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Background: Cervical cancer is the fourth most common cancer among females globally, with a high incidence and high mortality among females in developing countries. This retrospective case–control study aimed to investigate the association between oral contraceptives and cervical cancer, on which insufficient evidence still exists.Material and Methods: To examine the association between oral contraceptives and cervical cancer based on 7,496 females aged over 20 years from the National Health and Nutrition Examination Survey, multivariable logistic regression conducted from 1999 to 2016 was used.Results: Contraceptive use was positively associated with cervical cancer risk. In model 1 (unadjusted), a 195% increased risk of cervical cancer was observed among those who used oral contraceptives (odds ratio [OR] = 2.27, 95% confidence interval [CI] = 1.39–3.98, p = 0.002) compared to those who did not. In addition, the ORs for the exposed population were 1.74 (95% CI = 1.05–3.08, p = 0.041) and 1.93 (95% CI = 1.16–3.44, p = 0.017) in model 2 (adjusted for age, race, and body mass index [BMI]) and model 3 (adjusted for education level, ratio of family income to poverty, drinking status, smoking status, number of pregnancies, age at first sex, number of sexual partners, and whether to receive the human papillomavirus (HPV) vaccine in addition to model 2), respectively. Furthermore, subgroup analyses stratified by age, smoking status, BMI, age at first sex, number of sexual partners, and whether to receive the HPV vaccine also revealed that oral contraceptives were significantly associated with cervical cancer.Conclusion: This study demonstrated that oral contraceptive use increased the risk of cervical cancer. In addition, the higher risk, including individuals older than 45 years, having a high BMI (≥30 kg/m2), being current smokers, and having more than five sexual partners, may contribute to the development of cervical cancer.

In the actual environment, there are difficult points such as complicated mechanical system fault types, random fault locations, and inconspicuous minor fault signals, which make it difficult to accurately diagnose faults. This paper proposes a new method for fault diagnosis of an adaptive multisensor bearing-gear system based on GAF/MTF (Gramian angular fields and Markov transition fields) and ResNet (deep residual network). First, we establish a multisensor signal acquisition system to monitor the running signals of the bearing-gearbox composite test bench in real time. Faulty parts include multiple types of composite faults of different sizes, different fault types, and different transmission stages. Second, based on GAF/MTFs, the multichannel timing signal collected by using the acquisition system is converted into multichannel pictures, and pictures are fused and compressed into three-channel pictures. Finally, we input these pictures into ResNet for fault diagnosis. The experimental results show that the GAF/MTF-ResNet model has a recognition accuracy of 72.14% for a total of 520 classification label test sets under different motor speeds, different sampling times, and different types of faults. Among them, the accuracy of the motor speed and sampling time is close to 100%, and the accuracy of gearbox failure and bearing failure is 75.25% and 88.97%, respectively. This shows that the method provides new ideas for the composite fault diagnosis of mechanical systems under different working conditions and different types of faults and has theoretical guiding significance.

Purpose: Accumulating evidence suggests that solute carrier family 39 member 1 (SLC39A1) conceivably function as a tumor suppressor, but the underlying mechanism in renal cell carcinoma (RCC) is poorly understood.Methods: OSRC-2 renal cancer cells were first transfected with SLC39A1 overexpressed vectors and empty vectors and then used in transcriptomics, proteomics, and metabolomics integrated analyses.Results: SLC39A1 significantly altered several metabolisms at transcriptional, protein and metabolic levels, including purine and pyrimidine metabolism, amino acids and derivatives metabolism, lactose metabolism, and free fatty acid metabolism. Additionally, SLC39A1 could promote ferroptosis, and triggered significant crosstalk in PI3K-AKT signal pathway, cAMP signal pathway, and peroxisome proliferators-activated receptor (PPAR) signal pathway.Conclusion: We found SLC39A1 transfection impaired tumor metabolism and perturbed tumor metabolism-related pathways, which was a likely cause of the alteration in cell proliferation, migration, and cell cycle progression in RCC cells. These multi-omics analyses results provided both a macroscopic picture of molecular perturbation by SLC39A1 and novel insights into RCC tumorigenesis and development.

PurposeAccumulating literature has suggested that hZIP1 and HIF-1α play vital roles in the tumor process of clear cell renal cell carcinoma (ccRCC). However, the functional roles of hZIP1 and HIF-1α in ccRCC remain largely unknown.MethodsHIF-1α protein level was evaluated by a western blot in ccRCC tissues and cell lines. ccRCC cell lines were transfected with HIF-1α-siRNA to downregulate the expression level of HIF-1α. Then the proliferative, migratory and invasive abilities of ccRCC cells in vitro were detected by real-time cell analysis (RTCA) assay, wound healing assay and transwell assay, respectively. The role of HIF-1α in vivo was explored by tumor implantation in nude mice. Then the effect on glycolysis‐related proteins was performed by western blot after hZIP1 knockdown (overexpression) or HIF-1α knockdown. The effect on NF‐kB pathway was detected after hZIP1 overexpression.ResultsHIF-1α was markedly downregulated in ccRCC tissues compared with normal areas. But HIF-1α presented almost no expression in HK-2 and ACHN cells. Immunofluorescence indicated HIF-1α and PDK1 expression in both the cytoplasm and nucleus in ccRCC cells. Downregulation of HIF-1α suppressed ccRCC cell proliferation, migration, and invasion and resulted in smaller implanted tumors in nude mice. Furthermore, hZIP1 knockdown elevated HIF-1α protein levels and PDK1 protein levels in ccRCC cells. Interestingly, a sharp downregulated expression of HIF-1α was observed after hZIP1 overexpression in OSRC-2 and 786-O cells, which resulted from a downtrend of NF-kB1 moving into the cell nucleus.ConclusionOur work has vital implications that hZIP1 suppresses ccRCC progression by inhibiting NF-kB/HIF-1α pathway.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalent neuropsychiatric disorders and frequently co-occur concomitantly. Individuals suffering from this dual diagnosis often exhibit increased symptom severity and poorer treatment outcomes than those with only one of these diseases. Lacking standard preclinical models limited the exploration of neurobiological mechanisms underlying PTSD and AUD comorbidity. In this review, we summarize well-accepted preclinical model paradigms and criteria for developing successful models of comorbidity. We also outline how PTSD and AUD affect each other bidirectionally in the nervous nuclei have been heatedly discussed recently. We hope to provide potential recommendations for future research.

Abstract The incidence of bladder cancer has increased in the last few decades, thus novel markers for early diagnosis and more efficacious treatment are urgently needed. It found that METTTL13 protein is aberrant expression in variety of human cancers and METTL13 was involved in oncogenic pathways. However, the role of METTL13 has been unexplored in bladder cancer to date. Here, expression of METTL13 was lower in bladder cancer tissue samples and cancer cell lines than in normal bladder tissue and cell lines. METTL13 was downregulated in the late stages of the disease and was maintained at low level throughout the tumor progression process based on tumor node metastasis (TNM) staging. Further research suggested that METTL13 negatively regulates cell proliferation in bladder cancer and reinstates G1/S checkpoint via the coordinated downregulation of CDK6, CDK4 and CCND1, decreased phosphorylation of Rb and subsequent delayed cell cycle progression. Moreover, METTL13-dependent inhibition of bladder cancer cell migration and invasion is mediated by downregulation of FAK (Focal adhesion kinase) phosphorylation, AKT (v-akt murine thymoma viral oncogene) phosphorylation, β-catenin expression and MMP-9 expression. These integrated efforts have identified METTL13 as a tumor suppressor and might provide promising approaches for bladder cancer treatment and prevention.

Objective: To understand the depression, anxiety, stress and other mental health conditions of personnel undergoing hospital isolation during the COVID-19 pandemic and the influencing factors. Methods: This was retrospective study. A total of 120 personnel undergoing Baoding No.1 Hospital isolation who completed the questionnaires were included from June 10, 2021 to February 07, 2022. The Patient Health Questionnaire-9(PHQ-9), the Generalized Anxiety Scale (GAD7) and psychological stress measurement table (PSTR) were used for psychological problem screening for personnel undergoing hospital isolation. Results: The incidence of depression was the lowest, while that of stress was the highest. The difference in the incidence of depression, anxiety and stress among personnel undergoing hospital isolation with different gender, age, income statuses, marital statuses and attitude towards isolation was statistically significant (p< 0.05), while the difference in the incidence of these problems among personnel with different degree of education was not statistically significant(p> 0.05). Multivariate Logistic regression analysis showed that age, gender, marital status, economic status and attitude towards isolation are factors associated with stress. Economic status and attitude towards isolation are factors associated with depression. A high economic level is a protective factor against depression, while a negative attitude is a risk factor for depression. Conclusion: During the COVID-19 pandemic, anxiety, depression and stress increased to different extents in personnel undergoing hospital isolation, especially in females with poor economic conditions and poor attitudes towards isolation. Therefore, necessary psychological counseling and social support should be provided to these people. [ABSTRACT FROM AUTHOR]

Tripterygium wilfordii Hook F (TWHF) is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus (SLE), with triptolide (TP) as its main active ingredient. However, its side effects also induced by TP, especially hepatotoxicity and reproductive toxicity, largely limit its application in a subset of patients. Monoclonal antibodies (mAbs) developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens, such as CD19, have failed in clinical trials, partly due to their poor efficacy in consuming B cells. Here, we report the development of a rationally designed antibody‒drug conjugate (ADC), CD19 mAb-TP conjugate, to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb. The CD19 mAb-TP conjugate, which was named ADC-TP, selectively depleted B cell subsets both in vitro and in vivo and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP. Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE, providing a feasible method for improving the current agents used for treating SLE.

By conducting organic geochemical analysis of the samples taken from the drilled wells in Baiyun Sag of Pearl River Mouth Basin, China, the development characteristics of hydrocarbon source rocks in the sag are clarified. Reconstruct the current geothermal field of the sag and restore the tectonic-thermal evolution process to predict the type, scale, and distribution of resources in Baiyun Sag through thermal pressure simulation experiments and numerical simulation. The Baiyun Sag is characterized by the development of Paleogene shallow lacustrine source rocks, which are deposited in a slightly oxidizing environment. The source rocks are mainly composed of terrestrial higher plants, with algae making a certain contribution, and are oil and gas source rocks. Current geothermal field of the sag was reconstructed, in which the range of geothermal gradients is (3.5–5.2) °C/100 m, showing an overall increasing trend from northwest to southeast, with significant differences in geothermal gradients across different sub-sags. Baiyun Sag has undergone two distinct periods of extensional process, the Eocene and Miocene, since the Cenozoic era. These two periods of heating and warming events have been identified, accelerating the maturation and evolution of source rocks. The main body of ancient basal heat flow value reached its highest at 13.82 Ma. The basin modelling results show that the maturity of source rocks is significantly higher in Baiyun main sub-sag than that in other sub-sags. The Eocene Wenchang Formation is currently in the stage of high maturity to over maturity, while the Eocene Enping Formation has reached the stage of maturity to high maturity. The rock thermal simulation experiment shows that the shallow lacustrine mudstone of the Wenchang Formation has a good potential of generating gas from kerogen cracking with high gas yield and long period of gas window. Shallow lacustrine mudstone of the Enping Formation has a good ability to generate light oil, and has ability to generate kerogen cracking gas in the late stage. The gas yield of shallow lacustrine mudstone of the Enping Formation is less than that of shallow lacustrine mudstone of the Wenchang Formation and the delta coal-bearing mudstone of the Enping Formation. The numerical simulation results indicate that the source rocks of Baiyun main sub-sag generate hydrocarbons earlier and have significantly higher hydrocarbon generation intensity than other sub-sags, with an average of about 1 200×104 t/km2. Oil and gas resources were mainly distributed in Baiyun main sub-sag and the main source rocks are distributed in the 3rd and 4th members of Wenchang Formation. Four favorable zones are selected for the division and evaluation of migration and aggregation units: No. Panyu 30 nose-shaped structural belt, No. Liuhua 29 nose-shaped uplift belt and Liwan 3 nose-shaped uplift belt, No. gentle slope belt of Baiyun east sag, and No. Baiyun 1 low-uplift.

Abstract Aim The purpose of this study was to interpret real-world clinical data to analyze the surgical safety and survival outcomes of patients with initial unresectable hepatocellular carcinoma (uHCC) after conversion therapy. Methods A retrospective analysis was performed on 2984 hepatocellular carcinoma (HCC) patients hospitalized in Shandong Cancer Hospital Affiliated to Shandong First Medical University from June 1st, 2019 to June 1st, 2023. Clinicopathological features, response to systemic and/or loco-regional treatments, surgical resection rate after conversion therapy, surgical safety, and postoperative recurrence were analyzed. Results A total of 38 patients were successfully converted to obtain surgical resection. 35 patients underwent radical resection. A high objective response rate (ORR) (52.6% under RECIST v1.1 and 78.9% under mRECIST criteria) was observed in patients under conversion therapy, and the disease control rate (DCR) was 100%. Pathologic complete response (pCR) was 42.9%. Treatment-related adverse events (TRAEs) of any grade were observed in 37 patients (97.4%). Safety of conversion or direct surgery continues to improve. The median follow-up time was 19.3 months. The 1-year Disease-free survival (DFS) rate of patients with direct surgery and patients with conversion surgery were 91.4% and 86.8%, respectively. Conclusions With conversion therapy, a small percentage (1.81%) of uHCC patients are likely to be converted to radical resection. Local combined systemic therapy is a relatively safe and effective conversion therapy, and the safety of surgery is gradually improved after successful conversion. Preliminary follow-up data showed satisfactory survival benefits for patients undergoing conversion surgery. Trial registration This was a retrospective study and it did not interfere with treatment decisions.

Abstract Fluid management remains a critical challenge in the treatment of septic shock, with individualized approaches lacking. This study aims to develop a statistical model based on transcriptomics to identify subgroups of septic shock patients with varied responses to fluid strategy. The study encompasses 494 septic shock patients. A benefit score is derived from the transcriptome space, with higher values indicating greater benefits from restrictive fluid strategy. Adherence to the recommended strategy is associated with a hazard ratio of 0.82 (95% confidence interval: 0.64–0.92). When applied to the baseline hospital mortality rate of 16%, adherence to the recommended fluid strategy could potentially lower this rate to 13%. A proteomic signature comprising six proteins is developed to predict the benefit score, yielding an area under the curve of 0.802 (95% confidence interval: 0.752–0.846) in classifying patients who may benefit from a restrictive strategy. In this work, we develop a proteomic signature with potential utility in guiding fluid strategy for septic shock patients.

Abstract Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the “hot” (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct “cold” (immune-desert) phenotype, differing from the features of “hot” tumors. Additionally, there is a more nuanced “excluded” immune phenotype, positioned between the “cold” and “hot” categories, known as the immune “excluded” type. Effective differentiation between “cold” and “hot” tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on “hot” tumors, with limited efficacy against “cold” or “altered” tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert “cold” or “altered” tumors into “hot” ones. Therefore, aligning with the traits of “cold” and “hot” tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on “cold” and “hot” tumors to assess clinical efficacy.

Abstract After cutaneous wounds successfully heal, keratinocytes that underwent the epithelial-mesenchymal transition (EMT) regain their epithelial characteristics, while in scar tissue, epidermal cells persist in a mesenchymal state. However, the regulatory mechanisms governing this reversion are poorly understood, and the impact of persistent mesenchymal-like epidermal cells in scar tissue remains unclear. In the present study, we found that during wound healing, the regulatory factor GRHL2 is highly expressed in normal epidermal cells, downregulated in EMT epidermal cells, and upregulated again during the process of mesenchymal-epithelial transition (MET). We further demonstrated that interfering with GRHL2 expression in epidermal cells can effectively induce the EMT. Conversely, the overexpression of GRHL2 in EMT epidermal cells resulted in partial reversion of the EMT to an epithelial state. To investigate the effects of failed MET in epidermal cells on skin wound healing, we interfered with GRHL2 expression in epidermal cells surrounding the cutaneous wound. The results demonstrated that the persistence of epidermal cells in the mesenchymal state promoted fibrosis in scar tissue, manifested by increased thickness of scar tissue, deposition of collagen and fibronectin, as well as the activation of myofibroblasts. Furthermore, the miR-200s/Zeb1 axis was perturbed in GRHL2 knockdown keratinocytes, and transfection with miR-200s analogs promoted the reversion of EMT in epidermal cells, which indicates that they mediate the EMT process in keratinocytes. These results suggest that restoration of the epithelial state in epidermal cells following the EMT is essential to wound healing, providing potential therapeutic targets for preventing scar formation.

Abstract Aiming at the problem of limited transmission energy of liquid crystal tunable filter (LCTF), a dual-wavelength transmission system with high signal-to-noise ratio (SNR) is proposed in this paper. The proposed transmission factor Qp is the main influence on the number and location of transmission wavelengths as well as the bandwidth of each transmission wavelength for dual-wavelength systems. Dual-wavelength LCTF can improve the effective transmission energy of the system by increasing the number of filtering channels, and the transmission energy can be increased by about 1.8 times and 70% at short and long wavelengths, respectively, which improves the signal-to-noise ratio (SNR) of the system. Moreover, the dual-wavelength LCTF system is even possible to increase the transmission energy by about 7% at a 33% increase in spectral resolution. Therefore, the dual-wavelength LCTF transmission method not only can improve the SNR of target detection with dual-wavelength response features, but also can effectively solve the problem of contradiction between spectral resolution and spectral transmission energy.

Abstract RNAs and their encoded proteins intricately regulate diverse cell types and states within the human body. Dysregulated RNA expressions or mutations can lead to various diseased cell states, including tumorigenesis. Detecting and manipulating these endogenous RNAs offers significant promise for restoring healthy cell states and targeting tumors both in research and clinical contexts. This study presents an RNA-IN and RNA-OUT genetic circuit capable dynamically sensing and manipulating any RNA target in a programmable manner. The RNA-IN module employes a programmable CRISPR-associated protease (CASP) complex for RNA detection, while the RNA-OUT module utilizes an engineered protease-responsive dCas9-VPR activator. Additionally, the CASP module can detect point mutations by harnessing an uncovered dual-nucleotide synergistic switching effect within the CASP complex, resulting in the amplification of point-mutation signals from initially undetectable levels (1.5-fold) to a remarkable 94-fold. We successfully showcase the circuit’s ability to rewire endogenous RNA-IN signals to activate endogenous progesterone biosynthesis pathway, dynamically monitor adipogenic differentiation of mesenchymal stem cells (MSCs) and the epithelial-to-mesenchmal trans-differentiation, as well as selective killing of tumor cells. The programmable RNA-IN and RNA-OUT circuit exhibits tremendous potential for applications in gene therapy, biosensing and design of synthetic regulatory networks.

Abstract Background Pancreatic ductal adenocarcinoma tumors exhibit resistance to chemotherapy, targeted therapies, and even immunotherapy. Dendritic cells use glucose to support their effector functions and play a key role in anti-tumor immunity by promoting cytotoxic CD8+ T cell activity. However, the effects of glucose and lactate levels on dendritic cells in pancreatic ductal adenocarcinoma are unclear. In this study, we aimed to clarify how glucose and lactate can impact the dendritic cell antigen-presenting function and elucidate the relevant mechanisms. Methods Glycolytic activity and immune cell infiltration in pancreatic ductal adenocarcinoma were evaluated using patient-derived organoids and resected specimens. Cell lines with increased or decreased glycolysis were established from KPC mice. Flow cytometry and single-cell RNA sequencing were used to evaluate the impacts on the tumor microenvironment. The effects of glucose and lactate on the bone marrow-derived dendritic cell antigen-presenting function were detected by flow cytometry. Results The pancreatic ductal adenocarcinoma tumor microenvironment exhibited low glucose and high lactate concentrations from varying levels of glycolytic activity in cancer cells. In mouse transplantation models, tumors with increased glycolysis showed enhanced myeloid-derived suppressor cell infiltration and reduced dendritic cell and CD8+ T cell infiltration, whereas tumors with decreased glycolysis displayed the opposite trends. In three-dimensional co-culture, increased glycolysis in cancer cells suppressed the antigen-presenting function of bone marrow-derived dendritic cells. In addition, low-glucose and high-lactate media inhibited the antigen-presenting and mitochondrial functions of bone marrow-derived dendritic cells. Conclusions Our study demonstrates the impact of dynamic glycolytic reprogramming on the composition of immune cells in the tumor microenvironment of pancreatic ductal adenocarcinoma, especially on the antigen-presenting function of dendritic cells.

Abstract Strain engineering plays an important role in tuning electronic structure and improving catalytic capability of biocatalyst, but it is still challenging to modify the atomic-scale strain for specific enzyme-like reactions. Here, we systematically design Pt single atom (Pt1), several Pt atoms (Ptn) and atomically-resolved Pt clusters (Ptc) on PdAu biocatalysts to investigate the correlation between atomic strain and enzyme-like catalytic activity by experimental technology and in-depth Density Functional Theory calculations. It is found that Ptc on PdAu (Ptc-PA) with reasonable atomic strain upshifts the d-band center and exposes high potential surface, indicating the sufficient active sites to achieve superior biocatalytic performances. Besides, the Pd shell and Au core serve as storage layers providing abundant energetic charge carriers. The Ptc-PA exhibits a prominent peroxidase (POD)-like activity with the catalytic efficiency (K cat/K m) of 1.50 × 109 mM−1 min−1, about four orders of magnitude higher than natural horseradish peroxidase (HRP), while catalase (CAT)-like and superoxide dismutase (SOD)-like activities of Ptc-PA are also comparable to those of natural enzymes. Biological experiments demonstrate that the detection limit of the Ptc-PA-based catalytic detection system exceeds that of visual inspection by 132-fold in clinical cancer diagnosis. Besides, Ptc-PA can reduce multi-organ acute inflammatory damage and mitigate oxidative stress disorder.

Abstract Autoimmune attack toward pancreatic β cells causes permanent loss of glucose homeostasis in type 1 diabetes (T1D). Insulin secretory granules store and secrete insulin but are also thought to be tissue messengers for T1D. Here, we show that the crinophagic granules (crinosome), a minor set of vesicles formed by fusing lysosomes with the conventional insulin dense-core granules (DCG), are pathogenic in T1D development in mouse models. Pharmacological inhibition of crinosome formation in β cells delays T1D progression without affecting the dominant DCGs. Mechanistically, crinophagy inhibition diminishes the epitope repertoire in pancreatic islets, including cryptic, modified and disease-relevant epitopes derived from insulin. These unconventional insulin epitopes are largely undetectable in the MHC-II epitope repertoire of the thymus, where only canonical insulin epitopes are presented. CD4+ T cells targeting unconventional insulin epitopes display autoreactive phenotypes, unlike tolerized T cells recognizing epitopes presented in the thymus. Thus, the crinophagic pathway emerges as a tissue-intrinsic mechanism that transforms insulin from a signature thymic self-protein to a critical autoantigen by creating a peripheral-thymic mismatch in the epitope repertoire.

Background:. Partly due to the limited effect of chemotherapy or other therapeutic strategies, which may be due to the insufficient knowledge of the tumor promotion markers and targets, pancreatic cancer (PC) holds the position of one of the most malignant tumors. This study aims to find a diagnosis/therapeutic molecule that can predict the prognosis of PC with different gene background. Methods:. The Cancer Genome Atlas (TCGA) pancreatic duct adenocarcinoma (PAAD)–based single nucleotide polymorphisms and gene expression data were used to find the differentially expressed genes (DEGs) between KRAS/TP53 mutant samples and no gene mutation samples. Gene Set Enrichment Analysis (GSEA)-based Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and R-based gene oncology (GO) or immune cell invasion assay were used to explore the above DEGs involved pathways. The single-center PC cohort accompanied with next-generation sequence testing was used to verify the TCGA PAAD–based bioinformatic results. Results:. First, we found PC patients who harbored KRAS and/or TP53 gene mutation have poor overall survival. Besides, the enrichment analysis showed that mutant KRAS/TP53 was correlated with PC tumor-promotion–related pathways and immune microenvironment. Next, we detected that prostate stem cell antigen (PSCA) was one of the most differential genes in KRAS/TP53 mutant PC tissues. Indeed, the bioinformatic analysis and our clinical data showed that PSCA was a biomarker of poor prognosis in PC. Conclusion:. PSCA is a critical biomarker for predicting the prognosis of KRAS/TP53 mutant PC patients.

When simulating drying-rewetting process of grid cells in numerical groundwater modeling using the block-centered finite-difference approach, the models is highly probable to run into non-convergence, which could greatly affect the applicability of groundwater models. This study used ideal case and practical simulation in Denmark to comprehensively compare the simulation capabilities and characteristics of two algorithms, namely the empirical trial (ET) method proposed by MODFLOW and the always active cell (AAC) method proposed by COMUS, in the drying-rewetting simulation. The results show that: (1) For the ET method, the selection of parameter combination has a significant influence on the model convergence and the simulation results. It is compulsory to continuously optimize the parameter to avoid model failures such as non-convergence and large simulation errors when using the ET method, which greatly increases the difficulty of groundwater model application and time cost. (2) The simulation results from the AAC method are more reliable than those from the ET method. Theoretically, the effect of the AAC method is equivalent to the optimal parameter set in the ET method. Therefore, parameter optimization is no longer needed in the AAC method, which can effectively reduce the difficulty of using groundwater models and meanwhile reduce the uncertainty of simulation results. (3) The numerical accuracy of the intercell horizontal hydraulic conductance in the AAC method is consistent with that of the classical harmonic average method, demonstrating that the AAC method can also be used in the simulation without the drying-rewetting process. In summary, the AAC method is more suitable for simulating the drying-rewetting process of groundwater model cells and is expected to be more widely used in groundwater numerical simulation.

Abstract In this study, we successfully established a novel gallbladder cancer cell line, designated as GBC-X1, derived from a primary tumor of a gallbladder cancer patient. By comprehensively analyzing the cell line’s phenotype, molecular characteristics, biomarkers, and histological characteristics, we confirmed that GBC-X1 serves as a valuable model for investigating the pathogenesis of gallbladder cancer and developing therapeutic agents. GBC-X1 has been continuously cultured for one year, with over 60 stable passages. Morphologically, GBC-X1 exhibits typical features of epithelial tumors. The population doubling time of GBC-X1 is 32 h. STR analysis validated a high consistency between GBC-X1 and the patient’s primary tumor. Karyotype analysis revealed an abnormal hypertetraploid karyotype for GBC-X1, characterized by representative karyotypes of 98, XXXX del (4) p (12) del (5) p (21) der (10). Under suspension culture conditions, GBC-X1 efficiently forms tumor balls, while subcutaneous inoculation of GBC-X1 cells into NXG mice leads to xenograft formation with a rate of 80%. Drug sensitivity testing demonstrated that GBC-X1 is resistant to oxaliplatin and sensitive to 5-FU, gemcitabine, and paclitaxel. Immunohistochemistry revealed positive expression of CK7, CK19, E-cadherin, MMP-2, CD44, SOX2, and TP53 in GBC-X1 cells, weak positive expression of Vimentin, and a Ki67 positive rate of 35%. Our research highlights GBC-X1 as a novel gallbladder cancer cell line and emphasizes its potential as an effective experimental model for investigating the pathogenesis of gallbladder cancer and drug development.

Abstract Diabetes mellitus (DM) is a well-documented risk factor of intervertebral disc degeneration (IVDD). The current study was aimed to clarify the effects and mechanisms of NADH: ubiquinone oxidoreductase subunit A3 (NDUFA3) in human nucleus pulposus cells (HNPCs) exposed to high glucose. NDUFA3 was overexpressed in HNPCs via lenti-virus transduction, which were co-treated with high glucose and rotenone (a mitochondrial complex I inhibitor) for 48 h. Cell activities were assessed for cell viability, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) ratio, oxygen consumption rate (OCR) and mitochondrial complexes I activities. High glucose decreased cell viability, increased apoptotic cells, increased ROS production, decreased MMP levels and OCR values in HNPCs in a dose-dependent manner. Rotenone co-treatment augmented the high glucose-induced injuries on cell viability, apoptosis, ROS production and mitochondrial function. NDUFA3 overexpression counteracted the high glucose-induced injuries in HNPCs. HDAC/H3K27ac mechanism was involved in regulating NDUFA3 transcription. NDUFA3 knockdown decreased cell viability and increased apoptotic cells, which were reversed by ROS scavenger N-acetylcysteine. HDAC/H3K27ac-mediated transcription of NDUFA3 protects HNPCs against high glucose-induced injuries through suppressing cell apoptosis, eliminating ROS, improving mitochondrial function and oxidative phosphorylation. This study sheds light on candidate therapeutic targets and deepens the understanding of molecular mechanisms behind DM-induced IVDD.

Abstract Background This study aimed to compare the impact of olanzapine, magnesium valproate, and lamotrigine as adjunctive treatments for anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. And it is expected to add supporting points related to the rebalance of neurotransmitters in the brain through adjuvant therapy in the clinical management of anti-NMDAR encephalitis. Methods This retrospective study included patients diagnosed with anti-NMDAR encephalitis who received standardized immunotherapy at Hunan Brain Hospital between January 2018 and December 2020. Results Compared to the olanzapine group, both the magnesium valproate and lamotrigine groups showed lower scores on the positive and negative symptom scale (PANSS) total score after 3 weeks of treatment (all P 0.05). Conclusion Compared with olanzapine, the addition of magnesium valproate or lamotrigine to immunotherapy might be associated with a lower PANSS score, higher MoCA score, and lower mRS score. The improvement of neurological functions and cognitive function may be related to the decreased Glx/Cr ratio.

Abstract Edge computing nodes close to the perception layer of IoT systems are susceptible to data leaks and unauthorized access. To address these security concerns, this paper proposes a trusted IoT data sharing method based on secure multi-party computation (SMC). By running a reliable third-party blockchain service at edge computing nodes, the data computation relationships between IoT devices in the perception layer are registered in blockchain smart contracts. This constructs a publicly verifiable IoT data sharing method combining on-chain audit verification and off-chain SMC. Furthermore, a Bloom filter is maintained at the on-chain smart contract layer to track the trust status of IoT devices in the perception layer, filtering out non-trustworthy device requests and enabling secure data sharing among trusted devices. Comparative analysis and performance tests demonstrate the proposed method’s high computational efficiency for IoT device nodes.

Abstract In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.

Abstract Terahertz frequency band (0.1 ~ 10 THz) can provide ultra-high transmitting rates for massive emerging applications. However, due to the radio frequency impairments and limited signal processing property of baseband devices, it is difficult for the current terahertz communication systems to be used in real applications. In this work, we report a 0.22 THz communication system, which can provide 84 Gbps air interface rate over 1.26 kilometers distance. Such a system is underpinned by three breakthroughs, namely, integrating the reported terahertz wireless communication system, redesigning the signal processing in baseband devices, and increasing the cut-off frequency and transmitting power of radio frequency component by parameter optimizing. Being applied to realize the real-time transmission of the uncompressed 8K ultra high-definition video in the 31st International University Sports Federation in Chengdu, China, this work is a leaping advancement to enable terahertz systems from experiment to promising applications.

Abstract Background Lung squamous cell carcinoma (LUSCs) is associated with high mortality (20–30%) and lacks of effective treatments. Almost all LUSC exhibit somatic mutations in TP53. Wee1, a tyrosine kinase, regulates the cell cycle at the G2/M checkpoint. In TP53-deficient cells, the dependence on G2/M checkpoints increases. PD0166285 is the first reported drug with inhibitory activity against both Wee1 and PKMYT1. Methods Protein expression was determined by Western blot analysis. Cell proliferation was assessed using cell colony formation and CCK-8 assays. Cell cycle was performed by PI staining with flow cytometry. Apoptosis was evaluated using Annexin V-Phycoerythrin double staining and flow cytometry. DNA damage was detected through comet assay and immunofluorescence assay. In vivo, apoptosis and anti-tumor effects were assessed using the TUNEL assay, a nude mouse model, and immunohistochemistry (IHC). Co-immunoprecipitation assay was used to detect protein–protein interactions. We analyzed Wee1, PKMYT1, and Stat1 expression in pan-cancer studies using the Ualcan public database and assessed their prognostic implications with Kaplan–Meier curves. Result PD0166285, a Wee1 inhibitor, effectively inhibits Wee1 activity, promoting cell entry into a mitotic crisis. Moreover, PD0166285 sensitizes cells to cisplatin, enhancing clinical outcomes. Our study demonstrated that PD016628 regulates the cell cycle through Rad51 and results in cell cycle arrest at the G2/M phase. We observed increased apoptosis in tumor cells treated with PD0166285, particularly when combined with cisplatin, indicating an enhanced apoptotic response. The upregulation of γ-H2AX serves as an indicator of mitotic catastrophe. Co-immunoprecipitation and data analysis revealed that apoptosis in LUSC is mediated through the Stat1 pathway, accompanied by decreased levels of Socs3. Furthermore, IHC staining confirmed significant differences in the expression of Phospho-CDK1 and γ-H2AX in LUSCs, suggesting involvement in DNA damage. Conclusions In summary, our study suggests that PD0166285, an inhibitor of Wee1, sensitizes LUSC cells to cisplatin and modulates DNA damage and apoptosis pathways through Rad51 and Stat1, respectively. These findings highlight the combination of PD0166285 and cisplatin as a promising therapeutic approach for treating LUSC.