photosynthetically active radiation and waterlogging. The responses of vegetation photosynthesis to extreme precipitation were regulated by both vegetation type and topography. Crops in the lowland areas in eastern China were severely damaged due to their higher vulnerability and exposure to extreme precipitation. The topography-induced redistribution of precipitation accounts for the modulation of vegetation response to extreme precipitation. Our research highlights the urgent need for effective management and adaptive measures of croplands under the elevated risk of extreme precipitation in the future.

Background: Perihilar cholangiocarcinoma (PHCC) is the most common subtype of cholangiocarcinoma(CCA). We previously investigated the expression pattern of Sprouty(SPRY) in intrahepatic cholangiocarcinoma(ICC), but the expression and clinical significance of SPRY family members in PHCC are still unknown. Methods: The expression of SPRY family members(SPRY1-4) was detected in different subtypes of CCA and corresponding adjacent tissues. SPRY4 expression in 142 cases of PHCC was detected by immunohistochemistry, and its clinical significance was evaluated using univariate and multivariate analyses. The functions of SPRY4 in the FGFR-induced proliferation and migration of PHCC cells were investigated through in vitro and in vivo experiments. We further investigated the effects and mechanisms of SPRY4 on FGFR-induced ERK phosphorylation and cell cycle distribution in the presence of FGFR and ERK inhibitors. Findings: SPRY4 was the only SPRY family member associated with PHCC prognosis, and it was identified as an independent factor predicting favorable prognosis. In PHCC, SPRY4 expression was extensively associated with FGFR2, and its expression can be induced by ectopic FGFR2 activation. Through in vitro and in vivo experiments, we demonstrated that SPRY4 suppressed FGFR-induced proliferation and migration by inhibiting ERK phosphorylation. Moreover, SPRY4 knockdown was shown to decrease the percentage of cells in the G1 phase and promote the percentage of cells in the S and G2/M phases by increasing cyclin D1 expression, which also required FGFR-induced ERK phosphorylation. Interpretation: High expression of SPRY4 was an independent biomarker of favorable prognosis in PHCC. SPRY4 expression can be induced by ectopic FGFR2 activation in PHCC. SPRY4 arrested the cell cycle at G1 phase and suppressed FGFR-induced proliferation and migration by inhibiting ERK phosphorylation, indicating that SPRY4 may be a potential therapeutic target in PHCC. Keywords: Sprouty 4, Perihilar cholangiocarcinoma, Prognosis, Proliferation, Cell cycle

Second-line treatment options for advanced/metastatic non-small cell lung cancer (NSCLC) patients are limited. We aimed to evaluate the efficacy and safety of docetaxel/sodium cantharidinate combination vs. either agent alone as second-line treatment for advanced/metastatic NSCLC patients with wild-type or unknown EGFR status. A randomized, open-label, phase III study was performed at 12 institutions. Patients with failure of first-line platinum regimens were randomized to receive either single-agent sodium cantharivsdinate (SCA) or single-agent docetaxel (DOX) or docetaxel/sodium cantharidinate combination (CON). The primary endpoints were centrally confirmed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. A total of 148 patients were enrolled in our study between October 2016 and March 2020. After a median follow-up time of 8.02 months, no significant difference was observed among the three groups in ORR (SCA vs. DOX vs. CON: 6.00% vs. 8.33% vs. 10.00%, respectively; p=0.814) and DCR (74.00% vs. 52.00% vs. 62.50%, respectively; p=0.080). In additional, the mOS was significantly higher in the CON group, compared with the single-agent groups (7.27 vs. 5.03 vs. 9.83 months, respectively; p=0.035), while no significant differences were observed in terms of PFS (2.7 vs. 2.9 vs. 3.1 months, respectively; p=0.740). There was no significant difference in the baseline QoL scores between the three groups (p>0.05); after treatment, life quality in SCA and CON group was significantly better than that in the DOX group (p

BackgroundTo explore the efficacy and toxicity of simultaneous modulated accelerated radiotherapy (SMART) concurrently with cisplatin (CDDP) and S1 (tegafur/gimeracil/oteracil) in elderly patients with esophageal squamous cell carcinoma (ESCC).MethodsThis single-arm, phase II study enrolled pathologically confirmed, stage II–IVa ESCC of 70–80 years old and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Patients received SMART (64 Gy to gross tumor volume and 48 Gy to clinical target volume in 30 fractions) with concurrent CDDP (day 1 of each week) and S1 (days 1–14, 22–35). The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicities.ResultsThirty-seven eligible patients were analyzed with median follow-up of 25.7 months for all and 46.1 months for survivors. The ORR was 88.9%. Patients with baseline weight loss

Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus.Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis.Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43–2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11–2.74), and obesity (OR: 1.72; 95% CI: 1.13–2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1–35.8% vs. 16.4%, 95% CI: 13.4–19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9–36.1%), which is similar with the overall result of GLS.Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.

ObjectiveTo analyze changes in volume and position of target regions and organs at risk (OARs) during radiotherapy for esophageal cancer patients.MethodsOverall, 16 esophageal cancer patients who underwent radiotherapy, including 10 cases of intensity-modulated radiation therapy (IMRT) and six of three-dimensional conformal radiotherapy (3D-CRT), were enrolled. The prescription doses for the planning target volumes (PTVs) were as follows: PTV1, 64 Gy/32 fractions; and PTV2, 46 Gy/23 fractions. Repeat computed tomography (CT) was performed for patients after the 5th, 10th, 15th, 20th, and 25th fractions. Delineation of the gross tumor volume (GTV) and OAR volume was determined using five repeat CTs performed by the same physician. The target and OAR volumes and centroid positions were recorded and used to analyze volume change ratio (VCR), center displacement (ΔD), and changes in the distance from the OAR centroid positions to the planned radiotherapy isocenter (distance to isocenter, DTI) during treatment.ResultsNo patient showed significant changes in target volume (TV) after the first week of radiotherapy (five fractions). However, TV gradually decreased over the following weeks, with the rate slowing after the fourth week (40 Gy). The comparison of TV from baseline to 40 Gy (20 fractions) showed that average GTVs decreased from 130.7 ± 63.1 cc to 92.1 ± 47.2 cc, with a VCR of −29.21 ± 13.96% (p

Pediatric brain tumors are the most common solid tumors in children and represent a heterogenous group of diagnoses. While some are treatable with current standard of care, relapsed/refractory disease is common and some high-risk diagnoses remain incurable. A growing number of therapy options are under development for treatment of CNS tumors, including targeted therapies that disrupt key tumor promoting processes and immunotherapies that promote anti-tumor immune function. While these therapies hold promise, it is likely that single agent treatments will not be sufficient for most high-risk patients and combination strategies will be necessary. Given the central role for radiotherapy for many pediatric CNS tumors, we review current strategies that combine radiation with targeted therapies or immunotherapies. To promote the ongoing development of rational combination treatments, we highlight 1) mechanistic connections between molecular drivers of tumorigenesis and radiation response, 2) ways in which molecular alterations in tumor cells shape the immune microenvironment, and 3) how radiotherapy affects the host immune system. In addition to discussing strategies to maximize efficacy, we review principles that inform safety of combination therapies.

Abstract Background Small cell carcinoma of the esophagus (SCCE) is characterized by its progressive feature and poor prognosis. There is no consensus on a standard therapeutic modality for SCCE. In this study, we aimed to characterize the outcomes of primary SCCE patients treated by radiation therapy as part of treatment and investigate prognostic factors. Methods We retrospectively analyzed the data of 42 SCCE patients who were treated by RT as part of treatment at the Sun Yat-sen University Cancer Center from 2001 to 2014. The Kaplan-Meier and log-rank method were used to analyze survival. Cox’s hazard regression model was applied to determine prognostic factors. Results Of the 42 enrolled patients, 25 had limited disease (LD) and 17 with extensive disease (ED). The overall response rate (CR + PR) was 60.0% (21/35). The median overall survival time (OS) for whole and LD group were 12.9 and 36.8 months. The 1-, 3- and 5-year OS rates of the whole cohort were 64.9, 31.3, and 13.9%, respectively. OS was significantly longer in patients with ECOG performance score (ECOG PS)

Background: Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. Methods: Potential PHCCA biomarkers were screened by transcriptome sequencing of 5 pairs of PHCCA and adjacent tissues. The clinical significance of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables, and the prognostic value of ANXA10 was evaluated with univariate and multivariate analyses. The function of ANXA10 in the epithelial-mesenchymal transition (EMT), proliferation, invasion and metastasis was detected with in vitro and in vivo experiments. Moreover, we screened the key molecule in ANXA10-induced CCA progression by mRNA sequencing and evaluated the correlation between PLA2G4A and ANXA10. The effect of PLA2G4A downstream signaling, including Cyclooxygenase 2, Prostaglandin E2(PGE2) and Signal transducer and activator of transcription 3(STAT3), on EMT and metastasis was further detected with in vitro and in vivo experiments. Findings: ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and prognosis. ANXA10 promoted the proliferation, migration and invasion of the PHCCA cells. PLA2G4A expression was regulated by ANXA10 and high PLA2G4A predicted poor prognosis in PHCCA and DCCA. ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. Interpretation: ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the progression of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA. Keywords: Annexin 10, Perihilar cholangiocarcinoma, Distal cholangiocarcinoma, Prognosis, Metastasis, Epithelial-mesenchymal transition

Background: Perihilar cholangiocarcinoma (PHCC) is the most common type of cholangiocarcinoma with the worst prognosis. Radical resection of PHCC is difficult; thus, few effective biomarkers or useful molecular profiles for PHCC have been reported in recent years. Therefore, in this study, we aimed to assess biomarkers for PHCC. Methods: We screened potential biomarkers for PHCC using exome and transcriptome sequencing with PHCC tissues and paired normal tissues. Transcription factor 7 (TCF7) expression was evaluated using quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. The correlations between TCF7 and clinicopathological factors were analyzed with Chi-square test, and the prognostic significance of TCF7 was evaluated with univariate and multivariate analyses. The functions of TCF7 and its main effectors in PHCC cells were investigated in vitro and in vivo. Findings: TCF7 expression was upregulated in PHCC and was an unfavorable prognostic biomarker. c-Myc was a main effector of TCF7 in PHCC cells and modulated TCF7-induced proliferation, invasion, and migration. FOS-like antigen 1 (FOSL1) was identified as a downstream target of TCF7 and was required in TCF7-induced PHCC proliferation. Triple-positive expression of TCF7, c-Myc, and FOSL1 predicted a much worse prognosis in patients with PHCC than TCF7 expression alone. Interpretation: Postoperative detection of TCF7, c-Myc, and FOSL1 may be useful for stratifying patients with a high risk of unfavorable prognosis, and suppressing TCF7 or its downstream effectors may be a promising strategy for the treatment of PHCC. Keywords: Transcription factor 7, Perihilar cholangiocarcinoma, C-Myc, FOS-like antigen 1, Prognosis, Progression

The ocean’s swirling eddies are known to influence primary productivity, yet understanding of these processes has been hampered by a lack of resolution. Here the authors combine in-situ drifter, altimeter-based feature tracking, and satellite chlorophyll data to quantify how phytoplankton respond to surface mesoscale phenomena across the globe.

Satellite observations of the last two decades have led to a major breakthrough emphasizing the existence of a strongly energetic mesoscale turbulent eddy field in all the oceans. This ocean mesoscale turbulence is characterized by cyclonic and anticyclonic eddies (with a 100‐ to 300‐km size and depth scales of ∼500–1,000 m) that capture approximatively 80% of the total kinetic energy and is now known to significantly impact the large‐scale ocean circulation, the ocean's carbon storage, the air‐sea interactions, and therefore the Earth climate as a whole. However, ocean mesoscale turbulence revealed by satellite observations has properties that differ from those related to classical geostrophic turbulence theories. In the last decade, a large number of theoretical and numerical studies has pointed to submesoscale surface fronts (1–50 km), not resolved by satellite altimeters, as the key suspect explaining these discrepancies. Submesoscale surface fronts have been shown to impact mesoscale eddies and the large‐scale ocean circulation in counterintuitive ways, leading in particular to up‐gradient fluxes. The ocean engine is now known to involve energetic scale interactions, over a much broader range of scales than expected one decade ago, from 1 to 5,000 km. New space observations with higher spatial resolution are however needed to validate and improve these recent theoretical and numerical results.

Particle reinforced metal matrix composites have many problems such as complicated preparation process, high production costs, weak interface bonding between the ceramic and metal matrix, uneven distribution of ceramic particles and so on. To solve these problems, the method of "shoot mixing + pressure compositing" (SM-PC) and a mixed regulation model of ceramic particles with molten steel were proposed. In the shoot mixing process, the special designed die casting equipment was used to make the particles with the molten metal mixed in the runner at a certain ejection speed (150 mm·s-1). After the mixture is filled with the mold, the pressure is maintained until the end of solidification. In order to optimize this method to obtain the more uniform particle distribution, the parameters (ejection speed, preheating temperature of particles, the shape and size of runner) in the model were selected for sample preparation. Taking the distribution index of particles as the evaluation criterion, it is concluded that the uniform distribution of particles can be promoted with the increase of ejection velocity, the increase of particle preheating temperature, and the small change of gate size. When the preheating temperature of particles was 1,100 °C, and the shape of the runner was trumpet, the optimal particle distribution composite parts was obtained. Meanwhile, the particles and the matrix achieved strong interface bonding - "Class I interface " under the pressure compositing, even though they're non-wetting.

Al-Ti-C master alloy agent is currently the most promising grain refiner. This work investigates the influence of Ti3AlC2 addition (1.0–3.0 wt.%) on the microstructure of a hypoeutectic cast iron (4.7 wt.% Cr, 2.3 wt.% C). Microstructures of the samples were examined by SEM (scanning electron microscope). It was demonstrated that the added Ti3AlC2 did reduce the size of coarse primary carbides. The XRD (X-ray diffraction) pattern shows that Ti3AlC2 is decomposed into TiC in the alloy substrate. The EDS (energy dispersive spectrometer) interfacial element analysis shows that TiC combines well with the matrix interface. As the Ti3AlC2 amount was increased, the finest microstructure was achieved. When 2 wt.% Ti3AlC2 was added, the wear-resistance property of the material improved and became two times harder than the former. However, when 3% Ti3AlC2 was added, TiC gathered at the crystal boundary, which caused a decrease in the wear resistance of the material.

In recent years, convolutional neural networks (CNNs) have achieved competitive performance in the field of ground-based cloud image (GCI) classification. Proposed CNN-based methods can fully extract the local features of images. However, due to the locality of the convolution operation, they cannot well establish the long-range dependencies between the images, and thus they cannot extract the global features of images. Transformer has been applied to computer vision with great success due to its powerful global modeling capability. Inspired by it, we propose a Transformer-based GCI classification method that combines the advantages of the CNN and Transformer models. Firstly, the CNN model acts as a low-level feature extraction tool to generate local feature sequences of images. Then, the Transformer model is used to learn the global features of the images by efficiently extracting the long-range dependencies between the sequences. Finally, a linear classifier is used for GCI classification. In addition, we introduce a center loss function to address the problem of the simple cross-entropy loss not adequately supervising feature learning. Our method is evaluated on three commonly used datasets: ASGC, CCSN, and GCD. The experimental results show that the method achieves 94.24%, 92.73%, and 93.57% accuracy, respectively, outperforming other state-of-the-art methods. It proves that Transformer has great potential to be applied to GCI classification tasks.

Cloud segmentation is a fundamental step in accurately acquiring cloud cover. However, due to the nonrigid structures of clouds, traditional cloud segmentation methods perform worse than expected. In this paper, a novel deep convolutional neural network (CNN) named MA-SegCloud is proposed for segmenting cloud images based on a multibranch asymmetric convolution module (MACM) and an attention mechanism. The MACM is composed of asymmetric convolution, depth-separable convolution, and a squeeze-and-excitation module (SEM). The MACM not only enables the network to capture more contextual information in a larger area but can also adaptively adjust the feature channel weights. The attention mechanisms SEM and convolutional block attention module (CBAM) in the network can strengthen useful features for cloud image segmentation. As a result, MA-SegCloud achieves a 96.9% accuracy, 97.0% precision, 97.0% recall, 97.0% F-score, 3.1% error rate, and 94.0% mean intersection-over-union (MIoU) on the Singapore Whole-sky Nychthemeron Image Segmentation (SWINySEG) dataset. Extensive evaluations demonstrate that MA-SegCloud performs favorably against state-of-the-art cloud image segmentation methods.

Objective: To investigate the effect of Mingmu Xiaomeng tablets (MMXM) on the expression of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)-related proteins in a diabetic rat model.Methods: Thirty-two male Sprague Dawley rats were randomly divided into four groups: normal control (NC), diabetic model (DM) control, MMXM, and calcium dobesilate (CD) Rats injected with streptozotocin (STZ) were used as an experimental diabetes model. After 14 weeks, autophagy and PI3K/Akt/mTOR signaling pathway proteins were detected by western blot. Glial fibrillary acidic protein (GFAP) expression in Müller cells was examined by immunohistochemistry. Retinal function was evaluated with electroretinography, and retinal ultrastructure was observed by transmission electron microscopy. Serum cytokine levels were detected with protein chip technology.Results: MMXM restored autophagy by decreasing the protein expression of LC3-II and p62 and reducing the phosphorylation of PI3K, Akt, and mTOR, thus promoting autophagy. MMXM decreased GFAP expression in retinal Müller cells; restored electrophysiology indexes and retinal ultrastructures; and reduced serum levels of interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor.Conclusion: MMXM may protect the diabetic retina by inhibiting PI3K/Akt/mTOR signaling and enhancing autophagy.

Abstract Objectives Transcriptional changes in cartilage can impact function by causing degradation such as that which occurs during the development of osteoarthritis (OA). Epigenetic regulation may be a key factor leading to transcriptional changes in OA. In this study, we performed a combined analysis of DNA methylation and gene expression microarray datasets and identified key transcription factors (TFs) central to the regulation of gene expression in OA. Methods A DNA methylation profile dataset (GSE63106) and a gene expression profiling dataset (GSE114007) were extracted from the Gene Expression Omnibus (GEO). We used ChAMP methylation analysis and the Limma package to identify differentially methylation genes (DMGs) and differentially expressed genes (DEGs) from normal and human knee cartilage samples in OA. Function enrichment analysis of DMGs was conducted using the DAVID database. A combined analysis of DEGs and DMGs was conducted to identify key TFs in OA. We then validated the mRNA expression of selected TFs in normal and OA cartilage by RT-qPCR. Primary chondrocytes were cultured and treated with the DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza) for functional validation. Results We identified 2,170 differential methylation sites (DMS) containing 1005 genes and 1986 DEGs between normal human and OA cartilage. Functional analysis of DMGs revealed that focal adhesion, extracellular matrix (ECM)-receptor interactions, the PI3K-Akt signaling pathway, and the FoxO signaling pathway were involved in OA. Integrated analysis showed a subset of 17 TFs. Four TFs (ELF3, SOX11, RARA, and FOXD2) were validated. RT-qPCR results showed the mRNA expression of SOX11, RARA, and FOXD2 were consistent with the results from the mRNA expression data. However, the expression of ELF3 could not be validated. Upon 5-Aza-2′-deoxycytidine (5-Aza) treatment, the mRNA levels of ELF3 and SOX11 were down-regulated, whilst RARA was up-regulated, and FOXD2 showed no significant change in expression level. Conclusions the effect of DNA methylation on the transcriptional regulation is related to the distribution of methylated sites across the genome. Epigenetic studies on the positions of DMS in transcriptional units can inform a better understanding of the function of DNA methylation and its transcription regulation.

ObjectiveTo improve the assessment of primary tumor heterogeneity in magnetic resonance imaging (MRI) of non-small cell lung cancer (NSCLC), we proposed a method using basic measurements from T1- and T2-weighted MRI.MethodsOne hundred and four NSCLC patients with different T stages were studied. Fifty-two patients were analyzed as training group and another 52 as testing group. The ratios of standard deviation (SD)/mean signal value of primary tumor from T1-weighted (T1WI), T1-enhanced (T1C), T2-weighted (T2WI), and T2 fat suppression (T2fs) images were calculated. In the training group, correlation analyses were performed between the ratios and T stages. Then an ordinal regression model was built to generate the tumor heterogeneous index (THI) for evaluating the heterogeneity of tumor. The model was validated in the testing group.ResultsThere were 11, 32, 40, and 21 patients with T1, T2, T3, and T4 disease, respectively. In the training group, the median SD/mean on T1WI, T1C, T2WI, and T2fs sequences was 0.11, 0.19, 0.16, and 0.15 respectively. The SD/mean on T1C (p=0.003), T2WI (p=0.000), and T2fs sequences (p=0.002) correlated significantly with T stages. Patients with more advanced T stage showed higher SD/mean on T2-weighted, T2fs, and T1C sequences. The median THI in the training group was 2.15. THI correlated with T stage significantly (p=0.000). In the testing group, THI was also significantly related to T stages (p=0.001). Higher THI had relevance to more advanced T stage.ConclusionsThe proposed ratio measurements and THI based on MRI can serve as functional radiomic markers that correlated with T stages for evaluating heterogeneity of lung tumors.

Purpose: To investigate the predictive values of plasma Epstein-Barr Virus (EBV)- deoxyribonucleic acid (DNA) copy number on disease progression and survival in stage I-III pulmonary lymphoepithelioma-like carcinoma (LELC).Patients and Methods: Patients with pathologically confirmed, initially diagnosed or locally recurrent stage I-III pulmonary LELC, who received locally radical treatment and had plasma EBV-DNA results, were retrospectively reviewed. Risk factors of progression-free survival (PFS) and overall survival (OS) were assessed, including the predictive value of pre- and post-treatment EBV-DNA levels. The EBV-DNA change during follow-up was analyzed to determine its association with tumor progression and survival.Results: A total of 102 patients were included in analysis. Eighty-eight patients had initially-diagnosed and 14 had locally recurrent disease. There were 33 patients treated with radical surgery, 55 with definite radiotherapy and 14 with both. EBV-DNA was tested pre-treatment (N = 66), post-treatment (N = 93) and/or during follow-up (N = 58). Forty-one patients had complete EBV-DNA results of all three time points. The overall 2-year PFS and OS were 66.3 and 96.0%, respectively. Pre-treatment EBV-DNA copy number > 10,000 copies/mL was a risk factor of PFS (2-year PFS, > 10,000 vs. ≤ 10,000 copies/mL, 37.2 vs. 75.1%, p = 0.007). Positive post-treatment EBV-DNA also indicated a worse PFS in univariable (2-year PFS, > 0 vs. 0 copy/mL, 25.6 vs. 76.8%, p < 0.001) and multivariable analysis (HR = 3.44, 95% CI, 1.52–7.78; p = 0.003). In the follow-up set, an increasing EBV-DNA exceeding 1,000 copies/mL strongly predicted disease progression within 3 months, with a specificity of 97.5% (95% CI: 86.8–99.6%) and was associated with impaired OS (2-year OS, > 1,000 vs. ≤ 1,000 copies/mL, 72.9 vs. 100%, p < 0.001).Conclusions: Regular testing of EBV-DNA is suggested for pulmonary LELC to predict disease progression. If EBV-DNA copy number was increasing and beyond 1,000 copies/mL during follow-up, intensive radiologic evaluations are recommended.

Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity.Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed.Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3–4 AEs.Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.

Abstract Satellite solar‐induced chlorophyll fluorescence (SIF) products from the Global Ozone Monitoring Experiment 2 (GOME‐2) and Orbiting Carbon Observatory 2 (OCO‐2) are used to investigate the responses of vegetation growth to the 2019 heat wave in Australia. Both satellite SIF data sets are more sensitive to water and heat stress than is the greenness‐based vegetation index (enhanced vegetation index). Moreover, the OCO‐2 SIF observations show a more significant reduction and earlier response to the heat stress than does GOME‐2 SIF, indicating that the two satellite SIF data sets differ in how they monitor the drought and heat wave event due to the different timing of observations. Eddy covariance measurements confirm the different responses of dryland vegetation to the 2019 heat wave at a subdaily time scale. The differences in the timing of the satellite SIF products can be used to assess different elements of the impact of heat and water stress on Australian dryland ecosystems.

Background: Perihilar cholangiocarcinoma (PHCCA) is the most common type of human cholangiocarcinoma with a very dismal prognosis. Tumor markers and target drugs of PHCCA are desperately needed. Protein phosphatase N3 (PTPN3) has dual roles in the progression of human cancers, but its expression and functions in PHCCA have not been elucidated. Materials and methods: The expression of PTPN3 in PHCCA was detected with western blotting, qRT-PCR and immunohistochemistry. The clinical significance of PTPN3 was identified by analyzing the correlations between its expression and the clinicopathological variables, and the prognostic value was evaluated by univariate and multivariate analyses. The functions of PTPN3 in the progression of PHCCA were estimated with both in vitro and in vivo experiments. Results: PTPN3 expression was down-regulated in PHCCA compared with normal bile duct. Low PTPN3 expression was markedly associated with large tumor size and unfavorable prognosis. After knocking down PTPN3, the percentages of G2/S phase of PHCCA cells were elevated, and the proliferation increased significantly. Moreover, we demonstrated that the phosphorylation of AKT was elevated by PTPN3 knockdown, and it was required in PTPN3-involved proliferation of PHCCA. Within vivo experiments, PTPN3 and AKT inhibitor MK-2206 were demonstrated to suppress tumor size of PHCCA. Conclusion: PTPN3 was a favorable prognostic biomarker of PHCCA. PTPN3 suppressed the proliferation of PHCCA by inhibiting AKT phosphorylation and arresting cell cycle. Our results suggested thatpost-operative detection of PTPN3 would be a helpful approach to stratify the PHCCA patients with high-risk.

Purpose. To determine whether the female gender is a barrier for the access to cataract surgery services in South Asia in the last two decades. Methods. Eligible cross-sectional studies were identified via computer searches and reviewing the reference lists of the obtained articles. The cataract surgical coverage (CSC) by sex based on person and eyes at visual acuity

The atmospheric response to subseasonal variability of Tibetan Plateau snow cover has been largely ignored. Here the authors show that the fast subseasonal variability of Tibetan Plateau snow cover is closely related to the subsequent East Asian atmospheric circulation at medium-range time scales.

Turbulent mixing is critically important for ocean circulation, but their latitudinal distribution are poorly known. Here, the authors show that the generation mechanism of the W-shaped distribution of turbulent mixing in the tropical-extratropical Pacific is latitude dependent.