In recent years, immune checkpoint inhibitor has achieved remarkable success in multiple cancer treatment. However, how to pre‐judge which patients are suitable for immune checkpoint inhibitor is a ...difficult problem. We use the existing public bioinformatics database to comprehensively analyze the relationship between clinical data of various cancers with immune checkpoint blocking molecules and long non‐coding RNAs (lncRNAs), and try to find the potential predictive value of lncRNA for immunotherapy with checkpoint inhibitors. In this study, we found that: (a) high expression of lncRNA MIR155 host gene (MIR155HG) was closely related to better overall survival (OS) in cholangiocarcinoma (CHOL), lung adenocarcinoma (LUAD), and skin cutaneous melanoma (SKCM), and have better disease‐free survival (DFS) in CHOL. Meanwhile, the high level of MIR155HG was associated with poorer OS in glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM). (b) The expression of MIR155HG was significantly correlated with infiltrating levels of immune cells and immune molecules, especially with immune checkpoint molecules such as programmed cell death protein 1 (PD‐1), PD‐1 ligand 1 (PD‐L1), and cytotoxic T lymphocyte‐associated antigen 4 (CTLA4) in most kinds of cancers. (c) Detection of clinical CHOL and liver hepatocellular carcinoma tissues confirmed that there was a strong positive correlation between MIR155HG expression and the levels of CTLA4 and PD‐L1. MIR155 host gene can be used as a prognostic marker in multiple cancers, and of great value in predicting the curative effect of immune checkpoint inhibitor therapy owing to it is closely related with immune cells infiltration and immune checkpoint molecules expression.
Long non‐coding RNA MIR155 host gene (MIR155HG) was closely related to overall survival in cholangiocarcinoma, lung adenocarcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, glioblastoma multiforme, kidney renal clear cell carcinoma, brain lower grade glioma, and uveal melanoma. The expression of MIR155HG was significantly correlated with infiltrating levels of immune cells, molecules, and immune checkpoint molecules.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Carbamoyl phosphate synthase 1 (CPS1) is the rate‐limiting enzyme in the first step of the urea cycle and an indispensable enzyme in the metabolism of human liver. However, CPS1 epigenetic regulation ...involves promoter analysis and the role of liver‐enriched transcription factors (LETFs), which is not fully elucidated. In this work, the promoter region of hCPS1 gene was cloned, and its activity was investigated. An LETF, hepatocyte nuclear factor 3‐beta (HNF3β), was found to promote the transcriptional expression of CPS1 in liver‐derived cell lines. In addition, dual‐luciferase reporter assay shows that the essential binding sites of the HNF3β may exist in the oligonucleotide −70 nt to +73 nt. Two putative binding sites are available for HNF3β. Mutation analysis results show that the binding site 2 of HNF3β was effective, and the transcriptional activity of CPS1 promoter significantly decreased after mutation. Electrophoretic mobile shift assay (EMSA) and ChIP assay confirmed that HNF3β can interact with the binding site in the CPS1 promoter region of −70 nt to +73 nt promoter region in vivo and in vitro to regulate the transcription of CPS1. Moreover, HNF3β overexpression enhanced the transcription of CPS1 and consequently improved the mRNA and protein levels of CPS1, whereas the knockdown of HNF3β showed the opposite effects. Finally, urea production in cells was measured, and ammonia detoxification improved significantly in cells after transfection with HNF3β. HNF3β plays a vital role in regulation of CPS1 gene and could promote the metabolism of ammonia by regulating CPS1 expression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The infection rate of human papillomavirus (HPV) is high in the coastal regions of China. However, the infection rate among high-risk genotypes of women in Putian City is unknown. Therefore, this ...study aimed to analyse the epidemiology of high-risk HPV infection among women in Putian and provide a reference for the diagnosis, treatment and vaccination of cervical cancer in this region. The data used were obtained from the Chinese government's public health program ("Cervical and Breast Cancer Screening Project"). A total of 40,693 female cervical cell exfoliation samples screened for high-risk HPV at the Affiliated Hospital of Putian University from July 2020 to December 2021 were enrolled. DNA was extracted using a fully automatic extractor. Then, 14 high-risk genotypes of HPV were detected by polymerase chain reaction. The characteristics of HPV infection, distribution of high-risk genotypes, infection types and thinprep cytologic test (TCT) classification at different age groups were analysed. Among the 40,693 samples, 3899 were infected with HPV, with an infection rate of 9.6%. Accordingly, HPV infection rates gradually increased with age, and statistically significant differences were observed among age groups (chl.sup.2 = 74.03, P < 0.01). The infection rates of high-risk HPV52, HPV58 and HPV16 were in the top three and increased with age. Single infection was dominant (84.7%), followed by double infections (12.7%). The cervical cytology of 3899 HPV-positive people can be classified into negative for intraepithelial lesion and malignancy (NILM, 88.0%), atypical squamous cells of undetermined significance (ASC-US, 6.6%), atypical squamous cells--cannot exclude high-grade squamous intraepithelial lesion (ASC-H, 1.4%), low-grade squamous intraepithelial lesion (LSIL, 3.2%) and high-grade squamous intraepithelial lesion (HSIL, 0.8%). HPV16 infection rate increased with increasing severity of cervical cytology (chl.sup.2.sub.trend = 43.64, P < 0.01), whereas the infection rates of HPV52 (chl.sup.2.sub.trend = 13.89, P < 0.01) and HPV58 (chl.sup.2.sub.trend = 13.50, P < 0.01) showed opposite trends. The infection rate of female HPV high-risk screening in this region was 9.6% and mainly involved single infections. In addition, HPV16, HPV52 and HPV58 were closely related to the severity of cervical cytology. Effective screening, vaccination and education are needed. The 9-valent vaccine will be effective in reducing cervical pre-invasive disease. It would also be reasonable to state that the rising trend in HPV infection and high grade cytology with age emphasises the need to target older women with screening. Vaccination of younger women (aged less than or equai to 25) will lay the foundation for better cancer outcomes in the future.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study aims to explore the infection and age distribution of Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Herpes simplex virus type II (HSV II) among ...the outpatients of Reproductive Medicine Center in Putian, Fujian Province to provide a clinical basis for the early diagnosis and treatment of various reproductive tract diseases and infertility in this region.
A total of 1736 samples of secretions and exfoliated cervical cells were collected from the outpatients of the Reproductive Medicine Center of the Affiliated Hospital of Putian University from December 2021 to April 2023. The infections of UU, CT, NG and HSVII were detected by real-time fluorescence polymerase chain reaction (PCR), and the infection statuses of the patients with different genders, ages and diagnoses were analysed.
Among the 1736 patients, 611 were male and 1125 were female. The male patients had higher UU infection rate but lower HSV II infection rate than the female patients. No significant difference in CT and NG infection rates was observed between the genders. The CT infection rate gradually decreased with the increase in the age. The difference in UU, NG and HSV II infection rates among the different age groups was not statistically significant. For UU infection, the male infertile patients had the highest rate of 37.72% (172/456). Meanwhile, the differences in CT, NG and HSV II infection rates among the different diagnosis groups were not statistically significant. Among the male and female infertile patients, the CT infection rate was the highest in the 21-25 years of age group at 11.11% (2/18) and 9.47% (9/95), respectively. No statistically significant difference in UU, CT, NG and HSV II infection rates was observed among the different age groups of patients diagnosed in relation to the family planning guidance and between the male and female patients with other diagnoses results.
This study showed that UU was the most frequently identified pathogen in infertile men in Putian, Fujian Province. The CT infection rate was the highest in people under 20 years old, and the infection showed a tendency toward young individuals. Therefore, the publicity of sexual health knowledge must be strengthened, and the prevention and treatment of venereal diseases among young and middle-aged people must be improved. Moreover, the pathogen infection is related to infertility to a certain extent, which is conducive to clinical diagnosis and treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background2,5-dimethylcelecoxib (DMC) is a targeted inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), a key enzyme in the PGE2 synthesis pathway of inflammatory mediators. Previous ...studies have confirmed that DMC can inhibit the growth of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, it is not known whether DMC is involved in the changes of tumor immune microenvironment.MethodsIn this study, we explored the effects of DMC on HBV-related HCC immune microenvironment, and deeply analyzed its unique effect and mechanism on programmed death receptor 1 (PD-1)/and its ligand 1 (PD-L1) pathway.ResultsClinical hepatoma tissues detection showed that compared with non-virus-related HCC, the level of CD8 of HBV-related HCC was significantly lower, while the levels of PD-L1 and CD163 were higher. In vivo experiments indicated that DMC could increase the level of tumor infiltrating CD8+ T cells in hepatitis B virus X (HBx) (+) hepatoma cells implanted mouse models, and inhibit the expression of PD-L1 and CD163 in tumor tissues. DMC combined with atezolizumab had more significant antitumor effect and stronger blocking effect on PD-1/PD-L1 pathway. Mechanism studies have shown that DMC can promote ubiquitin degradation of HBx-induced PD-L1 protein in HCC cells by activating adenosine 5′-monophosphate-activated protein kinase pathway. Further experiments confirmed that this process was mainly mediated by E3 ligase RBX1.ConclusionsOur results uncover a role for DMC in promoting HBV-related HCC immune microenvironment, which not only enrich the relationship between inflammatory factors (mPGES-1/PGE2 pathway) and immunosuppression (PD-L1), but also provide an important strategic reference for multitarget or combined immunotherapy of HBV-related HCC.
The aim of this paper is to model the effects of threading dislocations on both gate and drain currents of AlGaN/GaN high electron mobility transistors (HEMTs). The fraction of filled traps increases ...with the threading dislocations, while the trapping effects cause a decrease in drain current and an increase in gate leakage current. To model the drain current drop, the two simplified RC subcircuits with diodes are proposed to capture the charge trapping/detrapping characteristics. The trap voltages
and
generated by RC networks are fed back into the model to capture the effects of traps on drain current. Considering acceptor-decorated dislocations, we present a novel Poole-Frenkel (PF) model to precisely describe the reverse leakage gate current, which plays a dominant role in the gate leakage current. The proposed model, which uses physical parameters only, is implemented in Verilog-A. It is in excellent agreement with the experimental data.
Background2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the ...expression of programmed death-ligand 1 on hepatocellular carcinoma (HCC) cells to prevent tumor progression. However, the effect and mechanism of DMC on HCC infiltrating immune cells remain unclear.MethodsIn this study, single-cell-based high-dimensional mass cytometry was performed on the tumor microenvironment of HCC mice treated with DMC, celecoxib and MK-886 (a known mPGES-1 inhibitor). Moreover, 16S ribosomal RNA sequencing was employed to analyze how DMC improved the tumor microenvironment of HCC by remodeling the gastrointestinal microflora.ResultsWe found that (1) DMC significantly inhibited the growth of HCC and improved the prognosis of the mice, and this depended on the stronger antitumor activity of natural killer (NK) and T cells; (2) compared with celecoxib and MK-886, DMC significantly enhanced the cytotoxic and stem-like potential, and inhibited exhaustion of NK and T cells; (3) mechanistically, DMC inhibited the expression of programmed cell death protein-1 and upregulated interferon-γ expression of NK and T cells via the gastrointestinal microbiota (Bacteroides acidifaciens, Odoribacter laneus, and Odoribacter splanchnicus)-AMPK-mTOR axis.ConclusionsOur study uncovers the role of DMC in improving the tumor microenvironment of HCC, which not only enriches the relationship between the mPGES-1/prostaglandin E2 pathway and the antitumor function of NK and T cells, but also provide an important strategic reference for multitarget or combined immunotherapy of HCC.Cite Now
mPGES-1 is a terminal rate-limiting enzyme responsible for inflammation-induced PGE2 production. The inhibition of mPGES-1 has been considered as a safe and effective target for the treatment of ...inflammation and cancer. However, a specific, efficient, and simple method for high-throughput screening of mPGES-1 inhibitors is still lacking. In this study, we developed a fluorescence imaging strategy to monitor the expression of mPGES-1 via CRISPR/Cas9 knock-in system. Immunofluorescence colocalisation, Sanger sequencing, RNAi, and IL-1β treatment all confirmed the successful construction of mPGES-1 reporter cells. The fluorescence signal intensity of the reporter cells treated with four conventional mPGES-1 inhibitors was considerably attenuated via flow cytometry and fluorescent microplate reader, demonstrating that the reporter cells can be used as an efficient and convenient means for screening and optimising mPGES-1 inhibitors. Moreover, it provides a new technical support for the development of targeted small molecule compounds for anti-inflammatory and tumour therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We propose a surface potential (SP)-based compact model of p-GaN gate high electron mobility transistors (HEMTs) which solves the Poisson equation. The model includes all possible charges in the GaN ...channel layer, including the unintended Mg doping density caused by out-diffusion. The SP equation and its analytical approximate solution provide a high degree of accuracy for the SP calculation, from which the closed-form I-V equations are derived. The proposed model uses physical parameters only and is implemented in Verilog-A code.
Classical conditioning (CC) and operant conditioning (OC), also known as associative memory, are two of the most fundamental and critical learning mechanisms in the biological brain. However, the ...existing designs of associative memory memristive circuits mainly focus on CC, and few studies have used memristors to imitate OC at the behavioral level, as well as the OC-CC cascaded associative memories that are widespread in biological learning processes. This work proposes an OC-CC cascaded circuit composed of OC and CC circuits. With the OC memristive circuit, bio-like functions such as random exploration, feedback learning, experience memory, and experience-based decision-making are achieved, which enables the circuit to continuously reshape its own memories and actions to adapt to changing environments. By cascading it with the CC memristive circuit that has the functions of associative learning, forgetting, generalization, and differentiation, the OC-CC cascaded circuit implements richer associative memories and has stronger environmental adaptability. Finally, the proposed circuits can perform on-line in-situ learning and in-memory computing. This is a more brain-like processing method, which is different from the von Neumann architecture. The simulation results of the proposed circuits in PSPICE show that they can simulate the above functions and have advantages in power consumption and hardware overhead. This work provides a possible realization idea for large-scale bionic learning.
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