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Abstract In order to solve the problem of logging calibration without a free pipe in the process of acoustic variable density logging and the subjective problem of the free pipe calibration method, this paper studies an attenuation rate calibration method based on acoustic variable density logging. Using the developed acoustic wave probe response relationship device and the acoustic wave probe calibration device, the response consistency of the receiving probe of the acoustic wave instrument and the frequency of the transmitting probe can be calibrated in the laboratory, and the response consistency and frequency calibration coefficient can be obtained. Through this coefficient, the acoustic wave attenuation rate can be derived. After converting the acoustic wave attenuation rate into a relative sound amplitude, the scale coefficients of the well can be obtained. The relative acoustic amplitude of each measuring point in the well can be obtained by using the scale coefficient to evaluate the cementing quality. The acoustic variable density field test of 18 wells in the oilfield shows that the relative acoustic amplitude calculation results obtained by the attenuation rate correlation calibration method are basically consistent with the theoretical values, and the maximum deviation is 6.9%. The deviation is caused by the presence of ahead fluid in the outer annulus of the casing, the presence of trace bubbles in the casing, and the incomplete centering of the instrument. Compared with the traditional free pipe calibration method, the attenuation rate correlation calibration method innovatively replaces the free pipe calibration in the well with the indoor calibration of the acoustic instrument and solves the problem of acoustic variable density calibration when there is no free pipe in cementing quality logging. This method has better accuracy and a greater application range, which lays a foundation for the quantitative interpretation of acoustic variable density.

Abstract With the advancement of precise hepatobiliary surgery concepts, the diagnostic and therapeutic approaches for hepatic echinococcosis have undergone significant transformations. However, whether these changes have correspondingly improved patient outcomes remains unclear. A retrospective analysis of these changes will provide crucial guidance for the prevention and treatment of hepatic echinococcosis. Clinical data from 6 hospitals in Xinjiang region of China from January 2009 to December 2023 were collected and systematically random sampling was conducted. The study was divided into the first stage (2009–2013), the second stage (2014–2018), and the third stage (2019–2023) with a 5-year time node to compare the changes in diagnosis and treatment mode and clinical features. There was no significant difference in the age of onset among patients across different phases (P = 0.759). The frequency of open cystectomy gradually decreased [302 (62.3%), 223 (53.0%), 165 (55.7%), P = 0.015], while the rate of total cystectomy increased steadily [82 (16.9%), 88 (20.9%), 94 (23.7%), P = 0.040]. The proportion of patients admitted due to screening also increased [367 (75.7%), 373 (88.6%), 364 (91.9%), P

Abstract Although the proof-of-concept (POC) phase is critical for the success of translational medical research (TMR), its use remains limited, and clinicians are frequently uncertain about how to seek assistance from POC teams when experiencing difficulties with TMR. Therefore, this study explored clinicians’ awareness of POC and the supportive reference services offered by POC teams. We distributed an internet-based questionnaire to 702 clinicians who conducted TMR between August 2022 and March 2023. Descriptive statistics, chi-square test, Wilcoxon rank sum test, Kruskal–Wallis rank sum test, and stepwise logistic regression analysis were applied. Clinicians’ awareness of POC was low (69.23%). However, young clinicians (aged 21–30 years) with a higher educational level than their colleagues, good understanding of POC, reliance on the hospital’s TMR policy and serviceability, and need or great need for services to identify suitable technology, literature, and intelligence services were likely to choose ‘agree’ over ‘disagree’ regarding the ability for POC services to help solve difficulties with TMR. Favourable conditions should be created to encourage clinicians to fully use POC services, and clinicians should actively acquire POC knowledge to enhance their understanding of the value of POC services in TMR. Notably, promoting the establishment of POC centres or platforms at the national level would facilitate the use of POC services by clinicians conducting TMR.

Abstract Background We aimed to study the prognostic risk factors affecting patients with anaplastic thyroid carcinoma (ATC), develop a clinical prognostic model, and assess patient survival outcomes. Methods Patients with anaplastic thyroid carcinoma from 2000 to 2019 were selected from the Surveillance, Epidemiology, and End Results (SEER) Program to extract the clinical variables used for analysis. The dataset was divided into training (70%) and validation (30%) sets based on a 7:3 ratio. Univariate and LASSO regression analyses were performed on clinical variables from the training set to identify independent prognostic factors. Independent prognostic factors were determined by Univariate and lasso regression according to the clinical variables of the training set, and a nomogram model was established to construct a prognostic model based on the contribution degree of the predictors. The prognostic model was evaluated and internally verified by C-index, ROC curve and calibration curve. Results A total of 713 ATC patients were included in the SEER database. LASSO regression results indicated that age, marital status, race, tumor size, whether the primary lesion was limited to the thyroid gland, surgery, radiotherapy and chemotherapy, were associated with overall survival(OS) prognosis of ATC, and were used to construct nomograms. In the training cohort, the OS nomogram’s C-index was 0.708 (95% CI 0.672–0.745); in the internal validation cohort, the C-index was 0.677 (95% CI 0.620–0.735). ROC curves demonstrated that the OS nomogram exhibits excellent predictive accuracy and discriminative ability. Calibration curves indicated strong consistency between the OS nomogram’s predicted survival rates and actual survival rates. Conclusions We established a survival prediction model for ATC, which can assist clinicians in assessing patient prognosis and making personalized treatment decisions.

Abstract Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-β1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-β1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

In this paper, a new hybrid meta-heuristic algorithm called CEBWO (cross-entropy method and beluga whale optimization) is presented to solve the mean-CVaR portfolio optimization problem based on jump-diffusion processes. The proposed CEBWO algorithm combines the advantages of the cross-entropy method and beluga whale optimization algorithm with the help of co-evolution technology to enhance the performance of portfolio selection. The method is evaluated on 29 unconstrained benchmark functions from CEC 2017, where its performance is compared against several state-of-the-art algorithms. The results demonstrate the superiority of the hybrid method in terms of solution quality and convergence speed. Finally, Monte Carlo simulation is employed to generate scenario paths based on the jump-diffusion model. Empirical results further confirm the effectiveness of the hybrid meta-heuristic algorithm for mean-CVaR portfolio selection, highlighting its potential for real-world applications.

Abstract The reorientation of Earth through rotation of its solid shell relative to its spin axis is known as True polar wander (TPW). It is well-documented at present, but the occurrence of TPW in the geologic past remains controversial. This is especially so for Late Jurassic TPW, where the veracity and dynamics of a particularly large shift remain debated. Here, we report three palaeomagnetic poles at 153, 147, and 141 million years (Myr) ago from the North China craton that document an ~ 12° southward shift in palaeolatitude from 155–147 Myr ago (~1.5° Myr−1), immediately followed by an ~ 10° northward displacement between 147–141 Myr ago (~1.6° Myr−1). Our data support a large round-trip TPW oscillation in the past 200 Myr and we suggest that the shifting back-and-forth of the continents may contribute to the biota evolution in East Asia and the global Jurassic–Cretaceous extinction and endemism.

Hepatocellular carcinoma (HCC) is the major cause of cancer-associated mortality worldwide. Despite great advances have been made on the treatment of HCC, the survival rate of patients remains poor. Spindle apparatus coiled-coil protein 1 (SPDL1) is involved in the development of various cancers in humans. However, the role of SPDL1 in HCC remains unclear. In this study, we found high expression of SPDL1 in HCC tissues as compared to normal samples. In vitro, silencing of SPDL1 induced HCC cell apoptosis, and suppressed HCC cell propagation and migration. In vivo, knockdown of SPDL1 inhibited the tumor growth of HCC cells. These findings indicated the tumor-promoting role of SPDL1 in HCC. Mechanistically, we identified farnesyltransferase-beta (FNTB) as the downstream target protein of SPDL1 based on immunoprecipitation and mass spectrometry, which were confirmed by western blotting. Rescue assay determined that FNTB played a tumor promoting role in SPDL1-trigger HCC cell growth. Overexpression of FNTB recovered HCC cell viability and migration in SPDL1 knockdown cells. We also found that silencing of SPDL1 increased the sensitivity of Huh7 cells to sorafenib and lenvatinib, suggesting that SPDL1 is a new therapeutic target in HCC. Collectivity, the present study identified a new axis SPDL1/FNTB involved in the progression of HCC. Hence, SPDL1/FNTB is a potential target for the treatment of HCC.

Abstract Chemodynamic therapy (CDT) is seriously limited by the inadequacy of exogenous catalytic ions and endogenous H2O2 in tumors. Herein, a multifunction nano-bomb integrated with calcium peroxide (CaO2) and β-lapachone as donors of H2O2 and GSH-sensitive Fe-based coordination polymer as provider of catalytic ions was constructed for dual cascade-amplified tumor CDT. This hyaluronic acid (HA)-modified nano-bomb could be specially endocytosed by breast cancer cells through a targeting pathway, degraded and released cargoes in response to the GSH-rich cytoplasm. Furthermore, the released CaO2 and β-lapachone could significantly self-generated sufficient H2O2, which could dual-cascade amplify CDT and induce severe oxidative to tumors via cooperating with the delivered iron ions from nano-bombs. Moreover, the unloaded iron and calcium ions could further accelerate tumor damage by overloading Ca2+ and ferroptosis, as accompanied by good magnetic resonance imaging (MRI). In vitro and in vivo studies collectively reveal that this nano-bomb not only self-initiates double cascade-amplified CDT via self-generation of H2O2, but also efficiently activates ferroptosis and initiates Ca2+ overloading, consequently significantly tumor growth suppression. This study offers a novel tumor-initiated nano-bomb for dual cascade-amplified CDT and bioimaging with activated ferroptosis and self-supplying H2O2.

Network security situation awareness enables networks to actively and effectively defend against network attacks, relying on the extraction of network situation elements as an initial and decisive step. In existing studies, the stacked sparse autoencoder (SSAE) has been employed to extract features from unlabeled network flows. However, obtaining the optimal hyperparameter combination is challenging due to its numerous hyperparameters. To address this issue, we propose a novel approach named DBO-SSAE that leverages dung beetle optimization (DBO) to select the optimal hyperparameters for SSAE automatically. Applied to the well-known UNSW-NB15 dataset, our model yields an optimal feature subset, which is evaluated across various binary classifiers with different metrics. Experimental results demonstrate that our approach improves accuracy and $\textit{F}_{1}$ -measure by 0.2% to 1.5% while reducing the false negative rate (FNR) and false positive rate (FPR) by 0.06% to 7%, surpassing other feature extraction methods on the same classifier for the UNSW-NB15 dataset. Particularly, in conjunction with a lightweight bidirectional long short-term memory (BiLSTM), our model achieves metrics of 98.84% accuracy, 98.96% $\textit{F}_{1}$ -measure, 1.86% FNR, and 0.6% FPR. This study could provide novel insights into the effective representation of network situation elements and lay the groundwork for a high-efficiency intrusion detection system.

Abstract Background RNA modifications have been proven to play fundamental roles in regulating cellular biology process. Recently, maladjusted N7-methylguanosine (m7G) modification and its modifiers METTL1/WDR4 have been confirmed an oncogene role in multiple cancers. However, the functions and molecular mechanisms of METTL1/WDR4 in acute myeloid leukemia (AML) remain to be determined. Methods METTL1/WDR4 expression levels were quantified using qRT-PCR, western blot analysis on AML clinical samples, and bioinformatics analysis on publicly available AML datasets. CCK-8 assays and cell count assays were performed to determine cell proliferation. Flow cytometry assays were conducted to assess cell cycle and apoptosis rates. Multiple techniques were used for mechanism studies in vitro assays, such as northern blotting, liquid chromatography-coupled mass spectrometry (LC–MS/MS), tRNA stability analysis, transcriptome sequencing, small non-coding RNA sequencing, quantitative proteomics, and protein synthesis measurements. Results METTL1/WDR4 are significantly elevated in AML patients and associated with poor prognosis. METTL1 knockdown resulted in reduced cell proliferation and increased apoptosis in AML cells. Mechanically, METTL1 knockdown leads to significant decrease of m7G modification abundance on tRNA, which further destabilizes tRNAs and facilitates the biogenesis of tsRNAs in AML cells. In addition, profiling of nascent proteins revealed that METTL1 knockdown and transfection of total tRNAs that were isolated from METTL1 knockdown AML cells decreased global translation efficiency in AML cells. Conclusions Taken together, our study demonstrates the important role of METTL1/WDR4 in AML leukaemogenesis, which provides a promising target candidate for AML therapy.

The prolonged practice of continuous potato cropping, coupled with inadequate field management, disrupts the soil bacterial community equilibrium. Such disturbances compromise the resilience of the soil ecosystem, predisposing it to an increased incidence of potato diseases. However, the effects of the phosphorus fertiliser application rate on the rhizosphere soil bacterial community composition of potatoes and the occurrence of potato common scab (CS) have not been adequately studied. Here, diseased field soils from Dingxi and Huidong Counties were collected for potting tests, and field tests were conducted in Huidong County for validation. An examination of the relationship between the bacterial community composition in the potato rhizosphere soil and potato CS under different phosphate fertiliser treatments was conducted using 16S rRNA high-throughput sequencing. The results show that a lower phosphorus fertiliser application rate was more conducive to maintaining soil bacterial community diversity under different phosphorus fertiliser treatments in different habitats. In addition, the relative abundance of the txtA gene increased significantly (p < 0.05) with the increase in the phosphate fertiliser application rate. Field trials conducted in Huidong revealed that treatments F1, F2, and F3 had respective CS incidence rates of 28.33%, 46.67%, and 59.44%, while their corresponding disease severity indices were 7.67, 17.33, and 29.44. Further analysis revealed that the relative abundance of antagonistic genera of pathogenic S. scabies decreased significantly (p < 0.05) with increases in the phosphorus fertiliser application rate. In summary, the correlation between potato CS and changes in the bacterial community of rhizosphere soil was used to determine the optimal phosphorus application rate during potato production, which can provide a scientific basis for the management of phosphorus fertiliser in potato farmland.

Abstract Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential to modulate disease-associated proteins that have previously been considered undruggable, by employing the host destruction machinery. The exploration and discovery of cellular degradation pathways, including but not limited to proteasomes and lysosome pathways as well as their degraders, is an area of active research. Since the concept of proteolysis-targeting chimeras (PROTACs) was introduced in 2001, the paradigm of TPD has been greatly expanded and moved from academia to industry for clinical translation, with small-molecule TPD being particularly represented. As an indispensable part of TPD, biological TPD (bioTPD) technologies including peptide-, fusion protein-, antibody-, nucleic acid-based bioTPD and others have also emerged and undergone significant advancement in recent years, demonstrating unique and promising activities beyond those of conventional small-molecule TPD. In this review, we provide an overview of recent advances in bioTPD technologies, summarize their compositional features and potential applications, and briefly discuss their drawbacks. Moreover, we present some strategies to improve the delivery efficacy of bioTPD, addressing their challenges in further clinical development.

Abstract Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4ΔL12_16) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4ΔL12_16 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4ΔL12_16 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4ΔL12_16 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy.

This paper presents a contraction-based learning control architecture that allows for using model learning tools to learn matched model uncertainties while guaranteeing trajectory tracking performance during the learning transients. The architecture relies on a disturbance estimator to estimate the pointwise value of the uncertainty, i.e., the discrepancy between a nominal model and the true dynamics, with pre-computable estimation error bounds, and a robust Riemannian energy condition for computing the control signal. Under certain conditions, the controller guarantees exponential trajectory convergence during the learning transients, while learning can improve robustness and facilitate better trajectory planning. Simulation results validate the efficacy of the proposed control architecture.

Purpose To examine the accuracy of transperineal magnetic resonance imaging (MRI)-ultrasound (US) fusion biopsy (FB) in identifying men with prostate cancer (PCa) that has reached a clinically relevant stage. Methods This investigation enrolled 459 males. In 210 of these patients (FB group), transperineal MRI/US fusion-guided biopsies were performed on the suspicious region, and in 249 others, a systematic biopsy (SB) was performed (SB group). We compared these groups using Gleason scores and rates of cancer detection. Results PCa cases counted 198/459 (43.1%), including 94/249 (37.8%) in the SB group and 104/210 (49.5%) in the FB group. FB was associated with higher overall diagnostic accuracy relative to SB (88.5% and 72.3%, P = 0.024). FB exhibited greater sensitivity than SB (88.9% and 71.2%, P = 0.025). The area under the curve for FB and SB approaches was 0.837 and 0.737, respectively, such that FB was associated with an 11.9% increase in accuracy as determined based upon these AUC values. Relative to SB, FB was better able to detect high-grade tumors (GS ≥ 7) (78.85% vs. 60.64%, P = 0.025). Conclusion Transperineal MRI-US fusion targeted biopsy is superior to the systematic one as an approach to diagnosing clinically significant PCa, as it is a viable technical approach to prostate biopsy.

Objective： A method based on high-performance liquid chromatography-mass spectrometry was developed for the simultaneous determination of bisphenol A and nonylphenol in food packaging material. Methods: The extraction solvent and extraction method were investigated. Solid-phase extraction （SPE） conditions were optimized. The effects of solid phase extraction column, loading solvent, eluting solvent and elution solvent on the purification effect were systematically analyzed. The samples were ultrasonic extracted with dichloromethaneand cleaned up on a solid-phase extraction （SPE） cartridge equipped with packing material of silicone. The separation was performed on a Venusil MP C18（2）（100 mm×2.1 mm,2.6 μm）by gradient elution with 0.1% ammonia solution and methanol as mobile phase. The analytes were determined with multiple reaction monitoring （MRM） mode under electrospray negative ionization mode and quantified by an internal standard method. Results: The results indicated that good linearities was obtained for bisphenol A and nonylphenol both within the concentration range of 1.0~200.0 μg/L. The average recoveries of each analyte at three spiked levels of 1.0, 10.0, 200.0 μg/kg were in the range of 89.2%~101.2%, with relative standard deviations （RSD） of 3.1%~6.2%. The limits of detection （LODs） and limits of quantification （LOQs） were 0.5 μg/kg and 1.0 μg/kg, respectively. Conclusion: The method was proved to be a simple, accurate and sensitive method and was successfully applied to detect bisphenol A and nonylphenol in food packaging material. It can also provide reference for the determination of bisphenol A and nonylphenol in food.

Abstract Background Adaptation to high-altitude hypobaric hypoxia has been shown to require a set of physiological traits enabled by an associated set of genetic modifications, as well as transcriptome regulation. These lead to both lifetime adaptation of individuals to hypoxia at high altitudes and generational evolution of populations as seen for instance in those of Tibet. Additionally, RNA modifications, which are sensitive to environmental exposure, have been shown to play pivotal biological roles in maintaining the physiological functions of organs. However, the dynamic RNA modification landscape and related molecular mechanisms in mouse tissues under hypobaric hypoxia exposure remain to be fully understood. Here, we explore the tissue-specific distribution pattern of multiple RNA modifications across mouse tissues. Results By applying an LC-MS/MS-dependent RNA modification detection platform, we identified the distribution of multiple RNA modifications in total RNA, tRNA-enriched fragments, and 17–50-nt sncRNAs across mouse tissues; these patterns were associated with the expression levels of RNA modification modifiers in different tissues. Moreover, the tissue-specific abundance of RNA modifications was sensitively altered across different RNA groups in a simulated high-altitude (over 5500 m) hypobaric hypoxia mouse model with the activation of the hypoxia response in mouse peripheral blood and multiple tissues. RNase digestion experiments revealed that the alteration of RNA modification abundance under hypoxia exposure impacted the molecular stability of tissue total tRNA-enriched fragments and isolated individual tRNAs, such as tRNAAla, tRNAval, tRNAGlu, and tRNALeu. In vitro transfection experiments showed that the transfection of testis total tRNA-enriched fragments from the hypoxia group into GC-2spd cells attenuated the cell proliferation rate and led to a reduction in overall nascent protein synthesis in cells. Conclusions Our results reveal that the abundance of RNA modifications for different classes of RNAs under physiological conditions is tissue-specific and responds to hypobaric hypoxia exposure in a tissue-specific manner. Mechanistically, the dysregulation of tRNA modifications under hypobaric hypoxia attenuated the cell proliferation rate, facilitated the sensitivity of tRNA to RNases, and led to a reduction in overall nascent protein synthesis, suggesting an active role of tRNA epitranscriptome alteration in the adaptive response to environmental hypoxia exposure.

Abstract Background Nonalcoholic Fatty Liver Disease (NAFLD) is a chronic Liver Disease prevalent all over the world. It has become more and more common in Japan, China and most western developed countries. The global prevalence rate is 25.24%, and the trend is increasing year by year. Related studies have shown that Cynarine has certain liver protection, lipid lowering and immune intervention effects. So, this study to systematically predict and analyze the mechanism of Cynarine in the treatment of non-alcoholic fatty liver disease (NAFLD) based on the integration of network pharmacology, molecular docking, and cell experiment. Methods We performed Heatmap and Venn diagram analyses to identify genes and targets in Cynarine treat NAFLD. The network of Cynarine-therapeutic targets and the protein-protein interaction network (PPI) was constructed. We used gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to visualize associated functional pathways. The Sybyl tool was used to dock the Cynarine with key therapeutic targets molecularly. Finally, cell experiments were applied to validate the role of Cynarine in the treatment of NAFLD. Results The Cynarine could act on 48 targets of NAFLD, and the role of CASP3, TP53, MMP9, ELANE, NOTCH1 were more important. The PPI network showed that immune and inflammation-related targets played a pivotal role. The KEGG analysis found that the PI3K-Akt signaling pathway, cell cycle and MAPK signaling pathway may be the main pathways for Cynarine to prevent and treat NAFLD. Molecular docking studies confirmed that Cynarine has good binding activity with therapeutic targets. Cynarine reduced the fat deposition ability of NAFLD model cells, and effectively reduced the levels of ALT and AST released by liver cells due to excessive lipid accumulation. We also found that Cynarine inhibited the expression of AKT1 and MAPK1. Conclusions This study revealed that Cynarine could significantly reduce the fat deposition ability of NAFLD model cells, which may be closely related to the effective regulation of AKT1 and MAPK1 expression by Cynarine.

Abstract Background Protein arginine methyltransferase 5 (PRMT5) is upregulated in multiple tumors and plays a pivotal role in cancer cell proliferation. However, the role of PRMT5 in colorectal cancer remains poorly understood. Methods We detected the expression level of PRMT5 and glycolytic enzymes using online databases and colorectal cancer cell lines by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. And MTT and colony formation assays were conducted to investigate cell proliferation. Then, we evaluated ECAR and OCR levels using a biological energy analyzer to investigate the energy status of colorectal cancer, and the transcriptional regulation was detected by dual luciferase reporter assay and ChIP assay. Finally, the efficacy of combined treatment of tadalafil and 5-FU was verified. Results PRMT5 was highly expressed in colorectal cancer tissues compared with their normal counterparts and correlated with poor prognosis in CRC patients. Then, we demonstrated that PRMT5 knockdown or loss of function attenuated the viability of CRC cells, while overexpression of PRMT5 promoted cell proliferation. Mechanistically, PRMT5 enhanced glycolysis through transcriptionally activating LDHA expression. In addition, the PRMT5 inhibitor, tadalafil, rendered CRC cells sensitive to antitumor agent 5-FU in vitro and in vivo. Conclusions Our data indicates that PRMT5 promoted colorectal cancer proliferation partially through activating glycolysis and may be a potential target for colorectal cancer therapy.

Objective: The study aimed to explore the mechanism of Athelia rolfsii polysaccharides (AEPS) protected against liver of lead-exposed mice. Methods: Mice were randomly assigned into normal control group (NC), model control group (MC), positive control group (PC), AEPS low dose group (LD), AEPS middle dose group (MD), AEPS high dose group (HD), ATRA alone group (ATRA+NC), ATRA intervention group (ATRA+MC), ATRA+AEPS high dose group (ATRA+HD). Lead levels, antioxidant indexes and functional indexes in the liver of lead-exposed mice were determined, the pathological changes were also evaluated by hematoxylin-eosin (HE) staining. The activity of glutathione-s-transferase (GST) and the levels of glutathione (GSH) were also measured. The protein levels of apoptosis-associated proteins and multidrug resistance-associated protein 2 (MRP2) in liver tissues were determined, as well as nuclear factor erythroid-2-related factor 2 (Nrf2) in liver cell nucleus. Results: Low, middle and high dose of AEPS enhanced the lead ion excretion ability of MRP2 participation, decreased lead accumulation in mice liver significantly in a dose dependent manner (P

Abstract Significant progress has been made in the diagnosis and treatment of the drug‐resistant and highly recurrent refractory T cell acute lymphoblastic leukemia (T‐ALL). Primary tumor cell‐derived induced pluripotent stem cells (iPSCs) have become very useful tumor models for cancer research including drug sensitivity tests. In the present study, we investigated the mechanism underlying drug resistance in T‐ALL using the T‐ALL‐derived iPSCs (T‐iPSCs) model. T‐ALL cells were transformed using iPSC reprogramming factors (Sox‐2, Klf4, Oct4, and Myc) via nonintegrating Sendai virus. T‐iPSCs with the Notch1 mutation were then identified through genomic sequencing. Furthermore, T‐iPSCs resistant to 80 μM LY411575, a γ‐secretase and Notch signal inhibitor, were also established. We found a significant difference in the expression of drug resistance‐related genes between the drug‐resistant T‐iPSCs and drug‐sensitive groups. Among the 27 genes, six most differently expressed genes (DEGs) based on Log2FC >5 were identified. Knockdown analyses using RNA interference (RNAi) revealed that MAEL is the most important gene associated with drug resistance in T‐ALL cells. Also, MAEL knockdown downregulated expression of MRP and LRP in drug‐resistant T‐iPSCs. Interestingly, this phenomenon partially restored the sensitivity of the cells to LY411575. Furthermore, overexpression of the MAEL gene enhanced drug resistance against LY411575. Conclusively, MAEL promotes LY411575 resistance in T‐ALL cells increasing the expression of MRP and LRP genes.

Objective: The contents of main active ingredients, antioxidant and cholate binding ability of different ethanol extracts from Psoralea corylifolia L. were explored based on the mode of correlation of “components-efficacy”. Methods: Psoralea corylifolia L. was extracted with anhydrous ethanol, 75% ethanol, 50% ethanol and water. The contents of total flavonoids and total polyphenols in Psoralea corylifolia L. were determined. The antioxidant and lipid-lowering activities in vitro of Psoralea corylifolia L. were evaluated by three antioxidant systems and the binding ability of cholate salts, respectively, and the correlation analysis was conducted. Results: The contents of total flavonoids and total polyphenols in anhydrous ethanol extract were the highest, (50.317±0.018) mg/g and (3.860±0.045) mg/g, respectively. The 50% ethanol extract showed the best ability to scavenge ABTS＋· and DPPH·, the IC50 values were 0.76 and 1.63 mg/mL, respectively. The anhydrous ethanol extract showed the strongest reducing ability, the A0.5 value was 2.63 mg/mL. The water extract showed the strongest binding capacity to sodium cholate, the IC50 value was 0.67 mg/mL. The 50% ethanol extract showed the strongest binding capacity to sodium taurocholate and sodium glycinate, the IC50 values were 1.26 and 0.41 mg/mL, respectively. The correlation results showed that the content of total flavonoids of different ethanol extracts from Psoralea corylifolia L. had a significant positive correlation with DPPH· clearance rate and sodium taurocholate binding rate (P

Abstract Background Cotton production is adversely effected by drought stress. It is exposed to drought stress at various critical growth stages grown under a water scarcity environment. Roots are the sensors of plants; they detect osmotic stress under drought stress and play an important role in plant drought tolerance mechanisms. The seedling stage is very sensitive to drought stress, and it needed to explore the methods and plant characteristics that contribute to drought tolerance in cotton. Results Initially, seedlings of 18 genotypes from three Gossypium species: G. hirsutum, G. barbadense, and G. arboreum, were evaluated for various seedling traits under control (NS) and drought stress (DS). Afterward, six genotypes, including two of each species, one tolerant and one susceptible, were identified based on the cumulative drought sensitivity response index (CDSRI). Finally, growth rates (GR) were examined for shoot and root growth parameters under control and DS in experimental hydroponic conditions. A significant variation of drought stress responses was observed across tested genotypes and species. CDSRI allowed here to identify the drought-sensitive and drought-resistant cultivar of each investigated species. Association among root and shoots growth traits disclosed influential effects of enduring the growth under DS. The traits including root length, volume, and root number were the best indicators with significantly higher differential responses in the tolerant genotypes. These root growth traits, coupled with the accumulation of photosynthates and proline, were also the key indicators of the resistance to drought stress. Conclusion Tolerant genotypes have advanced growth rates and the capacity to cop with drought stress by encouraging characteristics, including root differential growth traits coupled with physiological traits such as chlorophyll and proline contents. Tolerant and elite genotypes of G. hirsutum were more tolerant of drought stress than obsolete genotypes of G. barbadense and G. arboreum. Identified genotypes have a strong genetic basis of drought tolerance, which can be used in cotton breeding programs.

Electrochemically deposited sensors and DNA biosensors have been widely used in the food industry, and various other fields due to their high sensitivity, fast response, easy operation, no pollution, and low price. A rare earth electrochemically deposited gadolinium ferricyanide thin film modified glassy carbon electrode, and the investigation of electrocatalytic oxidation of guanine by GaHCF/GCE is reported. We deposited electrochemically a rare earth terbium ferricyanide thin film modified glassy carbon electrode. OH was investigated through various characteristics such as capacitance–voltage, Differential Pulse Voltammetric and many more by the comparison of catalytic oxidation signal of guanine with ·OH in Fenton reaction.

Objective: The surfactant-assisted ultrasonic extraction of total flavonoids from persimmon leaves was optimized. Methods: With the extraction rate of total flavonoids and DPPH radical scavenging rate as the double-indicator response values, the effects of surfactant type and mass fraction, liquid-to-material ratio, ultrasonic time, and ultrasonic temperature were investigated, and the Box-Behnken design-double response surface methodology was used to optimize the extraction process of total flavonoids from persimmon leaves. Results: The obtained optimal extraction process was as follows: Ethanol volume fraction of 70%, the mass fraction of sodium dodecyl sulfate 0.6%, liquid-to-material ratio of 22:1 mL/g, ultrasonic temperature of 30 ℃ and time of 7.3 min. Under these conditions, the actual extraction rate of total flavonoids from persimmon leaves was (103.63±0.10) mg/g and the DPPH radical scavenging rate was (65.35%±0.12%). Conclusion: The optimized extraction process can effectively improve the yield of total flavonoids from persimmon leaves and provide a theoretical basis for the development and utilization of flavonoids resources from persimmon leaves.

This study aimed to investigate the differences in complications between hepatitis B virus (HBV)-related and alcohol-related cirrhoses.

Objective: Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system, accounting for approximately 70% of acute leukemias. Long noncoding RNA-DUXAP8 (lncRNA-DUXAP8) has been found to be abnormally expressed in a variety of tumors. However, its function and mechanism in AML have not been studied. We investigate the effect of lncRNA-DUXAP8 on AML and its mechanism so as to provide a new theoretical basis for the diagnosis and treatment of AML. Materials and Methods: The expression of lncRNA-DUXAP8 in AML bone marrow tissues and the THP-1, HL-60, TF-1, AML193, and U937 cell lines was detected by qRT-PCR. It was then altered by transfecting plasmids overexpressing si-DUXAP8 and lncRNA-DUXAP8, respectively. CCK8 and cell colony assay were performed to evaluate the proliferation ability of AML cells. In addition, flow cytometry was used to observe the apoptosis process. Glucose and lactate kits were utilized to detect glucose consumption and lactate levels. Finally, western blotting was performed to detect the expression of proteins related to the Wnt/β-catenin signaling pathway in cells. Results: LncRNA-DUXAP8 was downregulated in both AML bone marrow tissues and cell lines. Upon interfering with lncRNA-DUXAP8 in AML cell line THP-1, AML cell proliferation and glycolysis were promoted while cell apoptosis was inhibited. The opposite results were obtained after overexpressing lncRNA-DUXAP8. Meanwhile, western blotting confirmed that interference with lncRNA-DUXAP8 stimulated the expression of proteins Wnt5a, β-catenin, c-Myc, and cyclin-D1 in the Wnt/β-catenin pathway. Moreover, overexpression of lncRNA-DUXAP8 inhibited the expression of Wnt/β-catenin pathway proteins. Finally, LiCl, an activator of the Wnt/β-catenin pathway, reversed the regulation of AML cells by lncRNA-DUXAP8 upregulation compared with the DUXAP group. Conclusion: This study showed that lncRNA-DUXAP8 regulated the Wnt/β-catenin signaling pathway to inhibit glycolysis and induce apoptosis in AML. This experiment has provided new angles and an experimental basis for treating patients with AML.

BackgroundLynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. The definition of Lynch syndrome is based on clinical, pathological, and genetic findings. Therefore, the identification of susceptibility genes is essential for accurate risk assessment and tailored screening programs in LS monitoring.Patients and methodsIn this study, LS was diagnosed clinically in a Chinese family using Amsterdam II criteria. To further explore the molecular characteristics of this LS family, we performed whole genome sequencing (WGS) to 16 members in this family and summarized the unique mutational profiles within this family. We also used Sanger sequencing technology and immunohistochemistry (IHC) to verify some of the mutations identified in the WGS analysis.ResultsWe showed that mutations in mismatch repair (MMR) related genes, as well as pathways including DNA replication, base excision repair, nucleotide excision repair, and homologous recombination were enhanced in this family. Two specific variants, MSH2 (p.S860X) and FSHR (p.I265V) were identified in all five members with LS phenotypes in this family. The MSH2 (p.S860X) variant is the first reported variant in a Chinese LS family. This mutation would result in a truncated protein. Theoretically, these patients might benefit from PD-1 (Programmed death 1) immune checkpoint blockade therapy. The patients who received nivolumab in combination with docetaxel treatments are currently in good health.ConclusionOur findings extend the mutation spectrum of genes associated with LS in MLH2 and FSHR, which is essential for future screening and genetic diagnosis of LS.

Background and aim: Adrenocortical carcinoma (ACC) is uncommon in the elderly. This study aimed to compare the surgical prognosis and survival between senior and younger patients. We also explored the factors that were independently related to the survival of elderly patients.Methods: We identified ACC patients between 2010 and 2019 in the Surveillance, Epidemiology, and End Results (SEER) database and applied Kaplan-Meier curves to evaluate the overall survival (OS) and cancer-specific survival (CSS) with log-rank tests. We also used Cox regression analysis to estimate the OS and CSS. The Fine and Gray model with the Gray test was used to measure the cumulative incidence function (CIF) of CSS and other mortality causes of patients in a competing-risks setting.Results: Of 876 patients, 44.06% were elderly. A lower proportion of elderly patients underwent surgery, regional lymph node surgery, and chemotherapy than young patients. Elderly patients also had inferior OS and CSS than younger patients. The 1- and 5-year OS of elderly patients who underwent surgery were 68% [95% confidence interval (CI): 62%–74%] and 30% (95% CI: 24%–38%), and the 1- and 5-year CSS were 73% (95% CI: 67%–80%) and 40% (95% CI: 32%–47%). The factors independently related to worsened survival included age ≥60 [Hazard Ratio (HR): 1.47 (1.24–1.75)], metastatic disease [HR: 1.90 (1.49–2.51)], higher grade [HR: 1.94 (1.08–3.46)] and Network for the Study of Adrenal Tumors (ENSAT) stage [HR: 1.99 (1.48–2.66)].Conclusion: Younger ACC patients had better survival than the elderly. Factors independently related to worsened survival in elderly patients included age ≥60, metastatic disease, higher grade, and European ENSAT stage.

Abstract A simple and selective liquid chromatography tandem with mass spectrometry (LC-MS/ MS) method for quantification of lobetyolin in rat plasma was developed and validated. Chromatographic separation was achieved on a Thermo ODS C18 reversed-phase column using 0.1% aqueous formic acid-methanol (50:50, v/v) in an isocratic elution mode at a flow rate of 0.4 mL.min-1. LC/MS performance was done in a positive ion ESI mode and the MS/MS transitions were monitored at m/z 419.3 [M+Na]+ → m/z 203.1 for lobetyolin and m/z 394.9 [M+Na]+ → m/z 231.9 for IS, respectively. The assay exhibited a linear dynamic range over 1.0-500 ng.mL-1 for lobetyolin in plasma. Both the precision (%RSD) and accuracy (RE%) were within acceptable criteria (

The objective of this study was to investigate the effects and molecular mechanisms of total flavonoids from Cortex Juglandis Mandshuricae (TFC) on preventing alcohol-induced chronic liver injury and regulating gut microbiota in mice. The results showed that oral administration of TFC significantly attenuated alcoholic liver injury in mice. TFC improved lipid accumulation in mice with chronic alcoholic liver injury through activation of the AMPK/PPARα pathway. In addition, TFC maintained the integrity of the intestinal barrier in alcoholic mice, reducing endotoxin leakage from the intestine and further inhibiting the TLR4/NF-κB inflammatory pathway. More importantly, TFC regulated the intestinal microbiota composition and certain bacteria, including Akkermansia muciniphila, Lactobacillus and others. At the same time, reduced levels of short-chain fatty acids due to alcohol consumption were restored. In summary, TFC upregulated AMPK/PPARα signaling pathway to improve hepatic fat accumulation and oxidative stress; TFC positively regulated intestinal flora composition to reduce intestinal disorders caused by alcohol consumption, and further inhibited alcohol-induced inflammatory responses through the intestinal-liver axis. The above findings may be the mechanism of TFC’s pharmacological effects against alcoholic liver injury.

ObjectiveCognitive impairment (CI) is a common disorder in patients with epilepsy (PWEs). Objective assessment method for diagnosing CI in PWEs would be beneficial in reality. This study proposed to construct a diagnostic model for CI in PWEs using the clinical and the phase locking value (PLV) functional connectivity features of the electroencephalogram (EEG).MethodsPWEs who met the inclusion and exclusion criteria were divided into a cognitively normal (CON) group (n = 55) and a CI group (n = 76). The 23 clinical features and 684 PLVEEG features at the time of patient visit were screened and ranked using the Fisher score. Adaptive Boosting (AdaBoost) and Gradient Boosting Decision Tree (GBDT) were used as algorithms to construct diagnostic models of CI in PWEs either with pure clinical features, pure PLVEEG features, or combined clinical and PLVEEG features. The performance of these models was assessed using a five-fold cross-validation method.ResultsGBDT-built model with combined clinical and PLVEEG features performed the best with accuracy, precision, recall, F1-score, and an area under the curve (AUC) of 90.11, 93.40, 89.50, 91.39, and 0.95%. The top 5 features found to influence the model performance based on the Fisher scores were the magnetic resonance imaging (MRI) findings of the head for abnormalities, educational attainment, PLVEEG in the beta (β)-band C3-F4, seizure frequency, and PLVEEG in theta (θ)-band Fp1-Fz. A total of 12 of the top 5% of features exhibited statistically different PLVEEG features, while eight of which were PLVEEG features in the θ band.ConclusionThe model constructed from the combined clinical and PLVEEG features could effectively identify CI in PWEs and possess the potential as a useful objective evaluation method. The PLVEEG in the θ band could be a potential biomarker for the complementary diagnosis of CI comorbid with epilepsy.

The aim of our study was to examine the production of monocyte chemoattractant protein (MCP-4) and eotaxin-3 during the onset and progression of COPD. The expression levels of MCP-4 and eotaxin-3 were evaluated in COPD samples and healthy controls using immunostaining and ELISA. The relationship between the clinic pathological features in the participants and the expression of MCP-4 and eotaxin-3 were evaluated. The association of MCP-4/eotaxin-3 production in COPD patients was also determined. The results revealed enhanced production of MCP-4 and eotaxin-3 in COPD patients especially the cases with AECOPD in both bronchial biopsies and bronchial washing fluid samples. Furthermore, the expression signatures of MCP-4/eotaxin-3 show high AUC values in distinguishing COPD patients and healthy volunteers and AECOPD and stable COPD cases, respectively. Additionally, the number of MCP-4/eotaxin-3 positive cases was notably increased in AECOPD patients compared to those with stable COPD. Moreover, the expression of MCP-4 and eotaxin-3 was positively correlated in COPD and AECOPD cases. In addition, the levels of MCP-4 and eotaxin-3 could be increased in HBEs stimulated with LPS, which is a risk factor of COPD. Moreover, MCP-4 and eotaxin-3 may exert their regulatory functions in COPD by regulating CCR2, 3, and 5. These data indicated that MCP-4 and eotaxin-3 were potential markers for the clinical course of COPD, which could provide guidance for accurate diagnosis and treatment for this disease in future clinical practice.

The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, HPPPH@L@B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.

In the current industrial revolution, advanced technologies and methods can be effectively utilized for the detection and verification of defects in high-speed steel filament production. This paper introduces an innovative methodology for the precise detection and verification of micro surface defects found in steel filaments through the application of the Eddy current principle. Permanent magnets are employed to generate a magnetic field with a high frequency surrounding a coil of sensors positioned at the filament’s output end. The sensor’s capacity to detect defects is validated through a meticulous rewinding process, followed by a thorough analysis involving scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS). Artificial defects were intentionally introduced into a sample, and their amplitudes were monitored to establish a threshold value. The amplitude signal of these created defect was identified at approximately 10% FSH, which corresponds to a crack depth of about 20 µm. In the experimental production of 182 samples covering 38 km, the defect ratio was notably high, standing at 26.37%. These defects appeared randomly along the length of the samples. The verification results underscore the exceptional precision achieved in the detection of micro surface defects within steel filaments. These defects were primarily characterized by longitudinal scratches and inclusions containing physical tungsten carbide.

A large-scale underwater volcanic eruption occurred at the volcano of Hunga Tonga-Hunga Ha’apai (HTHH) on 15 January 2022. At present, there is no consensus on the ionospheric response characteristics and interaction mechanism during volcanic eruptions. Based on the Global Navigation Satellite System (GNSS), AQUA satellite’s Atmospheric Infrared Sounder (AIRS), the experiment studies the response characteristics of the ionosphere and gravity waves during the eruption of the volcano and their interaction mechanisms and the International Real-Time Geomagnetic Observation Network (INTERMAGNET). First, a geomagnetic anomaly was detected before the eruption, which caused variations in the ionospheric VTEC (Vertical Total Electron Content) by about 15 TECU. Based on the IGS (International GNSS Service) observations, the VTEC distribution between 60° north and south latitudes was retrieved. The results show that before and after the eruption of Tonga Volcano, significant ionospheric anomalies were observed to the south, northwest and southwest of the volcano, with a maximum anomaly of 15 TECU. The study indicates that the geomagnetic anomaly disturbance is one of the precursors of volcanic eruption and has a certain degree of impact on the ionosphere. A correlation between geomagnetic anomalies and ionospheric anomalies was found to exist. The vast impact from the volcanic eruption excites gravity waves over the surface, which then propagate longitudinally, further perturbing the ionosphere. It is also detected that the ionospheric anomaly perturbation has a high coincidence effect with the gravity wave anomaly. Therefore, the gravity waves generated by atmospheric variations are used to explain the ionospheric perturbation phenomenon caused by volcanic eruptions.

Anaerobic digestion (AD) has the advantages of utilizing complex substrates and producing renewable energy and is currently one of the mainstream technologies for food waste (FW) resourcing. However, at high organic loads and low inoculum-to-substrate ratios (ISRs), AD with FW as substrate is prone to acid accumulation, resulting in a drastic decrease in gas production and system collapse. This study investigated the effect of the coupled addition of zero-valent iron (ZVI) and activated carbon (AC) on the AD of FW at three low ISRs of 0.715, 0.625, and 0.5. The results showed that the control group acidified and stopped producing biogas when the ISR decreased to 0.625 and 0.5, but ZVI coupled with AC alleviated the acidification and increased the cumulative biogas yield. Especially at ISR = 0.5, the cumulative biogas yield for the ZVI + AC group was 31.5%, 99.5%, and 11.43 times higher than that of the ZVI, AC, and control groups, respectively. ZVI coupled with AC also increased the degradation of volatile fatty acids (70.5–84.4%) and soluble chemical oxygen demand (50.0–72.9%) while decreasing propionate concentration and improving the stability of the AD system. COD mass balance analyses indicated that the coupled addition of ZVI and AC promoted the conversion of particulate organic matter to soluble organic matter and increased the conversion of carbon sources to methane.

Abstract Background The high misdiagnosis rate of asymptomatic neurosyphilis (ANS) has long challenged infectious disease clinicians. We aim to develop a model for diagnosing ANS in asymptomatic syphilis (AS) patients without CSF indicators. Results 277 AS patients with HIV-negative and underwent lumbar puncture were enrolled in this horizontal study.The area under the curve for predicting ANS by CSF leukocytes and protein was 0.643 and 0.675 [95% CI, 0.583–0.699VS.0.616–0.729]. Through LRM, the AUC increased to 0.806 [95% CI, 0.732–0.832], and the Youden's index was 0.430. If the score is ≤ 0.159, ANS can be excluded with a predictive value of 92.9%; we can identify ANS while the score is over 0.819, with a predictive value of 91.7% and a specificity of 99.25%. This study showed that the LRM can diagnose ANS in AS patients effectively. Conclusion Given a large number of misdiagnosis ANS patients and CSF results' insufficiency, the model is more practical. Our research will help clinicians track suspected syphilis, especially those who cannot accept the CSF test.

Background: The incidence of respiratory diseases and the respiratory disease mortality rate have increased in recent years. Recent studies have shown that long non-coding RNA (lncRNA) MALAT1 is involved in various respiratory diseases. In vascular endothelial and cancer cells, MALAT1 expression triggers various changes such as proinflammatory cytokine expression, cancer cell proliferation and metastasis, and increased endothelial cell permeability.Methods: In this review, we performed a relative concentration index (RCI) analysis of the lncRNA database to assess differences in MALAT1 expression in different cell lines and at different locations in the same cell, and summarize the molecular mechanisms of MALAT1 in the pathophysiology of respiratory diseases and its potential therapeutic application in these conditions.Results: MALAT1 plays an important regulatory role in lncRNA with a wide range of effects in respiratory diseases. The available evidence shows that MALAT1 plays an important role in the regulation of multiple respiratory diseases.Conclusion: MALAT1 is an important regulatory biomarker for respiratory disease. Targeting the regulation MALAT1 could have important applications for the future treatment of respiratory diseases.

Fluorouracil, also known as 5-FU, is one of the most commonly used chemotherapy drugs in the treatment of advanced gastric cancer (GC). Whereas, the presence of innate or acquired resistance largely limits its survival benefit in GC patients. Although accumulated studies have demonstrated the involvement of tumor microenvironments (TMEs) in chemo-resistance induction, so far little is known about the relevance of GC TMEs in 5-FU resistance. To this end, in this study, we investigated the relationship between TME features and 5-FU responses in GC patients using a combined analysis involving both bulk sequencing data from the TCGA database and single-cell RNA sequencing data from the GEO database. We found that depleted extracellular matrix (ECM) components such as capillary/stroma cells and enhanced immune processes such as increased number of M1 polarized macrophages/Memory T cells/Natural Killer T cells/B cells and decreased number of regulatory T cells are two important features relating to 5-FU beneficial responses in GC patients, especially in diffuse-type patients. We further validated these two features in the tumor tissues of 5-FU-benefit GC patients using immunofluorescence staining experiments. Based on this finding, we also established a Pro (63 genes) and Con (199 genes) gene cohort that could predict 5-FU responses in GC with an AUC (area under curve) score of 0.90 in diffuse-type GC patients, and further proved the partial applicability of this gene panel pan-cancer-wide. Moreover, we identified possible communications mediated by heparanase and galectin-1 which could regulate ECM remodeling and tumor immune microenvironment (TIME) reshaping. Altogether, these findings deciphered the relationship between GC TMEs and 5-FU resistance for the first time, as well as provided potential therapeutic targets and predicting rationale to overcome this chemo-resistance, which could shed some light on developing novel precision treatment strategies in clinical practice.

Abstract Invasive cancer growth and metastasis account for the poor prognosis of high‐grade breast cancer. Recently, we reported that kinectin 1 (KTN1), a member of the kinesin‐binding protein family, promotes cell invasion of triple‐negative breast cancer and high‐grade breast cancer cells by augmenting the NF‐κB signaling pathway. However, the upstream mechanism regulating KTN1 is unknown. Therefore, this functional study was performed to decipher the regulatory cohort of KTN1 in high‐grade breast cancer. Bioinformatic analysis indicated that transcription factor Yin Yang 1 (YY1) was a potential transactivator of KTN1. High YY1 expression correlated positively with pathological progression and poor prognosis of high‐grade breast cancer. Additionally, YY1 promoted cell invasive growth both in vitro and in vivo, in a KTN1‐dependent manner. Mechanistically, YY1 could transactivate the KTN1 gene promoter. Alternatively, YY1 could directly interact with a co‐factor, DEAD‐box helicase 3 X‐linked (DDX3X), which significantly co‐activated YY1‐mediated transcriptional expression of KTN1. Moreover, DDX3X augmented YY1‐KTN1 signaling‐promoted invasive cell growth of breast cancer. Importantly, overexpression of YY1 enhanced tumor aggressive growth in a mouse breast cancer model. Our findings established a novel DDX3X‐assisted YY1‐KTN1 regulatory axis in breast cancer progression, which could lead to the development novel therapeutic targets for breast cancer.

Placenta accreta spectrum (PAS) is a high-risk obstetrical complication associated with significant morbidity and mortality. Here the authors discover a uniquely high prevalence of circulating trophoblasts clusters in PAS and explore their diagnostic potential to augment current diagnostic modalities for the early detection of PAS.

Abstract Background Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Recent studies have shown that the polytopic enzyme membrane associated ring-CH-type finger 6 (MARCH6) participates in tumorigenesis, but its function in HCC development needs to be investigated. This study aimed to explore the role of MARCH6 in HCC. Methods Expression of MARCH6 in human HCC samples was checked by immunohistochemical staining assay. Clinical relevance of MARCH6 and activating transcription factor 2 (ATF2) was analyzed from TCGA database. CCK-8, EdU staining, colony formation and transwell were performed to assess cell proliferation, growth and migration. Xenografted tumorigenesis was used to examine in vivo role MARCH6. Immunoblotting was applied to detect protein abundance. Results We found that MARCH6 expression was elevated in human HCC samples. Over-expression of MARCH6 was associated with poor prognosis of HCC patients. Up-expression of MARCH6 promoted cell growth and migration of HCC cells. In contrast, the HCC cell growth and migration were suppressed by MARCH6 knockdown. Furthermore, the DNA synthesis was enhanced by MARCH6. The expression of ATF2 was potentiated by MARCH6 over-expression, while it was suppressed by MARCH6 silencing. TCGA database showed positive correlation between the expression of MARCH6 and ATF2. Importantly, ATF2 expression contributed to the oncogenic function of HCC cells. Conclusion Our findings suggest that MARCH6-mediated ATF2 up-regulation contributes to HCC development. MARCH6 may be a promising target for the diagnosis and treatment of HCC.

Abstract Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer. Various endeavor has been made to explore the molecular biology basis of TNBC. Herein, we reported a novel function of factor Kinectin 1 (KTN1) as a carcinogenic promoter in TNBC. KTN1 expression in TNBC was increased compared with adjacent tissues or luminal or Her2 subtypes of breast cancer, and TNBC patients with high KTN1 expression have poor prognosis. In functional studies, knockdown of KTN1 inhibited the proliferation and invasiveness of TNBC both in vitro and in vivo, while overexpression of KTN1 promoted cancer cell proliferation and invasiveness. RNA-seq analysis revealed that the interaction of cytokine-cytokine receptor, particularly CXCL8 gene, was upregulated by KTN1, which was supported by the further experiments. CXCL8 depletion inhibited the tumorigenesis and progression of TNBC. Additionally, rescue experiments validated that KTN1-mediated cell growth acceleration in TNBC was dependent on CXCL8 both in vitro and in vivo. Furthermore, it was found that KTN1 enhanced the phosphorylation of NF-κB/p65 protein at Ser536 site, and specifically bound to NF-κB/p65 protein in the nucleus and cytoplasm of cells. Moreover, the transcription of CXCL8 gene was directly upregulated by the complex of KTN1 and NF-κB/p65 protein. Taken together, our results elucidated a novel mechanism of KTN1 gene in TNBC tumorigenesis and progression. KTN1 may be a potential molecular target for the development of TNBC treatment.

Abstract Background This study aimed to explore the collaborative relationship in translational medical research from the perspective of clinicians in China. The findings are expected to help practitioners optimize and experience the greatest advantages of collaboration. Methods We conducted a national internet-based survey from July 29 to October 12, 2020. Of the 806 responses, 804 were completed with valid responses (valid response rate = 99.8%). The collected data were presented as descriptive statistics and analyzed using nonparametric tests (including the Wilcoxon rank test and Kruskal–Wallis H test) and stepwise logistic regression. Results Of the 804 participants, 733 were either willing or very willing to collaborate in translational medical research. Clinicians’ willingness was influenced by their current research type, role in current translational medical research, burdens of their present research, preferred partners for collaboration at the institutional or individual level, and preferences for independent or dependent relationships. Conclusions Clinicians should evaluate their time, role, burdens, personal preferences for research relationships, and appropriate partners based on their current translational medical research and its goals, before deciding to collaborate.