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Abstract Background Ovarian cancer (OC), particularly high-grade serous ovarian carcinoma (HGSOC), is the leading cause of mortality from gynecological malignancies worldwide. Despite the initial effectiveness of treatment, acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPis) represents a major challenge for the clinical management of HGSOC, highlighting the necessity for the development of novel therapeutic strategies. This study investigated the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a pivotal regulator of glycolysis, in PARPi resistance and explored its potential as a therapeutic target to overcome PARPi resistance. Methods We conducted in vitro and in vivo experiments to assess the role of PFKFB3 in OC and its impact on PARPi resistance. We analyzed PFKFB3 expression and activity in primary OC tissues and cell lines using western blotting and immunohistochemistry. CRISPR-Cas9 and pharmacological inhibitors were employed to inhibit PFKFB3, and the effects on PARPi resistance, homologous recombination (HR) repair efficiency, and DNA damage were evaluated. RNA sequencing and proximity labeling were employed to identify the molecular mechanisms underlying PFKFB3-mediated resistance. The in vivo efficacy of PARPi and PFK158 combination therapy was evaluated in OC xenograft models. Results PFKFB3 activity was significantly elevated in OC tissues and associated with PARPi resistance. Inhibition of PFKFB3, both genetically and pharmacologically, sensitized OC cells to PARPis, impaired HR repair and increased DNA damage. Proximity labeling revealed replication protein A3 (RPA3) as a novel PFKFB3-binding protein involved in HR repair. In vivo, the combination of PFK158 and olaparib significantly inhibited tumor growth, increased DNA damage, and induced apoptosis in OC xenografts without exacerbating adverse effects. Conclusions Our findings demonstrate that PFKFB3 is crucial for PARPi resistance in OC. Inhibiting PFKFB3 sensitizes HR-proficient OC cells to PARPis by impairing HR repair, leading to increased DNA damage and apoptosis. PFKFB3 represents a promising therapeutic target for overcoming PARPi resistance and improving outcomes in OC patients.

Abstract Long non-coding RNAs (lncRNAs) are typically described as RNA transcripts exceeding 200 nucleotides in length, which do not code for proteins. Recent advancements in technology, including ribosome RNA sequencing and ribosome nascent-chain complex sequencing, have demonstrated that many lncRNAs retain small open reading frames and can potentially encode micropeptides. Emerging studies have revealed that these micropeptides, rather than lncRNAs themselves, are responsible for vital functions, including but not limited to regulating homeostasis, managing inflammation and the immune system, moderating metabolism, and influencing tumor progression. In this review, we initially outline the rapidly advancing computational analytical methods and public tools to predict and validate the potential encoding of lncRNAs. We then focus on the diverse functions of micropeptides and their underlying mechanisms in the pathogenesis of disease. This review aims to elucidate the functions of lncRNA-encoded micropeptides and explore their potential applications as therapeutic targets in cancer.

In the present research, the Nb-Si-Ti-Cr-Al-Ta-Hf alloys with different Ho addition were prepared. Their microstructure, compressive properties and oxidation behaviors were investigated preliminarily. The results exhibit that the Nb-Si-Ti-Cr-Al-Ta-Hf alloy has coarse microstructure which is mainly composed of Nb solid solution, Nb5Si3 and Ti5Si3 phases. The minor Ho addition could refine the microstructure and suppress the precipitation of Ti5Si3 phase. Moreover, the Ho addition also leads to the formation of Ho2Hf2O7, which prefers to precipitate along the Nbss/Nb5Si3 phase interface. Compared with the Nb-Si-Ti-Cr-Al-Ta-Hf alloy, the minor Ho addition improves the room-temperature and high-temperature compressive properties of the alloy. Its room-temperature compressive strength and ductility obtain the maximum value of 1825 MPa and 16.5% when the Ho content is 0.1 at.%. Moreover, its best compressive strength at 873 K, 1273 K and 1473 K is 1495 MPa, 765 MPa and 380 MPa, respectively, when the Ho addition is 0.1 at.%. The oxidation behavior of the Nb-Si-Ti-Cr-Al-Ta-Hf alloy is diversified with the Ho addition. The oxidation rate of the alloy with 0.1 at.% Ho addition is the lowest while the alloy with 0.2 at.% Ho addition is the highest. Therefore, the 0.1 at.% Ho would be the appropriate content for the Nb-Si-Ti-Cr-Al-Ta-Hf alloy.

The Parker-Oldenburg method, as a classical frequency-domain algorithm, has been widely used in Moho topographic inversion. The method has two indispensable hyperparameters, which are the Moho density contrast and the average Moho depth. Accurate hyperparameters are important prerequisites for inversion of fine Moho topography. However, limited by the nonlinear terms, the hyperparameters estimated by previous methods have obvious deviations. For this reason, this paper proposes a new method to improve the existing Parker-Oldenburg method by taking advantage of the invasive weed optimization algorithm in estimating hyperparameters. The synthetic test results of the new method show that, compared with the trial and error method and the linear regression method, the new method estimates the hyperparameters more accurately, and the computational efficiency performs excellently, which lays the foundation for the inversion of more accurate Moho topography. In practice, the method is applied to the Moho topographic inversion in the South China Sea. With the constraints of available seismic data, the crust-mantle density contrast and the average Moho depth in the South China Sea are determined to be 0.535 g/cm3 and 21.63 km, respectively, and the Moho topography of the South China Sea is inverted based on this. The results of the Moho topography show that the Moho depth in the study area ranges from 5.7 km to 32.3 km, with more obvious undulations. Among them, the shallowest part of the Moho topography is mainly located in the southern part of the Southwestern sub-basin and the southern part of the Manila Trench, with a depth of about 6 km. Compared with the CRUST 1.0 model and the model calculated by the improved Bott’s method, the RMS between the Moho model and the seismic point difference in this paper is smaller, which proves that the method in this paper has some advantages in Moho topographic inversion.

In this article, the elastocaloric effect of a commercial superelastic NiTi shape memory alloy (SMA) tube (with an outer diameter of 5 mm and wall thickness of 1 mm) to be applied in a compressive cooler was measured and analyzed. The elastocaloric effect of the tube was measured vs the applied strain and strain rate. The largest temperature changes of 21 K during loading and 16 K during unloading were measured at an applied strain of 3.30% and strain rate of 0.33 s−1. In the fatigue testing of the sample, only 0.20% of the residual strain accumulated after a runout of 1 × 106 sinusoidal force-controlled loading–unloading cycles at a maximum compressive stress of 1100 MPa and frequency of 20 Hz. Numerical results of the cooling characteristics of a compressive device using a single NiTi tube with the above-mentioned cross section and an aspect ratio of 60:1 as the refrigerant showed that the device could produce a total cooling power of up to 20 W and a coefficient of performance of up to 6.5. The results of this article demonstrate that superelastic NiTi SMA tubes of suitable wall thickness and aspect ratios are good candidates to be applied in a compressive elastocaloric cooler.

Abstract Background Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined. Methods CRISPR-Cas9 and shRNA mediated knockout and knockdown of PLA2G3 in OC cells were used to evaluate lipid droplet (LD) biogenesis by confocal and Transmission electron microscopy analysis, and the cell viability and sensitization of the cells to platinum-mediated cytotoxicity by MTT assay. Regulation of primary ciliation by PLA2G3 downregulation both genetically and by metabolic inhibitor PFK-158 induced autophagy was assessed by immunofluorescence-based confocal analysis and immunoblot. Transient transfection with GFP-RFP-LC3B and confocal analysis was used to assess the autophagic flux in OC cells. PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Efficacy of PFK158 alone and with platinum drugs was determined in patient-derived primary ascites cultures expressing PLA2G3 by MTT assay and immunoblot analysis. Results Downregulation of PLA2G3 in OVCAR8 and 5 cells inhibited LD biogenesis, decreased growth and sensitized cells to platinum drug mediated cytotoxicity in vitro and in in vivo OVCAR5 xenograft. PLA2G3 knockdown in HeyA8MDR-resistant cells showed sensitivity to carboplatin treatment. We found that both PFK158 inhibitor-mediated and genetic downregulation of PLA2G3 resulted in increased number of percent ciliated cells and inhibited cancer progression. Mechanistically, we found that PFK158-induced autophagy targeted PLA2G3 to restore primary cilia in OC cells. Of clinical relevance, PFK158 also induces percent ciliated cells in human-derived primary ascites cells and reduces cell viability with sensitization to chemotherapy. Conclusions Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis.

Abstract PD‐1/PD‐L1 (programmed cell death‐1 and programmed death‐ligand 1) inhibitors utilization in neoadjuvant therapy has been assessed in tumors. This study focused on the clinical benefits of neoadjuvant anti‐PD‐1/PD‐L1 therapy. A comprehensive search was conducted in electronic databases to identify eligible studies. Major response rate (MRR) and complete response rate (CRR) were pooled in this analysis to assess the efficacy of neoadjuvant anti‐PD‐1/PD‐L1 utilization, all grades and high‐grade adverse events (AEs) were pooled to evaluate its safety. Twenty studies were included in this meta‐analysis, with 828 patients suffering from different tumors. The pooled CRR of triple‐negative breast cancer was 0.569 (95% CI 0.514, 0.624, I2 = 0%) and the pooled MRR of lung cancer was 0.471 (95% CI 0.267, 0.575, I2 = 0%). The most frequent adverse event was fatigue (0.272 95% CI 0.171, 0.402, I2 = 87%), and the most common high‐grade adverse event was febrile neutropenia (0.084 95% CI 0.063, 0.112, I2 = 85%). In conclusion, neoadjuvant anti‐PD‐1/PD‐L1 therapy received satisfactory clinical results in these tumors included.

Abstract The outbreak of coronavirus disease 2019 (COVID-19) triggered by the new member of the coronaviridae family, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created an unprecedented challenge for global health. In addition to mild to moderate clinical manifestations such as fever, cough, and fatigue, severe cases often developed lethal complications including acute respiratory distress syndrome (ARDS) and acute lung injury. Given the alarming rate of infection and increasing trend of mortality, the development of underlying therapeutic and preventive treatment, as well as the verification of its effectiveness, are the top priorities. Current research mainly referred to and evaluated the application of the empirical treatment based on two precedents, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), including antiviral drugs targeting different stages of virus replication, immunotherapy modulating the overactivated inflammation response, and other therapies such as herbal medicine and mesenchymal stem cells. Besides, the ongoing development of inventing prophylactic interventions such as various vaccines by companies and institutions worldwide is crucial to decline morbidity and mortality. This review mainly focused on promising candidates for the treatment of COVID-19 and collected recently updated evidence relevant to its feasibility in clinical practice in the near future.

Abstract Background Given the two different kinds of epiretinal membranes, this study aimed to compare both the structural and functional outcomes of lamellar macular holes with and without lamellar hole-associated epiretinal proliferation (LHEP) after surgery. Method Publications up to July 2020 that compared the surgical outcomes of lamellar macular hole with and without LHEP were included. Forest plots were created by using a weighted summary of proportion meta-analysis. Fixed or random effects models were used on the basis of I2 heterogeneity estimates. Meanwhile, to evaluate the stability of the meta-analysis, a sensitivity analysis was carried out. Results Eight pertinent publications that contained a total of 176 eyes without LHEP and 173 eyes with LHEP were included. They were all retrospective studies and had a follow-up of at least 6 months. In all studies, the preoperative best corrected visual acuity showed no significant differences between the two groups, and the visual acuity improved in both groups after surgery. The pooled result for the improved best corrected visual acuity was 0.18 (95% confidence interval (CI), 0.10 to 0.26; P

Summary: Ovarian cancer (OC) is a heterogeneous disease with the highest mortality rate and the poorest prognosis among gynecological malignancies. Because of the absence of specific early symptoms, most OC patients are often diagnosed at late stages. Thus, improved biomarkers of OC for use in research and clinical practice are urgently needed. The last decade has seen increasingly rapid advances in sequencing and biotechnological methodologies. Consequently, multiple omics technologies, including genomic/transcriptomic sequencings and proteomic/metabolomic mass spectra, have been widely applied to analyze tissue- and liquid-derived samples from OC patients. The integration of multi-omics data has increased our knowledge of the disease and identified valuable OC biomarkers. In this review, we summarize the recent advances and perspectives in the use of multi-omics technologies in OC research and highlight potential applications of multi-omics for identifying novel biomarkers and improving clinical assessments.

Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair of DNA double-strand breaks. Loss of BRCA1 is lethal to embryos due to extreme genomic instability and the activation of p53-dependent apoptosis. However, the apoptosis is resisted in BRCA1-deficient cancer cells even though their p53 is proficient. In this study, by analysis of transcriptome data of ovarian cancer patients bearing BRCA1 defects in TCGA database, we found that cAMP signaling pathway was significantly activated. Experimentally, we found that BRCA1 deficiency caused an increased expression of ADRB1, a transmembrane receptor that can promote the generation of cAMP. The elevated cAMP not only inhibited DNA damage-induced apoptosis through abrogating p53 accumulation, but also suppressed the proliferation of cytotoxic T lymphocytes by enhancing the expression of immunosuppressive factors DKK1. Inhibition of ADRB1 effectively killed cancer cells by abolishing the apoptotic resistance. These findings uncover a novel mechanism of apoptotic resistance in BRCA1-deficient ovarian cancer cells and point to a potentially new strategy for treating BRCA1-mutated tumors.

In this paper, we propose a novel method for planning grinding trajectories on curved surfaces to improve the grinding efficiency of large aluminum alloy surfaces with welds and defect areas. Our method consists of three parts. Firstly, we introduce a deficiency positioning method based on a two-dimensional image and three-dimensional point cloud, which enables us to accurately and quickly locate the three-dimensional defective areas. Secondly, we propose a 2D weld positioning method based on the defect area and obtain the spatial position of the 3D weld by combining the relationship between 2D and 3D images. Additionally, we propose an orthogonal projection method from the point cloud to the aluminum alloy surface to calculate the weld reinforcement. Thirdly, we present a space spiral grinding trajectory planning method for complex curved surfaces based on the characteristics of the weld reinforcement, spatial position, and spatial position information of the defect area. This method shortens the grinding time of the defect area and improves efficiency. Simulation and experimental results show that our grinding trajectory planning method is more efficient than other grinding methods in removing defects from the surface of aluminum alloys. Moreover, the defect area after grinding is smoother than before.

Individuals' capacity to participate in leisure activities is contingent upon their ability to overcome obstacles. It is worthwhile to investigate how individuals perceive constraints on their leisure activities participation during the COVID-19 pandemic. This study demonstrates that the connotation of leisure constraints during pandemic includes personal health concerns, shock on economic revenue, reduced freedom of travel, and inconvenience associated with epidemic prevention. Reduced travel freedom is the most influential factor on participation intentions, followed by personal health concerns. Significant differences in perceptions of constraints are observed between groups with different characteristics.

Abstract Background Helicobacter pylori (H. pylori) is thought to have an oncogenic effect on the development of gastric malignancies. However, the effect of H. pylori status on the prognosis of gastric diffuse large B-cell lymphoma (DLBCL) remains unconfirmed. This study aimed to identify the prognostic importance of H. pylori infection in de novo gastric DLBCL. Methods One hundred and twenty-nine patients diagnosed with primary de novo gastric DLBCL at the West China Hospital of Sichuan University from 1st January 2009 to 31st May 2016 were included. The clinical features of the patients were documented. H. pylori status was assessed via urease breath tests and histologic examinations. The prognostic value of H. pylori was verified via univariate and multivariate analyses. Results Over a median follow-up of 52.2 months (range 4–116), the 5-year overall survival (OS) for all patients was 78.7%. Patients with H. pylori infections had significantly better 5-year PFS and OS than did the H. pylori-negative subgroup (5-year PFS, 89.3% vs. 74.1%, P = 0.040; 5-year OS, 89.7% vs. 71.8%, P = 0.033). Negative H. pylori status and poor ECOG performance were independent negative prognostic indicators for both PFS and OS (PFS, P = 0.045 and P = 0.001, respectively; OS, P = 0.021 and P

ObjectivesThe purpose of this study aimed at investigating the reliability of radiomics features extracted from contrast-enhanced CT in differentiating pancreatic cystadenomas from pancreatic neuroendocrine tumors (PNETs) using machine-learning methods.MethodsIn this study, a total number of 120 patients, including 66 pancreatic cystadenomas patients and 54 PNETs patients were enrolled. Forty-eight radiomic features were extracted from contrast-enhanced CT images using LIFEx software. Five feature selection methods were adopted to determine the appropriate features for classifiers. Then, nine machine learning classifiers were employed to build predictive models. The performance of the forty-five models was evaluated with area under the curve (AUC), accuracy, sensitivity, specificity, and F1 score in the testing group.ResultsThe predictive models exhibited reliable ability of differentiating pancreatic cystadenomas from PNETs when combined with suitable selection methods. A combination of DC as the selection method and RF as the classifier, as well as Xgboost+RF, demonstrated the best discriminative ability, with the highest AUC of 0.997 in the testing group.ConclusionsRadiomics-based machine learning methods might be a noninvasive tool to assist in differentiating pancreatic cystadenomas and PNETs.

SARS-CoV-2, a member of the family coronaviridae, has triggered a lethal pandemic termed coronavirus disease 2019 (COVID-19). Pediatric patients, mainly from families with a cluster of infection or a history of exposure to epidemic areas, get infected via direct contacts or air-borne droplets. Children (aged below 18 years) are susceptible to COVID-19, with an average incubation period of about 6.5 days. Most cases present asymptomatic or common cold symptoms such as fever, cough, and myalgia or fatigue, which is milder than adult patients. Besides, most abnormal laboratory and radiologic findings in children with COVID-19 are non-specific. Since no specific chemotherapeutic agents have been approved for children, timely preventive methods could effectively forestall the transmission of SARS-CoV-2. To date, mostly studied cases have been adults with COVID-19, whereas data on pediatrics patients remain poorly defined. We herein conducted a literature review for papers published in PubMed and medRxiv (preprints) between December 2019 and December 2020 that reported on pediatrics patients (aged below 18 years) with a confirmed COVID-19 diagnosis. In this review, we summarized and discussed the pathogenesis, epidemiology, and clinical management of COVID-19 in pediatrics patients to improve our understanding of this new disease in children.

BackgroundCurcumin, one of the promising candidates for supplementary therapy in cancer treatment, has been demonstrated by numerous preclinical and clinical evidence to be beneficial in treating various cancers. Apart from the critical role in a deluge of pathological processes, some mRNAs, in particular, microRNAs (miRNAs), are also involved in the anti-tumor activity. Therefore, our research focused on the possible effects of curcumin on small cell lung cancer (SCLC) cells and drew a comprehensive transcriptomes profile by high throughput sequencing to understand the molecular mechanism of curcumin as an anti-tumor agent.MethodsFirst, we calculated the apoptosis rate of H446 cells (a human SCLC cell line) cultured with curcumin. The high output sequencing uncovered the altered expression profile of genes and miRNAs. KEGG analysis selected the potential signal pathway associated with the antiproliferative property of curcumin. Finally, miRNAs significantly changed, as well as the regulatory roles of those miRNAs in cell apoptosis were determined.ResultThe apoptosis rate of H446 cells increased under the elevated concentration of curcumin treatment. And cell cycle-related genes downregulated in the curcumin-treated cells. Besides, miRNA-548ah-5p of a high level acted as a negative role in the anticarcinogenic activity of curcumin.ConclusionOur findings not only enriched the understanding of anti-tumor activity initiated by curcumin through figuring out the downregulated cell cycle-related pathways but also shed light on its novel therapeutic application.

Objectives: This study compared the diagnostic ability of image-based parameters with texture parameters in the differentiation of hepatocellular carcinoma (HCC) and hepatic lymphoma (HL) by positron emission tomography–computed tomography (PET/CT).Methods: Patients with pathological diagnosis of HCC and HL were included in this study. Image-based and texture parameters were obtained by manual drawing of region of interest. Receiver operating characteristic (ROC) was used to test the diagnostic capacity of each parameter. Binary logistic regression was used to transform the most discriminative image-based parameters, texture parameters, and the combination of these parameters into three regression models. ROC was used to test the diagnostic capacity of these models.Result: Ninety-nine patients diagnosed with HCC (n = 76) and HL (n = 23, 10 primary HL, 13 secondary HL) by histological examination were included in this study (From 2011 to 2018, West China hospital). According to the AUC and p-value, 2 image-based parameters and five texture parameters were selected. The diagnostic ability of texture-based model was better than that of image-based model, and after combination of those two groups of parameters the diagnostic capacity improved.Conclusion: Texture parameters can differentiate HCC from HL quantitatively and improve the diagnostic ability of image-based parameters.

In the present research, the carbon fiber reinforced thermoplastic (CFRTP) was laser joined with the Al alloy whose joining interface was pretreated by laser micro-texturing, anodizing, and hybrid of laser micro-texturing and anodizing. The surface morphology of the pretreated Al joining interface and bonding strength of the corresponding Al/CFRTP butt joint were investigated. The results show that the laser micro-texturing has fabricated the micro-pit or micro-furrow in the Al joining interface. With the increasing of laser scanning times, the size of the micro-pit or micro-furrow decreases, when the laser scanning distance is constant. The bonding strength of the Al/CFRTP butt joint with Al joining interface pretreated by micro-texturing fluctuates with the increasing of laser scanning distance and times, reaching the maximum value of 20 MPa at laser scanning distance of 0.1 mm and 1 time. The anodizing pretreatment has formed the Al2O3 oxide layer on the Al joining interface. The Al/CFRTP butt joint with Al joining interface pretreated by anodizing obtains the maximum bonding strength of 11 MPa at anodizing time of 10 min. The hybrid pretreatment of micro-texturing and subsequent anodizing fabricates the regular grid structure with smooth micro-furrow and micro-pit, while the hybrid pretreatment of anodizing and subsequent micro-texturing fabricates the Al joining interface with explosive micro-pit and micro-furrow. The bonding strength of the Al/CFRTP butt joint with hybrid-pretreated Al joining interface is relative better than that of the Al/CFRTP butt joint with anodizing-pretreated Al joining interface but almost lower than that of the Al/CFRTP butt joint with micro-texturing pretreated Al joining interface. Such results should be attributed to the surface morphology of the Al joining interface.

At present, the traditional way of placing building pipe fittings has many problems, such as labor, large space occupation, and insecurity, while the shelves on the market are not easy to remove the high pipe fittings and have low efficiency. In this paper, a new type of pipe laying frame is proposed, which consists of adjusting mechanism, taking mechanism and resetting mechanism. It not only optimizes the defects of the common display rack in the market, but also innovates the fixation and arrangement of the internal pipe fittings. It can not only solve the problems existing in the existing building pipe fitting display rack technology, but also reduce the problems and disadvantages in the use process. Under the actual application, it can improve the placement efficiency of the pipe fittings and reduce the staff, so as to improve the practicability of the rack.