Search

Abstract 53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the ‘leaky’ DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

With the increasing depth of coal mining, the stability control of surrounding rock in deep roadway has become one of major problems in the mining field, and the effect of surrounding rock control in deep roadway is directly related to the safe production and health of personnel in underground coal mines. The emergence of plastic zone after roadway excavation is the main reason for the stability of the surrounding rock of the roadway. From the perspective of the formation and expansion of the plastic zone, this paper discusses the intrinsic relationship between the roadway damage mode and the distribution of the plastic zone of surrounding rock on the basis of the results from collating and summarizing the existing roadway damage theory and the theory of the plastic zone of surrounding rock. It is believed that the control of the surrounding rock of roadway is essentially the process of controlling the formation and expansion of the plastic zone of surrounding rock. The expansion of the plastic zone of surrounding rock and the control effect of anchor support on the plastic zone of surrounding rock have become an important theoretical basis for the scientific and effective control of surrounding rock in roadway, and based on this, the authors propose the theory and technology for the stability control of surrounding rock in roadway. The results show that the plastic zone is the product of roadway excavation, and the formation and expansion of the plastic zone of surrounding rock is the result of mine pressure. For deep roadways, the appearance of the plastic zone of surrounding rock is inevitable. Scientific control of plastic zone requires a comprehensive understanding of the role played by the plastic zone in roadway surrounding rock. It is necessary to allow the surrounding rock to release the energy in the rock body through plastic failure, but also to prevent the disorderly expansion of the plastic zone. Therefore, in the process of controlling the surrounding rock of roadway, the self-bearing capacity of the surrounding rock should be given a full play as the main focus, and the support intervention should be supplemented. The control of plastic zone of surrounding rock in deep roadway is global and procedural. The control of the plastic zone of the surrounding rock in the whole life of roadway is divided into three stages. By regulating the shape of the plastic zone and inhibiting the expansion of the plastic zone, the stability control of the surrounding rock of deep roadway is realized.

Purpose: The purpose of this study is to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) or plus with chemotherapy in older patients. Methods: We enrolled 110 older patients with non-small cell lung cancer (NSCLC ≥75 years) who received either chemotherapy alone (chemo), ICI plus chemotherapy (ICI + chemo), or ICI alone and ICI plus other therapies, which included anti-angiogenesis drugs or other novel ICI (ICIs). Patient characteristics, treatment response, survival, and toxicity were evaluated. Results: In total population, the ICIs group has the highest disease control rate (DCR 75%). There were no significant differences in progression-free survival (PFS) and overall survival (OS) among older patients between ICI + chemo and ICIs groups (PFS: 5.3 months vs. 5.5 months, p = 0.70, OS: 10.7 months vs. 20.3 months, p = 0.995). Meanwhile, we observed ICIs had a longer PFS and OS than chemo group (PFS: 3.9 months vs. 5.5 months, p = 0.01, OS: 10.9 months vs. 20.3 months, p = 0.05). Subgroup analysis showed that patients with programmed death ligand-1 (PD-L1) ≥ 1% had a distinct longer trend toward OS in ICIs group compared to ICI + chemo group (22.4 months vs. 10.7 months, p = 0.605), even though there was no significant difference. In terms of safety, ICIs was more tolerable and had a lower discontinuation rate than ICI + chemo group. Conclusion: In the real world, ICI + chemo is more likely to be discontinued due to adverse effects and does not significantly improve patient survival compared with ICIs treatment in total population and subgroup. Therefore, ICI alone or ICIs plus other therapies, such as anti-angiogenesis drugs or other novel ICI (ICIs) could be recommended for older cases with PD-L1 positive NSCLC.

Abstract Background Lung Adenocarcinoma (LUAD) is a major component of lung cancer. Endoplasmic reticulum stress (ERS) has emerged as a new target for some tumor treatments. Methods The expression and clinical data of LUAD samples were downloaded from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database, followed by acquiring ERS-related genes (ERSGs) from the GeneCards database. Differentially expressed endoplasmic reticulum stress-related genes (DE-ERSGs) were screened and used to construct a risk model by Cox regression analysis. Kaplan–Meier (K-M) curves and receiver operating characteristic (ROC) curves were plotted to determine the risk validity of the model. Moreover, enrichment analysis of differentially expressed genes (DEGs) between the high- and low- risk groups was conducted to investigate the functions related to the risk model. Furthermore, the differences in ERS status, vascular-related genes, tumor mutation burden (TMB), immunotherapy response, chemotherapy drug sensitivity and other indicators between the high- and low- risk groups were studied. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA expression levels of prognostic model genes. Results A total of 81 DE-ERSGs were identified in the TCGA-LUAD dataset, and a risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was constructed by Cox regression analysis. K-M and ROC analyses showed that the high-risk group had a low survival, and the Area Under Curve (AUC) of ROC curves of 1-, 3- and 5-years overall survival was all greater than 0.6. In addition, functional enrichment analysis suggested that the risk model was related to collagen and extracellular matrix. Furthermore, differential analysis showed vascular-related genes FLT1, TMB, neoantigen, PD-L1 protein (CD274), Tumor Immune Dysfunction and Exclusion (TIDE), and T cell exclusion score were significantly different between the high- and low-risk groups. Finally, qRT-PCR results showed that the mRNA expression levels of 6 prognostic genes were consistent with the analysis. Conclusion A novel ERS-related risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was developed and validated, which provided a theoretical basis and reference value for ERS-related fields in the study and treatment of LUAD.

Abstract Background Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. Methods Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. Results Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. Conclusions Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity. Graphical Abstract

Fusarium pseudograminearum causes destructive crown disease in wheat. The velvet protein family is a crucial regulator in development, virulence, and secondary metabolism of fungi. We conducted a functional analysis of FpVelB using a gene replacement strategy. The deletion of FpVelB decreased radial growth and enhanced conidial production compared to that of wild type. Furthermore, FpVelB modulates the fungal responses to abiotic stress through diverse mechanisms. Significantly, virulence decreased after the deletion of FpVelB in both the stem base and head of wheat. Genome-wide gene expression profiling revealed that the regulation of genes by FpVelB is associated with several processes related to the aforementioned phenotype, including “immune”, “membrane”, and “antioxidant activity”, particularly with regard to secondary metabolites. Most importantly, we demonstrated that FpVelB regulates pathogen virulence by influencing deoxynivalenol production and modulating the expression of the PKS11 gene. In conclusion, FpVelB is crucial for plant growth, asexual development, and abiotic stress response and is essential for full virulence via secondary metabolism in F. pseudograminearum.

In previous studies of ship–ice interactions, most studies focused on ship–level ice interactions, overlooking potential rafted ice conditions in extreme ice conditions. The purpose of this study is to develop a numerical model for predicting ship resistance in rafted ice regions. Numerical modeling of rafted ice was carried out using preset grid cells. By comparing the model test results, the accuracy and reliability of the numerical model are verified. On this basis, we undertook the analysis of the impacts of different ice thicknesses, ship speeds, bending strengths, and crushing strengths on the ice resistance of ships under level and rafted ice conditions. The results show that the ice resistance of ships is significantly higher than that of rafted ice under the condition of level ice; however, level ice and rafted ice have different effects on ship ice resistance. Compared with level ice, the ice resistance of ships navigating in rafted ice is more concentrated. The findings of the present research can serve as a technical reference for studies focused on predicting ship resistance in rafted ice regions.

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

Abstract Background Currently there is no standard therapy recommended for second‐line treatment for thymic carcinoma. Our study compared multidrug chemotherapy, single‐agent chemotherapy, and PD‐1 inhibitors in patients diagnosed with advanced thymic carcinoma who had previous platinum‐based chemotherapy at the clinic. Methods The study included patients with thymic carcinoma who failed first‐line platinum‐based chemotherapy. Kaplan–Meier methods were applied in the study for estimating the progression‐free survival (PFS) and overall survival (OS) curves. Pearson chi‐square or Fisher's exact chi‐square test was adopted to make comparisons of the objective response rate (ORR) between treatment groups. Cox regression was used for the multivariate analyses in PFS and OS. Results Among the 92 patients enrolled, multidrug chemotherapy was used in 51 (55.4%) patients for second‐line therapy. Thirty‐six patients (35.9%) received single‐agent chemotherapy, and eight patients (8.7%) underwent PD‐1 inhibitors. The multidrug chemotherapy group showed better efficacy than the other two groups, with an ORR of 35.3% (p = 0.006). The median PFS of multidrug chemotherapy, single‐agent chemotherapy and PD‐1 inhibitors were 5.0 months, 3.0 months, and 4.0 months, respectively (p = 0.008). Patients in the multidrug chemotherapy group also showed an advantage in OS in comparison with the other two treatment groups (p = 0.045), with a median OS of 30.4 months. Multivariate analysis showed that second‐line treatment was independent factor for both PFS (p = 0.035) and OS (p = 0.037). Grade 3–4 AEs were mostly detected in patients receiving multidrug chemotherapy and were primarily hematologic. Treatment‐related mortality was not found in any of the groups. Conclusions Multidrug chemotherapy had a trend toward a more positive response rate and outcomes in longer survival time than single‐agent chemotherapy and PD‐1 inhibitors. Multidrug chemotherapy is a choice worth considering for second‐line therapy in patients with thymic carcinoma if tolerable.

Radar interferograms are usually influenced by factors such as atmospheric artifacts, orbital errors, and terrain errors. It is difficult to reduce the influence by using the conventional small baseline subset (SBAS) method when determining the deformation rate. This study uses the adjustment model with systematic parameters to improve the conventional SBAS method and employs it to determine the interseismic deformation rate of the Haiyuan fault system, providing a data reference for exploring the locking depth, strain accumulation state, and potential seismic risk assessment of different segments of the Haiyuan fault system. The results are as follows: (1) the simulation experiment verifies the feasibility and robustness of the modified SBAS method. This method can effectively reduce the influence of residual signals such as atmospheric artifacts, orbital errors and terrain errors in the interferograms. The deformation rate map can be significantly improved; (2) the deformation rate field in the radar's Line of Sight (LOS) direction shows that there are obvious differences between the north and south sides of Haiyuan fault system, which is consistent with the characteristics of the left-lateral strike-slip movement of the Haiyuan fault system. The deformation rate field and profiles reflect the complex trends among different segments of Haiyuan fault system in detail. (3) the deformation rate of the Jingtai pull-apart basin is higher than that of the surrounding areas, possibly indicating strong regional activity, which provides a reference for studying the seismic risk of the Jingtai pull-apart basin; and (4) the interseismic deformation rate and profiles across the fault show that the middle section of the Lao Hu Shan (LHS) segment and the western and middle sections of the Haiyuan segment are locked.

The deformation and re-crushing characteristics of different lithological caving crushed gangues in mine goaf directly affect the overburden strata movement, which significantly affects the surface subsidence of mining goaf. The effect of particle size on the re-crushing characteristics of different lithological caving crushed gangues in mine goaf is investigated in this study based on an innovative compression–AE (acoustic emission) measuring method. The results showed the following: (1) The compression deformation was divided into three stages: rapid, slow, and stable compaction. With the increase in axial pressure, the large particle skeletons were destroyed, medium particles were displaced and slid, and small particles filled the pores. (2) For singular lithologies, stress was positively correlated with pressure, and porosity was negatively correlated with stress. The composite sample was between the singular gangue samples. (3) The fractal dimension of crushed gangue samples was exponentially related to the proportion of gangue in singular and combined lithologies. (4) The cumulative AE count and energy of the combined lithological gangue samples were between those of the singular samples. The research results provide a theoretical foundation for further research into the characteristics of the overlying strata, surface movement, and safety management of the goaf.

Bipolaris maydis partitivirus 36 (BmPV36) is a mycovirus that can significantly reduce the virulence of the host Bipolaris maydis, but its hypovirulence mechanism is not clear. To investigate the response of B. maydis to BmPV36, the effects of BmPV36 on host cell structure and gene expression were studied via transmission electron microscopy and transcriptome sequencing using BmPV36-carrying and virus-free mycelium on the second and fifth culture. The results of transmission electron microscopy showed that the cell wall microfibrils of B. maydis were shortened, the cell membrane was broken, and membrane-bound vesicles and vacuoles appeared in the cells after carrying BmPV36. Transcriptome sequencing results showed that after carrying BmPV36, B. maydis membrane-related genes were significantly up-regulated, but membrane transport-related genes were significantly down-regulated. Genes related to carbohydrate macromolecule polysaccharide metabolic and catabolic processes were significantly down-regulated, as were genes related to the synthesis of toxins and cell wall degrading enzymes. Therefore, we speculated that BmPV36 reduces the virulence of B. maydis by destroying the host’s cell structure, inhibiting the synthesis of toxins and cell wall degrading enzymes, and reducing cell metabolism. Gaining insights into the hypovirulence mechanism of mycoviruses will provide environmentally friendly strategies for the control of fungal diseases.

Alcohol‐associated liver disease is the leading cause of chronic liver disease. We hypothesized that the expression of specific coding genes is critical for the progression of alcoholic cirrhosis (AC) from compensated to decompensated states. For the discovery phase, we performed RNA sequencing analysis of 16 peripheral blood RNA samples, 4 healthy controls (HCs) and 12 patients with AC. The DEGs from the discovery cohort were validated by quantitative polymerase chain reaction in a separate cohort of 17 HCs and 48 patients with AC (17 Child‐Pugh A, 16 Child‐Pugh B, and 15 Child‐Pugh C). We observed that the numbers of differentially expressed messenger RNAs (mRNAs) were more pronounced with worsening disease severity. Pathway analysis for differentially expressed genes for patients with Child‐Pugh A demonstrated genes involved innate immune responses; those in Child‐Pugh B belonged to genes related to oxidation and alternative splicing; those in Child‐Pugh C related to methylation, acetylation, and alternative splicing. We found significant differences in the expression of heme oxygenase 1 (HMOX1) and ribonucleoprotein, PTB binding 1 (RAVER1) in peripheral blood of those who died during the follow‐up when compared to those who survived. Conclusion: Unique mRNAs that may implicate disease progression in patients with AC were identified by using a transcriptomic approach. Future studies to confirm our results are needed, and comprehensive mechanistic studies on the implications of these genes in AC pathogenesis and progression should be further explored.

Excessive fertilization is associated with nutrient loss, soil compaction, and weak plant resistance. Straw returning can increase soil fertility with a consequent reduction in fertilizer, but the effects of fertilizer reduction coupled with straw returning on crop endophytic microbes and crop disease are poorly understood. Therefore, using metagenomic sequencing methods we investigated the responses of soil fertility, diversity, the function of root endophytic bacteria, and the occurrence of wheat crown rot due to the application of fertilizer (no, moderate and excessive fertilizer) coupled with or without straw returning after 7 years of treatments. The results showed that, after excessive fertilization, the wheat crown rot became severe, registering a disease index of 23. Compared with excessive fertilization, moderate fertilization coupled with straw returning significantly reduced the incidence of wheat crown rot, the disease index was reduced by 38.50%, and the richness and diversity of endophytic bacteria were increased by 61.20 and 11.93%, respectively, but the soil fertility was not significantly affected. In addition, moderate fertilization coupled with straw returning changed the community structure of endophytic bacteria and increased the relative abundance of carbohydrate metabolism and nitrogen fixation-related genes by 4.72 and 9.32%, respectively. Our results indicated that fertilizer reduction coupled with straw returning reduced the occurrence of wheat crown rot, increased the diversity of endophytic bacteria, and changed the community structure and function of endophytic bacteria, which will provide a better understanding of the interaction of fertilization coupled with straw returning, endophytic bacteria and wheat crown rot.

When ships navigate in polar regions, they may collide with ice masses, which may cause structural damage and endanger the safety of their occupants. Therefore, it is essential to promptly detect sea ice, icebergs, and passing ships. However, individual data sources have limits and should be combined and integrated to obtain more thorough information. A polar multi-target local-scale dataset with five categories was constructed. Sea ice, icebergs, ice melt ponds, icebreakers, and inter-ice channels were identified by a single-shot detector (SSD), with a final mAP value of 70.19%. A remote sensing sea ice dataset with 15,948 labels was constructed. The You Only Look Once (YOLOv5) model was improved with Squeeze-and-Excitation Networks (SE), Funnel Activation (FReLU), Fast Spatial Pyramid Pooling, and Cross Stage Partial Network (SPPCSPC-F). In the detection stage, a slicing operation was performed on remote sensing images to detect small targets. Simulated sea ice data were included to verify the model’s generalization ability. Then, the improved model was trained and evaluated in an ablation experiment. The mAP, recall (R), and precision (P) values of the improved YOLOv5 were 75.3%, 70.3, and 75.4%, with value increases of 3.5%, 3.4%, and 1.9%, respectively, compared to the original model. The improved YOLOv5 was also compared with other models such as YOLOv3, Faster-RCNN, and YOLOv4-tiny. The results indicated that the performance of the proposed model surpassed those of the other conventional models. This study achieved the detection of multiple targets on different scales in a polar region and realized data fusion, avoiding the limitations of using a single data source, and provides a method to support polar ship path planning.

Computer-generated hologram (CGH) is a diffractive optical element that has been commonly used as wavefront corrector in the interferometer and can be accurately manufactured to meet the requirements of high-precision detection. But the transmitted wavefront error (TWE) of the CGH substrate and the adjustment errors of cylindrical surface are influence factors of high accuracy measurement. In this paper, we propose the method of calibrating the CGH substrate TWE. After calibrating, the substrate TWE is 0.0052λ (RMS). Meanwhile, we obtain the general expression for the misalignment aberrations by describing the relationship between the wavefront of the measured cylindrical mirror and the corresponding adjustment errors. Then the adjustment errors of the test cylindrical surface can be completely separated by subtracting the fitting function from the measurement on the basis of least-square algorithm. After that, the PV value changes from 3.0565λ to 0.9825λ, and the RMS value changes from 0.5278λ to 0.1273λ, the measurement results have been greatly improved.

Fusarium pseudograminearum is a soil-borne pathogen that is capable of causing a highly destructive crown disease in wheat. Secondary metabolites (SMs), especially deoxynivalenol (DON), are the primary virulence factors during infection. Here, we characterised the global regulator FpLaeB, an orthologue of LaeB protein function, to regulate the SM in Aspergillus nidulans. Through the utility of the gene targeting approach, we found that the vegetative growth of the FpLaeB deletion mutant was drastically reduced compared to that of the wild type. FpLaeB was also important for conidiation because the FpLaeB deletion mutant formed fewer conidia in induced medium. In addition, the sensitivity of the FpLaeB deletion mutant to the cell wall integrity inhibitor was decreased, while its growth was more severely inhibited by the cell membrane inhibitor sodium dodecyl sulfate (SDS) than that of the wild type. More importantly, the virulence was decreased when the FpLaeB deletion mutant was inoculated onto the wheat stem base or head. Through genome-wide gene expression profiling, FpLaeB was found to regulate several processes related to the above phenotypes such as the carbohydrate metabolic process, which is an integral and intrinsic component of membranes, especially SMs. Furthermore, the generation of DON was impaired in the FpLaeB deletion mutant via ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay. These results showed that FpLaeB plays an important role in the growth, development, and maintenance of the cell wall, and in membrane integrity. More importantly, FpLaeB is required for SMs and full virulence in F. pseudograminearum.

Summary: Epithelial ovarian cancer (EOC) can originate from either fallopian tube epithelial (FTE) or ovarian surface epithelial (OSE) cells, but with different latencies and disease outcomes. To address the basis of these differences, we performed single cell RNA-sequencing of mouse cells isolated from the distal half of fallopian tube (FT) and surface layer of ovary. We find at the molecular level, FTE secretory stem/progenitor cells and OSE cells resemble mammary luminal progenitors and basal cells, respectively. An FT stromal subpopulation, enriched with Pdgfra+ and Esr1+ cells, expresses multiple secreted factor (e.g., IGF1) and Hedgehog pathway genes and may serve as a niche for FTE cells. In contrast, Lgr5+ OSE cells express similar genes largely by themselves, raising a possibility that they serve as their own niche. The differences in intrinsic expression programs and niche organizations of FTE and OSE cells may contribute to their different courses toward the development of EOCs.

Background: Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouring MET exon 14 skipping alteration ( MET ex14). Objective: To analyse post hoc , the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib. Design: A multicentre, single-arm, open-label phase 2 study. Methods: All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baseline MET ex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression. Results: Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable MET ex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline MET ex14 exhibited worse PFS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 0.88–3.57; p = 0.108] and OS (HR, 3.26; 95% CI, 1.35–7.89; p = 0.006) than those without, despite showing a numerically higher ORR. Among 24 patients with baseline detectable MET ex14 and evaluable postbaseline samples, 13 achieved MET ex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7–1.5). MET ex14 post-treatment clearance was associated with better ORR (92.3%; 95% CI, 64.0–99.8 versus 36.4%; 95% CI, 10.9–69.2; p = 0.0078), PFS (HR, 0.44; 95% CI, 0.2–1.3; p = 0.1225) and OS (HR, 0.31; 95% CI, 0.1–1.0; p = 0.0397) versus non-clearance. Among 22 patients with disease progression, 10 acquired pathway alterations (e.g. in RAS/RAF and PI3K/PTEN) alone or with secondary MET mutations (D1228H/N and Y1230C/H/S). Conclusion: ctDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients with MET ex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline MET ex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. Registration: The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

In recent years, safety issues respecting polar ship navigation in the presence of ice have become a research hotspot. The accurate prediction of propulsion power plays an important role in ensuring safe ship navigation and evaluating ship navigation ability, and deep learning has been widely applied in the field of shipping, of which the artificial neural network (ANN) is a common method. This study combines the scientific problems of ice resistance and propulsion power for polar ship design, focusing on the design of an ANN model for predicting the propulsion power of polar ships. Reference is made to the traditional propulsion power requirements of various classification societies, as well as ship model test and full-scale test data, to select appropriate input features and a training dataset. Three prediction methods are considered: building a radial basis function–particle swarm optimization algorithm (RBF-PSO) model to directly predict the propulsion power; based on the full-scale test and model test data, calculating the propulsion power using the Finnish–Swedish Ice Class Rules (FSICR) formula; using an ice resistance artificial neural network model (ANN-IR) to predict the ice resistance and calculate the propulsion power using the FSICR formula. Prediction errors are determined, and a sensitivity analysis is carried out with respect to the relevant parameters of propulsion power based on the above methods. This study shows that the RBF-PSO model based on nine feature inputs has a reasonable generalization effect. Compared with the data of the ship model test and full-scale test, the average error is about 14%, which shows that the method has high accuracy and can be used as a propulsion power prediction tool.

Thermophoresis is of common interest due to its influence on the deposition of particles. Present research on thermophoretic deposition mainly focused on the sub-micron particles, whereas the particle size during the radioactive aerosol monitoring process usually exceeds the range. In order to study the effect of thermophoresis on the deposition characteristics of aerosols ranging from 1 to 10 µm, direct numerical simulation (DNS) and experiments of particle deposition are performed in this paper aiming at still and turbulent flow respectively. The results obtained by DNS coupled with Lagrangian particle tracking (LPT) are validated by the experimental data and the theoretical values. The results indicate that thermophoresis has an influence on the deposition of micron-sized particles, and the effect of thermophoresis on deposition velocity depends on particle size. In the still air, when the temperature gradient is 3000 K/m, the deposition velocity of 1 and 10 µm particles will be increased by 87% and 4.8% respectively when compared with gravitational deposition velocity. In the turbulent flow, the motion of particles is dominated by turbulent motion. In the region near the wall, thermophoresis can increase the deposition rate on the cold wall.

The Pound–Drever–Hall technique is widely used for laser frequency or optical cavity length stabilization. We propose a method to broaden its dynamic range. The conventional error signal divided by the transmission power serves as the new error signal, which increases the dynamic range in the linear regime. The use of an extended Kalman filter improves the resilience to noise when the transmitted power is low. This expands the dynamic range into the nonlinear regime and achieves a deterministic auto-lock even in the presence of a large disturbance. Such a nonlinear extension is, however, limited to an auto-lock for a previously locked state because the extended Kalman filter requires accurate prior knowledge of the initial state. For demonstration purposes, we simulate the implementation of this method for locking a ten-meter scale cavity with a single-stage suspension.

In order to evaluate the homogeneity of asphalt mixture quantitatively, the distribution characteristic of internal phases of asphalt mixture were identified based on digital image processing technique and stereology theory, and the homogeneity coefficient (i.e., K) was proposed. At the same time, the trend of variation and reliability of homogeneity of asphalt mixture were analyzed by changing the nominal maximum aggregate size, aggregate gradation and asphalt content. The results suggest that the homogeneity of asphalt mixture could be comprehensively described using DIP technique combined with stereology theory. The smaller the K, the better the distribution homogeneity of the asphalt mixture. An improvement in the homogeneity of an asphalt mixture is achieved with the decrease of the nominal maximum aggregate size and a finer aggregate gradation. The asphalt content corresponding to the optimal homogeneity of the internal structure of asphalt mixture specimen is the optimum asphalt content. According to the experimental study, the suggested values of the homogeneity coefficient were given, which provides theoretical support to control the construction quality of the hot mixture asphalt.

Aiming at the problem that it is difficult to achieve accurate laying of model and precise excavation of roadways in special surrounding rock structure roadway according to conventional physical similarity simulation, which reduces the reliability of experimental results. An accurate laying of model and precise excavation of roadway method, named “labeling positioning and drawing line, presetting roadway model” (LPDLPRM), was proposed. The physical similarity simulation of deformation and failure characteristics of surrounding rock of coal-rock rise, under the influence of repeated mining in close distance coal seams, was carried out based on the method and infrared detection. The results show that the coal-rock rise in close distance coal seams was affected by repeated mining disturbances, and the surrounding rock of coal-rock rise was characterized by obvious asymmetric deformation, specific for the stress and strain near the coal pillar were higher than that of other parts, and cracks near the coal pillar were denser than other parts; when the coal seam is mined in which the coal-rock rise is located, the stress concentration of the surrounding rock near the rise was weakened by mining pressure relief in the upper coal seam; the stress concentration of the surrounding rock near the rise increases when the coal and the lower coal seam are mined, and the stress on the right side (coal pillar side) near the coal-rock rise was the most concentrated. Therefore, it is important to take measures to strengthen support near the coal pillar and to control asymmetric deformation when the coal-rock rise is influenced by repeated mining.

In order to reveal the influence of the pull-out rate on the load-bearing properties of the coal–rock combined anchor body, the mechanical properties and failure characteristics of a coal–rock combined anchor body under different pull-out rates (10, 20, 30, 40, 50 mm/min) were studied using the pull-out test and theoretical analysis. The results show that the bearing capacity of the bolt on the coal–rock combined anchor body improves under a dynamic load, but the load-bearing properties of the coal–rock combined anchor body are different from those of the full rock (coal) anchor body. With the increase in the pull-out rate, the maximum pull-out load of the bolt on the coal–rock combined anchor body increases first, then decreases, and finally tends to be stable. Under the condition of a low drawing rate, the bearing capacity of the coal–rock combined anchor system can be greatly improved, but when the pull-out rate exceeds 20 mm/min, the bearing capacity of the anchor system is reduced. The debonding process of the anchoring section of the coal–rock combined anchor body gradually expands from the beginning section of the anchor to the bottom of the borehole. The coal–rock combined anchor body undergoes time differential development of cracks, and the failure of the coal and rock mass occurs at different times. Its failure process can be divided into three stages: (1) the coal anchor and rock anchor act together; (2) the rock anchor acts alone; and (3) the coal anchor and rock anchor have residual action.

Aggregate geometrical features directly affect asphalt pavement surface properties, which further affect the resistance to skidding of a road surface. In order to establish a relationship between the aggregate geometrical features and pavement surface properties, this paper employs an aggregate geometric characteristic evaluation system (AGCES) to describe the form property, angularity, and surface texture of aggregate particles. The geometrical feature parameters of 15 different aggregates were examined by AGCES and the corresponding surface properties of asphalt pavement prepared from the mentioned aggregates were evaluated by sand patch method, 2-Dimension Image-based Texture Analysis Method (2D-ITAM) and Walking Friction Tester (WFT), respectively. The relationships between the pavement surface property parameters and the aggregate geometric characteristic parameters studied were developed by the Levenberg-Marquarat and universal global optimization (LM-UGO). The results show that the calculated geometric characteristic parameters are in agreement with traditional manual measurement results. The pavement surface properties are significantly influenced by aggregate angularity and aggregate surface texture. Regression relationships were established to predict pavement surface properties from the aggregate geometrical features.

Objective: The purpose of this study is to systematically review the literature on the clinical outcomes following different surgical techniques in patients with refractory idiopathic intracranial hypertension (IIH). Background: IIH is a condition characterised by increased cranial pressure (ICP) in the absence of an intracranial lesion that does not adequately respond to different medical and surgical therapies. Cranial decompression or expansion surgeries are a last resort therapy for patients with refractory IIH. Methods: A systematic literature search of the databases of PubMed, Embase and Medline from inception to 2019 was performed. Searches were limited to the English language and to clinical studies. Studies were included if clinical outcomes following different cranial decompression or expansion techniques were reported. We also add one case of our own experience with performing a bilateral frontoparietal expansion craniotomy and subtemporal craniectomy. Results: Five manuscripts, describing 38 procedures, met the inclusion criteria. Thirty-one patients were female (82%). The mean age was 26.2 years. The techniques studied included subtemporal craniectomy (27/38, 71%), internal cranial expansion (10/38, 26%), and cranial morcellation decompression (1/38, 3%). Thirty-five patients presented with headaches of which 17 noted postoperative improvement or resolution (49%). Visual deficits were documented in 30 patients and 25 reported postoperative improvement (83%). Papilledema disappeared in 23 of 32 patients with this sign at presentation (72%). In our patient, symptoms completely resolved postoperatively and a 6% increase in intracranial volume was measured. Conclusions: Cranial vault decompression or expansion surgeries may be an effective last resort therapy for patients with refractory IIH. These surgeries expand the intracranial volume, and thus may normalise ICP, leading to clinical improvement. [ABSTRACT FROM AUTHOR]