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Wellbores drilled in igneous formation with weak interlayers face significant risk of instabilities. This study aims to investigate the underlying mechanisms of these instabilities by employing a combination of rock mechanics tests and numerical simulation techniques. The mechanical properties of igneous rocks are evaluated to determine core strength parameters and analyze the impact of drilling fluid immersion on core strength. The two-dimensional model of the igneous formation is refined, and theoretical derivations are made, including the linear elasticity principal equation and the extent of the plastic zone within the wellbore. A numerical simulation model is developed using ABAQUS to analyze the wellbore stability of the weak interlayer igneous formation, accounting for drilling fluid immersion and weak interlayer conditions. The numerical simulations focus on four key aspects of the weak interlayer formation: strength, permeability, horizontal in-situ stress anisotropy, and abnormal pore pressure. The study findings indicate that strengthening the weak interlayer effectively mitigates the risk of wellbore instability. Moreover, the permeability of the weak interlayer exhibits minimal impact on wellbore stability within the formation. However, an increase in horizontal in-situ stress anisotropy and the abnormal pore pressure both decrease wellbore stability along the direction of the maximum in-situ stress.

Background Cervical cancer (CC) is the fourth most frequent cancer in women worldwide, Patients with CC, those at an advanced stage or with recurrent disease, have a poor prognosis with limited treatment options. Cuproptosis, which is regulated by mitochondrial ferredoxin 1-mediated protein lipoylation, is a newly discovered form of cell death. This study aimed to explore the potential prognostic value of cuproptosis-related lncRNAs and their relationship to immune microenvironment in cervical cancer.Methods RNA-sequencing data and clinical data of female cervical cancer patients were obtained from The Cancer Genome Atlas (TCGA), and 19 cuproptosis-related genes were obtained from cuproptosis-related studies. 304 CC patients were randomly separated into training or validation cohorts in a 1:1 ratio. Pearson correlation analysis was used to screen out the lncrnas associated with copper-copper mineralization, and correlation analysis was conducted with 711 reported cuproptosis-related lncRNAs. Univariate, LASSO and multivariate Cox regression analyses were used to construct the characteristics of cuproptosis-related lncRNAs in the training cohort, and their prognostic value was further tested in the validation cohort. Patients were divided into high-and low-risk groups based on the median risk score. Independent prognostic analyses, ROC, C-index, and nomogram were carried out to assess the prognostic value of the signature. Subsequently, lncRNAs were analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumour mutation burden (TMB). Finally, we used tumor immune dysfunction and exclusion (TIDE) algorithms on immune escape and immunotherapy of cuproptosis-related lncRNAs for CC.Results A total of 10 cuproptosis-related lncRNAs were obtained, and patients were divided into high-and low-risk groups. We found that high-risk patients had worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Independent prognostic analyses, ROC, C-index, and nomogram showed that the cuproptosis-related lncRNAs can accurately predict the prognosis of patients. The nomogram and heatmap showed a distinct distribution of the high- and low-risk cuproptosis-related lncRNAs. Enrichment analysis showed that the biological functions of lncRNAs are associated with tumor development. Tumor immune microenvironmental analyses the risk score was positively correlated with the number of M0 macrophages, and mast cell activated, negatively correlated with Dendritic cells resting, M1 macrophages, mast cell resting, T cell CD4 memory activated, T cell gamma delta and T cells CD8. we analyzed immune-related functions to evaluate the immune status of the low-risk and high-risk groups, and the results showed that HLA, cytolytic activity, inflammation-promoting, check point, T-cell co-inhibition, APC co-inhibition, APC co-stimulation, CCR, MHC-I, and type I IFN response were significantly more active in the low-risk group than in the high-risk group (p > 0.05). The results of the expression levels of immune checkpoint molecules in high-risk group and low-risk group showed that the expression levels of common immune checkpoint molecules such as PDCD1, CD274, HAVCR2, CTLA4, and TIGIT in low-risk group were all higher than those in high-risk group. In terms of TME scores, immune scores and ESTIMATE scores were higher in low-risk patients than in high-risk patients, with no difference in stromal scores between them, suggesting a higher infiltration of immune cells in the low-risk group. In addition, OS was poorer in patients with low TMB. We were surprised to find that there was a negative correlation between the TIDE and risk scores, further suggesting that high-risk patients might react more actively to immunotherapy.Conclusion We identified a novel cuproptosis-related lncRNA signature which could precisely predict the prognosis of cervical cancer patients. Cuproptosis -related lncRNAs may may provide new insights into clinical applications and immunotherapy.

At present, the Chinese government is vigorously promoting the use of PPP mode to attract social capital and financial capital into the field of forestry, including ecological construction, protection and utilization, which is of great significance for promoting the construction of ecological civilization and the development of both the economy and the society. Because the financing, organization, implementation and environmental factors of PPP forestry projects are relatively complicated, there are certain risks for both the government and social capital. In order to evaluate the risks of China's forestry projects for the government and social capital, 43 risk factors were identified and divided into 4 groups based on Delphi method and questionnaire survey. 23 key risk factors were selected according to the standardized values. Then, the probability of occurrence (PO), impact size (IS) and overall risk level (ORL) of each key factor were determined by fuzzy synthetic evaluation(FSE) method, and each KRF, KRG and overall risk level (ORL) were calculated. Based on the results, "Government Decision Risk" in KRF was the most critical risk factor, and KRG "Financial Risk" was the most critical risk factor group. Overall, fuzzy comprehensive results showed that the ORL of China's forestry PPP project is relatively high. According to the analysis results, countermeasures were put forward. The research results could provide reference for all participants in PPP forestry projects to make decisions, and formulate a comprehensive risk management plan to use limited resources. In addition, this study could expand professional knowledge and enrich relevant results.

Rational and orderly passenger organization in subway station can improve travel efficiency and safety. How to improve the efficiency of security check, which has a significant impact on the passenger organization, to reduce passengers staying time in the terminal level has the potential to improve service satisfaction. The Weidong Station of Line 1 of Nanchang Metro was selected as the research object. Anylogic software was used to simulate the process of arrival, ticket purchase, security check, gate-crossing machine etc. The results indicate that the dynamic adjustment of security checkpoints and fast passage for passengers without luggage can improve the security efficiency and relieve the congestion in the station hall.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder with deficits in social communication and stereotypical behaviors. Whole-brain genome editing to correct single-base mutations and alleviate autistic-like behaviors in animal models has not been achieved. Here we developed an APOBEC-embedded cytosine base editor (AeCBE) system, for converting C·G to T·A base pairs. We demonstrate the effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo. We constructed a Mef2c L35P heterozygous mouse, which exhibited autistic-like behavioral deficits. We programmed AeCBE to edit the mutated C·G base pairs of Mef2cin the mouse brain, via the intravenous injection of blood brain barrier (BBB)-crossing AAV. This treatment restored MEF2C protein levels and reversed impairments in social interactions and repetitive behaviors in Mef2c mutant mice. This work presents an in vivo base editing paradigm in which a single-base mutation in the brain could be successfully corrected. One-Sentence Summary Base editing in vivo in the mouse brain corrects autistic-like behaviors.

Backgrounds: To explore the value of umbilical artery cord blood glucose (UACBG) in predicting hypoglycemia in gestational diabetes mellitus (GDM) and other at-risk newborns, and to provide a cut-off UACBG value for predicting hypoglycemia occurrence. Methods: In this prospective study, we enrolled at-risk infants delivered vaginally, including neonates born to mothers with GDM, premature, macrosomia, and low birth weight. We separated the infants into GDM group and other at-risk group. All subjects underwent UACBG measurement during delivery. Neonatal peripheral blood glucose measurement was performed at 0.5 hand 2 h after birth. The predictive performance of UACBGfor neonatal hypoglycemia was assessed using receiver operating characteristic curve (ROC), area under curve (AUC), sensitivity and specificity. Results: 916 newborns were included, 538 in GDM group and 378 in other at-risk group. For hypoglycemia prediction within 2 h, the best cut-off of UACBG was 4.150 mmol/L, yielding an AUC of 0.688 (95% CI 0.625-0.751). UACBG had a better performance at 0.5 h (AUC 0.757; 95% CI 0.690-0.824). In detail, the AUC was 0.703 in GDM group (95% CI 0.594-0.811), with the optimal cut-off of 4.550 mmol/L. In other at-risk group, the AUC was 0.797（95% CI 0.716-0.877), and the best threshold was 4.350 mmol/L. No significant differences were observed between GDM group and other at-risk group in AUC at 0.5 h, 2 h and within 2 h. Conclusions: UACBG may be an efficient, non-invasive approach to predicting neonatal hypoglycemia within 2 h after birth.

Purpose To explore the value of umbilical artery cord blood glucose (UACBG) in predicting hypoglycemia in gestational diabetes mellitus (GDM) and other at-risk newborns, and to provide a cut-off UACBG value for predicting hypoglycemia occurrence. Methods In this prospective study, we enrolled at-risk infants delivered vaginally, including neonates born to mothers with GDM, premature, macrosomia, and low birth weight. We separated the infants into GDM group and other at-risk group. All subjects underwent UACBG measurement during delivery. Neonatal peripheral blood glucose measurement was performed at 0.5 h and 2 h after birth. The predictive performance of UACBG for neonatal hypoglycemia was assessed using receiver operating characteristic curve (ROC), area under curve (AUC), sensitivity and specificity. Results 916 newborns were included, 538 in GDM group and 378 in other at-risk group. For hypoglycemia prediction within 2 h, the best cut-off of UACBG was 4.150 mmol/L, yielding an AUC of 0.688 (95% CI 0.625–0.751). UACBG had a better performance at 0.5 h (AUC 0.757; 95% CI 0.690–0.824). In detail, the AUC was 0.703 in GDM group (95% CI 0.594–0.811), with the optimal cut-off of 4.550 mmol/L. In other at-risk group, the AUC was 0.797(95% CI 0.716–0.877), and the best threshold was 4.350 mmol/L. No significant differences were observed between GDM group and other at-risk group in AUC at 0.5 h, 2 h and within 2 h. Conclusions UACBG may be an efficient, non-invasive approach to predicting neonatal hypoglycemia within 2 h after birth.

The review is to explore the connection between gestational hypertension diseases (GHD) and small for gestational age (SGA) in twin pregnancies.According to the recommendations of PRISMA, relevant studies were systematically searched through PubMed, Web of Science, Cochrane Library, Embase from inception until January 16, 2022. Subgroup analysis was performed according to chorionicity and diagnostic criteria of SGA. Odds ratios (OR) were assessed to judge the link between GHD and SGA in twin pregnant women. A random-effect model was used to estimate the pooled hazard ratio when there was significant heterogeneity (ISeven articles containing 470 589 twin pregnant women were included. The increased risk of SGA was connected to the twin pregnancies complicated with GHD (OR = 1.57, 95% confidence interval [CI] = 1.10-2.24, p = 0.01). After subgroup analysis, the connection between SGA and GHD had no statistical significance (OR = 1.17, 95% CI = 0.95-1.44, p = 0.14) when the enrolled studies using the SGA diagnosis referred to singleton birth weight, but significant (OR = 2.14, 95% CI = 1.77-2.60, p0.001) in the group using the SGA diagnosis referred to twin birth weight. Stratified by chorionicity, SGA was relevant to GHD in the dichorionic (DC) group (OR = 1.68, 95% CI = 1.17-2.42, p = 0.005), while not in the monochorionic (MC) group (OR = 1.68, 95% CI = 0.93-3.03, p = 0.09). More future articles are warranted to confirm these outcomes.Our review demonstrated that GHD in DC twin pregnancies was related to an enlarged risk of SGA. Two SGA diagnosis references led to different results. Twin pregnancies complicated with GHD were at significantly higher risk of SGA when twin birth weight reference was used.

An unprecedented 1,3-dipole cycloaddition between acyclic CF3-ketimines and N-benzyl azomethine ylide has been allowed by tungsten catalysis, furnishing a range of novel imidazolidines bearing a trifluoromethylated tetrasubstituted carbon center. This reaction appears as one of rare examples that challenging acyclic CF3-ketimines have been engaged in 1,3-cycloaddition reactions. The capability for gram-scale synthesis and variant derivatizations of cycloaddition adducts illustrates the synthetic potential of this approach. This protocol provides a facile access to a rapidly enlarging pool of motifs with a trifluoromethylated fully substituted carbon.

Through a systematic review and meta-analyses, we aimed to analyze the impact of chorionicity on neurodevelopment outcomes.We conducted a comprehensive search strategy through Medline, Embase, Web of Science, and reference lists of the retrieved studies until August 2022. Studies that examined the association between chorionicity and children's neurodevelopment outcomes were included.Twelve studies were included. Monochorionic (MC) twins increased the odds of neurodevelopment impairment, cerebral palsy compared to dichorionic (DC) twins. The differences in neurodevelopmental impairment and cerebral palsy between the two groups disappeared after excluding infants with twin-twin transfusion (TTTS). After fetoscopic laser surgery (FLS) for MC twins, there were no differences too.Compared to DC twins, MC twins were associated with an increased risk of neurodevelopment impairment. MC twins complicated by TTTS were at high risk of neurologic disability, and FLS was an acceptable treatment modality for them.

In order to overcome the complexity of the double auxiliary commutation circuit (DACC) and the coupling of the resonance process of the double auxiliary resonant commutated pole (DARCP) inverter, a modified DARCP inverter topology and its modulation strategy are proposed. The modified topology not only retains the advantage of reliable zero voltage switching (ZVS) turn-off of auxiliary switches and so on, but also realizes the simplification of the DACC and the decoupling of the resonance process. The cost of the inverter and the system oscillation caused by coupling resonance are reduced, and the performance and practicability of the inverter are improved. According to the equivalent circuits of different operation modes under the proposed modulation strategy, the operation principle, the soft-switching implementation condition, and the parameter design method are analyzed. Finally, a 10-kW, 16-kHz soft-switching inverter prototype is built. Experimental results are given to demonstrate the validity of the proposed inverter.

In this article, a new double-tapered rectangular tube (DTRT) with diaphragms is introduced as an energy absorber. The material tensile test and impact test were performed to verify the finite elem...

To realize a soft-switching inverter with the advantages of simple structure, high efficiency, low voltage stress, and easy to control, a novel parallel resonant dc link inverter with the function of pulse current regeneration is proposed in this paper. All switches in the inverter main circuit can achieve zero-voltage-switching (ZVS) turn-on and ZVS turn-off. All switches in the auxiliary commutation circuit (ACC) can achieve soft-switching. The power in the ACC is small. Freewheeling diodes in the inverter turn off under the zero-current condition, which can reduce the reverse recovery loss of freewheeling diodes. In addition, the bulk capacitors are avoided in the circuit and there is no neutral point potential variation problem. At the same time, the zero-voltage duration is independent of the load current, and the time of transition can be selected freely. According to the equivalent circuits in different operation modes under the proposed modulation strategy, the operation principle, soft-switching implementation condition, and parameter design procedure of the proposed inverter are analyzed successively in this paper. Finally, a 10-kW–10-kHz soft-switching inverter prototype with insulated gate bipolar transistor (IGBT)-based switches is built. Experimental results are given to demonstrate the validity and features of the soft-switching inverter.

A double-tapered rectangular tube with diaphragms (DTRTD) for energy absorbance in railway vehicles is proposed. The mean crushing force (MCF) of DTRTD was derived. The code LS-DYNA3D (971) was use...

To realize a soft-switching inverter with the advantages of a simple structure, high efficiency, low-voltage stress, and easy to control, a novel parallel resonant dc-link inverter with the function of pulse current regeneration is proposed in this paper. All switches in the inverter main circuit can achieve zero-voltage switching (ZVS) turn- on and ZVS turn- off . In addition, all switches in the auxiliary commutation circuit (ACC) can achieve soft switching. The power in the ACC is small. Freewheeling diodes in the inverter turn off under zero current condition, which can reduce the reverse recovery loss of freewheeling diodes. In addition, the bulk capacitors are avoided in the circuit and there is no neutral point potential variation problem. At the same time, the zero-voltage duration is independent of the load current, and the time of transition can be selected freely. According to the equivalent circuits in different operation modes under the proposed modulation strategy, the operation principle, soft-switching implementation condition, and parameter design procedure of the proposed inverter are analyzed successively in this paper. Finally, a 10 kW, 10 kHz soft-switching inverter prototype with insulated gate bipolar transistor based switches is built. Experimental results are given to demonstrate the validity and features of the soft-switching inverter.

CD38 is a multifunctional receptor and enzyme present on the surface of B lymphocytes, which can induce B lymphocytes proliferation and apoptosis by crosslinking related cytokines to affect the function of B cells, thus affecting immune regulation in humans and promoting tumorigenesis. The level of CD38 expression in B cells has become an important factor in the clinical diagnosis, treatment, and prognosis of malignant tumors and other related diseases. Therefore, studying the relationship between CD38 expression on the surface of B cells and the occurrence of the disease is of great significance for elucidating its association with disease pathogenesis and the clinical targeted therapy. In this paper, we review the effects of CD38 on B-cell activation, proliferation, and differentiation, and elaborate the functional role and mechanism of CD38 expression on B cells. We also summarize the relationship between the level of CD38 expression on the surface of B cells and the diagnosis, treatment, and prognosis of various diseases, as well as the potential use of targeted CD38 treatment for related diseases. This will provide an important theoretical basis for the scientific research and clinical diagnosis and treatment of B-cell-related diseases.

During a woman's reproductive period, the endometrial tissue is shed and regenerated every month to prepare for pregnancy or for the next cycle. The aim of the present study was to isolate, culture and characterize human endometrial cells (ECs) derived from menstrual blood (MB) and the endometrium (E). MB-derived ECs (MB-ECs) were isolated from women's MB. E-derived ECs (E-ECs) were isolated from women's endometrial tissues. The present study investigated the epithelial cell marker cytokeratin 18 (CK18) in MB-ECs and E-ECs. Cell proliferation analyses indicated that E-ECs (population doubling time, 20.85 h) grew faster than MB-ECs (population doubling time, 22.05 h; P

The aim of this study was to evaluate the outcome of autotransplantation or replantation of extracted teeth combining with reconstruction of alveolar bone defects in use of artificial bone grafting clinically and radiographically. This article presents a more useful and convenient method for repairing tooth and reconstruction of bone defecting with some interesting cases. Eleven patients (seven men and four women) in whom teeth with complete root formation were extracted and autotransplanted, the bone of receiving area was Insufficient. All transplanted teeth were stabilized with orthodontic wire and resin or 4-0 silk sutures; at the same time, artificial bone powder was filled. In 11 cases, the missing teeth were restored by autogenous teeth and the alveolar bone defect was restored by artificial bone, the improvement in the radiographic and clinical parameters strongly suggest that it may be a useful therapy to solve the problem of the missing teeth and alveolar bone insufficiency simultaneously. However, the risk of replacement root resorption remains.

Objective: To evaluate Coagulation and fibrinolytic parameters after total joint arthroplasty (TJA) and provide evidence for optimization of timing of perioperative anticoagulation medicine. Methods: The prospective study was conducted at the Jishuitan Hospital of Peking University from January to April in 2016, and comprised patients who were scheduled consecutively to undergo primary total knee arthroplasty (TKA) or total hip arthroplasty (THA). Blood samples were obtained at day 1 preoperatively and day1, day 3 postoperatively. Antigenic levels of protein C (PC), endothelial protein C receptor (EPCR), tissue factor pathway inhibitor (TFPI), antithrombin III (AT-III), plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) were measured with commercially available enzyme-linked immunosorbent assay kits. Results: Postoperative levels of coagulation parameters TFPI and AT-III were increased compared to preoperative values (118.7±34.6 vs 70.0±20.5 ?g/ml for AT-III, and 26.37±7.91vs 16.68±8.92 ?g/l for TFPI), while postoperative levels of coagulation parameters PC and EPCR were decreased (0.88±0.30 vs 2.03±0.66 ?g/ml for PC, and 100.8±31.0 vs 199.4±57.4 ?g/ml for EPCR). Postoperative levels of fibrinolytic parameter tPA was increased compared to preoperative values (2.87±0.83 vs 2.03±1.03 ?g/l), while its specific inhibitor PAI-1 was decreased (0.88±0.30 vs 2.03±0.66 ?g/l). Conclusion: These results demonstrated the perturbation of the coagulation and fibrinolytic system of patients undergoing TJA. Hypercoagulation and hyperfibrinolysis were observed in postoperative patients, which suggested anticoagulant therapy is effective and necessary. Keywords?Total joint arthroplasty, anticoagulation, fibrinolysis

Hybrid structures have the advantage of combining different types of materials at the same time. The trend of lightweight design in the transportation industry has promoted the development and application of composite materials with good crashworthiness performance. Low-density crushable foam-filled metal-composite hybrid structures have potential advantages as energy-absorbing components. This study investigated the mechanical characteristics of four different polyurethane foam-filled hybrid structures and their individual components under quasi-static axial compression. The experimental results showed foam-filled hybrid structures could change the deformation mode and improve stability during the compression process. Meanwhile, these hybrid structures could also improve energy absorption compared with their individual components. Among the different configurations, specimen C-PU-C (i.e., polyurethane foam filler between an outer CFRP tube and an inner CFRP tube) had the highest energy absorption capacity, at 5.4 kJ, and specific energy absorption, at 37.3 kJ/kg. Finally, a finite element (FE) model was established to analyze the mechanical characteristics of the hybrid structures by validating the simulation results against the experimental results.

Bruton’s tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases and plays critical roles in B-cell receptor (BCR) signaling. BTK is often overexpressed in B-cells of patients with hematological malignancies. BTK inhibition blocks BCR signals, prevents B-cell activation and malignant B-cell growth, and induces apoptosis. Early irreversible BTK inhibitors such as ibrutinib, which covalently binds to the cysteine residue (C481) of BTK, are effective against B-cell malignancies and have received approval for various B-cell lymphomas and leukemia including mantle cell lymphoma and chronic lymphocytic leukemia, but their effectiveness is often limited by toxicities from off-target inhibition of the Tec (e.g., ITK/TEC) and EGFR family (e.g., EGFR/HER2/HER4). Acquired resistance mutations in the C481 binding site are known to cause clinical resistance to irreversible BTK inhibitors, which accounts for over half of progression in patients received ibrutinib. There is thus unmet medical need for a novel BTK inhibitor with improved safety profile efficacious against C481 mutation. Here we introduce FCN-589, a novel and orally active next-generation BTK inhibitor. FCN-589 shows potent kinase activities against wild-type (WT) BTK and the most common resistant mutation BTK C481S with single-digit nanomolar IC50 and improved selectivity over clinically significant off-targets such as TRK and ITK compared with nemtabrutinib (MK-1026, ARQ 531), another BTK C481S inhibitor in development. FCN-589 exhibits remarkable anti-proliferating potency against a panel of human B-cell malignancies-derived cancer cell lines. FCN-589 is over 30x more potent against follicular lymphoma cells (DOHH2) and activated B-cell subset of diffuse large B-cell lymphoma (DLBCL) cells (OCI-LY10 and Ri-1), and about 4x more potent against germinal center B-cell like subset of DLBCL cells (SU-DHL-4) compared with ARQ 531. In HEK-293 cell line ectopically expressing WT or BTK C481S, FCN-589 markedly inhibits p-BTK expression with superior activity compared with ARQ 531. Consistently, FCN-589 shows significant and superior anti-tumor activities in mice xenograft models derived from human non-Hodgkin’s lymphomas compared with ARQ 531 and ibrutinib. In non-clinical studies, FCN-589 exhibits good pharmacokinetic (PK) and safety properties. In particular, FCN-589 has longer T1/2 in both rats and dogs, displays improved CYP450 inhibition profile, and is less plasma protein bound compared with ARQ 531. Overall, FCN-589 is a novel next-generation BTK inhibitor targeting WT and BTK C481S. FCN-589 possesses potent in vitro and in vivo anti-cancer activities with better selectivity against clinically significant off-targets and exhibits favorable PK and safety profiles compared with ARQ 531. FCN-589 has potential to be a more effective and safer option for patients with B-cell malignancies. Citation Format: Shu Lin, Haohan Tan, Qihong Liu, Yunling Wang, Bin Liu, Zhifu Li, Zhifang Chen, Xianlong Wang, Xingdong Zhao, Lihua Jiang, Xilei Wang, Tao Cheng, Jiashu Zhou, Weibo Wang. FCN-589, a novel, potent and selective BTK inhibitor, targets BTK C481S for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5438.

Fos-related antigen-1 (FRA-1) is a member of activator protein-1 (AP-1) transcription factor superfamily, and FRA-1 is highly expressed in colon cancer, breast cancer, gastric cancer, lung cancer, bladder cancer, and other tumors. The expression level of FRA-1 is closely related to the processes of tumor cell proliferation, apoptosis, transformation, migration, and invasion, which is a potential therapeutic target and prognostic factor for many tumors. Clarifying the detailed mechanism of action of FRA-1 could provide the theoretical basis for tumor diagnosis, treatment, and prognosis, and is of great significance for the study of tumor etiology and pathogenesis. In this paper, the expression levels and influencing factors of FRA-1 in various tumor tissues and cells are summarized, as well as the effect of FRA-1 expression level on the biological behavior of tumor cells and the signal transduction mechanism. At the same time, the signal transduction mechanism of FRA-1 in inflammation was expounded. In addition, the related metabolites, drugs and non-coding RNA that affect the expression and function of FRA-1 were summarized. Finally, it illustrates that FRA-1 may be taken as a key factor for tumor prognosis and a potential therapeutic target. This review provides a theoretical basis for the systematic understanding of the relationship between FRA-1 and tumors, its function, and possible mechanism.

This study aimed to explore the impact of social participation (SP) on physical functioning and depression among empty-nest elderly taking part in the fourth wave of the China Health and Retirement Longitudinal Survey (CHARLS, 2018). The instrumental variable (IV) method and propensity score matching (PSM) method were used to analyse the impact of SP. The two-stage regression results of the IV method showed that SP has a significant negative impact on the physical functioning scores of empty-nest elderly (&beta, = &minus, 3.539, p &lt, 0.001) and non-empty-nest elderly (&beta, 4.703, p &lt, 0.001), and SP has a significant negative impact on the depression scores of empty-nest elderly (&beta, 2.404, p &lt, 1.957, p &lt, 0.001). The results of the PSM method were basically consistent with the IV method. Compared with non-empty-nest elderly, SP had more positive effects on the depression of empty-nest elderly (Wald &chi, 2 = 6.62, p = 0.010). Providing a friendly and supportive environment for the SP of empty-nest elderly was an important measure to promote healthy ageing. Targeted SP may be one of the greatest opportunities to improve the mental health of empty-nest elderly.

The interaction between Tim-3 on T cell and its ligand, Galectin-9, negatively regulates cellular immune responses. However, the role of Tim-3/Galectin-9 pathway in the immune evasion of cervical cancer remains unknown. This study is to investigate the expression, function, and regulation of Tim-3/Galectin-9 signaling pathway in human papilloma virus (HPV) positive cervical cancer. Flow cytometry showed that Tim-3 expression on T cell and Galectin-9 expression on monocytes in HPV positive cervical cancer patients were significantly higher compared to cervical intraepithelial neoplasia and benign uterine fibroids Tim-3 + CD4+ Th1 cells and Tim-3 + CD8+ T cells in HPV positive cervical cancer patients were significantly reduced after surgery. Serum TGF-β and IL-10 levels were positively correlated with Tim-3 + Treg cells, while IFN-γ and IL-2 were negatively correlated with Tim-3 + Th1 cells. Additionally, Tim-3 + CD4+ T cells were positively correlated with Galectin-9 + monocytes. Survival curve analysis showed that Tim-3 + CD4+ T cells were negatively correlated with patient survival, and closely related to FIGO stage, degree of differentiation, and lymph node metastasis of HPV positive cervical cancer. In vitro experiments showed that by blocking the Tim-3/Galectin-9 pathway, the proliferation of T cells and their ability to express IFN-γ, IL-2, perforin, and granzyme B was significantly restored. In conclusion, high levels of Tim-3 and Galectin-9 in HPV positive cervical cancer patients play roles in the progression of disease by promoting Treg cells to inhibit the cytotoxic function of Th1 and CD8+ T cells. Tim-3/Galectin-9 may serve as a new immunotherapy target for patients with HPV positive cervical cancer.

Accurately and timely diagnosis of plant nitrogen (N) status is imperative for N fertilization management and yield prediction of summer maize. This study was aimed to identify the most sensitive/appropriate spectral band combinations to estimate the N nutrition index (NNI) by comprehensive analyses on canopy spectral reflectance from visible to near-infrared light, to develop the optimum vegetation indices for NNI during V6-V12 growth period, and to validate the regression models for estimating NNI of summer maize by comparing the two methods (direct and indirect) to determine the most appropriate method for practical use. Five multi-locational and multi-N rates (0–320 kg ha−1) field experiments were conducted during three growing seasons (2015, 2016 and 2017) using five summer maize cultivars. The measurements regarding canopy spectral reflectance, plant biomass, and plant N concentration were taken at critical stages of summer maize under the various N treatments. Comprehensive analyses on the different regression models of NNI for normalized difference spectral index (NDSI) and ratio spectral index (RSI) composed of any two bands between 325 and 905 nm of summer maize were made by using the reduced precise sampling method. The NNI values in the present study ranged from 0.68 to 1.15 under different N treatments. The most sensitive spectral bands were located at 710 nm (red edge band) and 512 nm (visible light band) and the optimum spectral vegetation index for estimating NNI was NDSI (R710, R512). The linear regression model between NDSI (R710, R512) and NNI was NNI = 0.95 NDSI (R710, R512) + 0.14. Additionally, the soil-adjusted vegetation index (SAVI) was used to correct NDSI(R710, R512), and the performance of the linear regression model was best when the parameter L (soil-brightness correction factor) of SAVI (R710, R512) was 0.05. The performances of the direct and indirect NNI estimation methods were compared. The validation results showed that the performance of the newly developed vegetation indices (NDSI (R710, R512) and SAVI (R710, R512)(L=0.05)) was the best with the relative root mean square error (RRMSE) values ranging from 11.4% and 13.1% in the direct method; while the performance of the existing vegetation indices (Ratio Vegetation Index II and modified SAVI) were best with RRMSE value of 16.9% in the indirect method. It was concluded that both the direct and indirect methods can be used to estimate NNI of summer maize, but the construction of the newly developed vegetation indices was easier in the direct method. The projected results will provide a technical basis for potential application of remote sensing technology for monitoring and diagnosis of plant N nutrition in summer maize production.

Cervical cancer is one of the most common malignant tumors in women all over the world. However, the exact etiology of cervical cancer remains unclear. The receptor for activated protein kinase C (RACK1) is reported to be involved in tumorigenesis and tumor progression. Besides, the prognostic value of RACK1 in several kinds of tumors has been identified. However, there are limited studies on the functional role of RACK1 in cervical cancer. In this study, we tested the expression level of RACK1 by immunohistochemistry and western blot technologies and find that it is upregulated in cervical cancer. Colony formation and CCK8 assays indicate that RACK1 promotes cell proliferation in CaSki cervical cancer cells. While the silence of RACK1 decreases the cell proliferation in CCK8 analysis. β-galactosidase staining suggests that RACK1 decreases cell senescence in cervical cancer cells. Invasion and migration assay show that RACK1 promotes the invasion and migration of cervical cancer cells. Also, when RACK1 was silenced, it exerts the opposite result. Furthermore, the mRNA expression levels of MMP‑3, MMP‑9 and MMP‑10 were upregulated in RACK1‑overexpressed CaSki cells by qPCR analysis. RACK1 also induces S phase accumulation in cell cycle analysis and suppresses cell apoptosis in cervical cancer cells. Flow cytometry analysis of mitochondria functions suggests that RACK1 increases the mitochondrial membrane potential (Δψm) levels to prevent mitochondrial apoptosis in cervical cancer cells. To explore the possible mechanism of RACK1, we tested and found that RACK1 upregulates the expression of NF-κB, cyclin D1 and CDK4 and downregulates the expression of p53, p38, p21 and STAT1 in cervical cancer cells. These results suggest that RACK1 promotes cell growth and invasion and inhibits the senescence and apoptosis in cervical cancer cells probably by affecting the p53 pathway.

Dual-functional probes, which not only enable visualization of diseased cells but also induce therapeutic cellular responses, are essential to biological studies. In the current work, a conjugated polyelectrolyte, PPET3-N2, was designed and synthesized as a dual-functional probe. The poly(phenylene ethynylene) terthiophene polymer backbone contributes to the polymer's light-harvesting property to ensure the strong fluorescence as well as photosensitization, whereas quantanary ammonium side chains interact with target organelle for localization. As a fluorescent probe, PPET3-N2 was endocytosed to lysosomes through clathrin-mediated endocytosis (CME) and macropinocytosis (MPC) pathways. Colocalization of the probe with commercial fluorescent lysosome labels confirmed that this probe localized on lysosomes with high specificity and photostability. Real-time monitoring of autolysosome formation in autophagic cells was also demonstrated, providing a viable platform for cell-based screening of autophagy inhibitors. Finally, as a photosensitizer, PPET3-N2 can efficiently generate singlet oxygen in living cells upon irradiation of white light, leading to the destruction of lysosome membrane and release of ROS and lysosomal enzymes in cytoplasma, causing cell death.

Background Inappropriate admissions cause excessive utilization of health services compared with outpatient services. However, it is still unclear whether inappropriate admissions cause excessive use of health services compared with appropriate admissions. This study aims to clarify the differences in the hospitalization performances between appropriately admitted inpatients and inappropriately admitted inpatients. Methods A total of 2575 medical records were obtained after cluster sampling in three counties. Admission appropriateness was assessed by appropriateness evaluation protocol (AEP). The propensity score matching (PSM) was computed to match patients in treatment and control group with similar characteristics, and to examine the differences in the utilization of hospitalization services between the two groups. The samples were matched in two major steps in this study. In the first step, total samples were matched to examine the differences in the utilization of hospital services between the two groups using 15 individual covariates. In the second step, PSM was computed to analyze the differences between the two groups in different disease systems using 14 individual covariates. Results For the whole sample, the inappropriate group has lower expenditure of hospitalization (EOH) (difference = − 0.12, p = 0.003) and shorter length of stay (LOS) (difference = − 0.73, p = 0.016) than the appropriate group. For number of clinical inspection (NCI), it has no statistically significant difference (difference = − 0.39, p = 0.082) between the two groups. Among different disease systems, no significant differences were observed between the two groups among EOH, LOS and NCI, except that the EOH was lower in the inappropriate group than that in the appropriate group for surgical disease (difference = − 0.169, p = 0.043). Conclusion Inappropriate admissions have generated excessive health service utilization compared with appropriate admissions, especially for internal diseases. The departments in charge of medical services and hospital managers should pay high attention to the health service utilization of the inappropriately admitted inpatients. Relevant medical policies should be designed or optimized to increase the appropriateness in health care service delivery and precision in clinical pathway management.

This study aimed to evaluate the effects of the differences between two typical payment methods for the new rural cooperative medical scheme (NRCMS) in China on the utilisation of inpatient services. Interrupted time-series analysis (ITSA) and propensity score matching (PSM) were used to measure the difference between two typical payment methods for the NRCMS with regard to the utilisation of inpatient services. After the reform was formally implemented, the level and slope difference after reform compared with pre-intervention (distribution of inpatients in county hospitals (DIC), distribution of inpatients in township hospitals (DIT) and the actual compensation ratio of inpatients (ARCI)) were not statistically significant. Kernel matching obtained better results in reducing the mean and median of the absolute standardised bias of covariates of appropriateness of admission (AA), appropriateness of disease (AD). The difference in AA and AD of the matched inpatients between two groups was &minus, 0.03 (p-value = 0.042, 95% CI: &minus, 0.08 to 0.02) and 0.21 (p-value &lt, 0.001, 95% CI: &minus, 0.17 to 0.25), respectively. The differences in the utilisation of inpatient services may arise owing to the system designs of different payment methods for NRCMS in China. The causes of these differences can be used to guide inpatients to better use medical services, through the transformation and integration of payment systems.