A hypoxia-related genes prognostic risk model, and mechanisms of hypoxia contributing to poor prognosis through immune microenvironment and drug resistance in acute myeloid leukemia.

Objective: Acute myeloid leukemia (AML) is a malignant hematologic cancer with poor prognosis. Emerging evidence suggests a close association between AML progression and hypoxia. The purpose of this study was to establish a new risk prognostic model for AML based on hypoxia-related genes, and to explore the mechanisms by which hypoxia-related genes affect the prognosis of AML based on tumor immune microenvironment (TIME) and drug resistance. Methods: The AML patient samples obtained from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database were classified into C1 and C2 based on hypoxia-related genes, followed by analysis utilizing Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). Through univariate and LASSO Cox regression analysis, the hypoxia-related hub genes 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) and 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) were identified to construct the model. AML patient samples were obtained from the TARGET and The Cancer Genome Atlas (TCGA) databases, serving as the training and the validation sets, and were stratified into high-risk and low-risk group according to the median risk score. The correlations between the model and TIME and anti-tumor drugs were analysed using CIBERSORT and Genomics of Drug Sensitivity in Cancer (GDSC) databases. The expressions of PSMD11/PSMD14 in clinical samples and AML sensitive and drug-resistant cell lines were detected by Western blot and real-time PCR. Results: The C1 group with high expression of hypoxia-related genes had lower overall survival (OS). Immune-related signaling pathways were different between C1/C2, and hypoxia was positively correlated with the activation of mammalian target of rapamycin (mTOR) signaling pathway. The model had good accuracy in both the training and the validation sets. The high-risk group exhibited lower OS and TIME activity, and was more sensitive to several anti-tumor drugs. PSMD11/PSMD14 were highly expressed in relapsed patients and AML drug-resistant cell lines. Conclusion: The established novel risk prognostic model and experiment results offer valuable insights for predicting AML prognosis and guiding drug selection. It also provides a fundamental framework for the mechanisms through which hypoxia impacts AML prognosis by modulating TIME and drug resistance.

Pulpotomy for teeth with irreversible pulpitis in immature permanent teeth: a retrospective case series study.

To evaluate the success of pulpotomy in treating immature permanent teeth with irreversible pulpitis. This case series included patients with irreversible pulpitis admitted to the Department of Oral Medicine at the author's Hospital between 2015 and 2020. The pulpotomies were carried out by clinicians with > 5 years of working experience. The follow-up findings and radiographic images were reviewed by two attending dentists. This study included 49 teeth from 48 children (25 boys and 23 girls). The follow-up was 23.3 ± 6.8 months (from 12 to 40 months). The success rate of pulpotomy was 85.7% (42/49). Pulpotomy failed in seven teeth (14.3%). The treatment success rate for traumatic crown fracture was lower than for dental caries and dens evaginatus (P < 0.001). There were no significant differences in the success rate of the pulp-capping agent, tooth root developmental phase, and pulpotomy method (all P > 0.05). Pulpotomy might be successfully used to treat immature permanent teeth with irreversible pulpitis in young patients mainly caused by caries and a fractured tubercle of dens evaginatus.

Erratum: [Corrigendum] Changes in expression of p53 and inflammatory factors in patients with ulcerative colitis.

[This corrects the article DOI: 10.3892/etm.2019.7253.].

Integrated investigation and experimental validation of PPARG as an oncogenic driver: implications for prognostic assessment and therapeutic targeting in hepatocellular carcinoma.

Peroxisome proliferator-activated receptor gamma (PPARG), a key transcription factor involved in lipid metabolism and glucose homeostasis, has been implicated in various types of cancer. However, its precise role in cancer remains unclear. In this study, we conducted a comprehensive pan-cancer analysis of PPARG expression using various types of cancer obtained from public databases. We observed significant heterogeneity in PPARG expression across different types of cancer. The association between PPARG expression and patient prognosis was investigated using Cox proportional hazards regression models and survival analysis. Clinical features and protein expression levels in the cohort showed that PPARG expression was strongly associated, suggesting its potential as a therapeutic target. We also evaluated the prognostic potential of PPARG by analyzing immune infiltration and genomic stability. We experimentally validated the potential of PPARG as a therapeutic target by analyzing drug sensitivity profiles, molecular docking simulations, and in vitro cell proliferation assays associated with PPARG expression. We identified common expression patterns of PPARG with other genes involved in key carcinogenic pathways. This provides deeper insights into the molecular mechanisms underlying its carcinogenic role. Additionally, functional enrichment analysis revealed significant enrichment of genes related to drug metabolism, cell proliferation, and immune response pathways associated with PPARG. Our findings highlight the importance of PPARG in the broader biology of cancer and suggest its potential as a diagnostic and therapeutic target for specific types of cancer. The results of our study provide strong support for the potential role of PPARG as a promising prognostic biomarker and immunotherapeutic target across various types of cancer.

[Molecular mechanism of sleep deprivation-induced body injury and traditional Chinese medicine prevention and treatment: a review].

Sleep occupies one-third of a person's lifetime and is a necessary condition for maintaining physiological function and health. With the increase in social and economic pressures, the growing use of electronic devices and the accelerated aging process of the population, insufficient sleep and its hazards have drawn widespread attention from researchers in China and abroad. Sleep deprivation refers to a decrease in sleep or a severe lack of sleep due to various reasons. Previous studies have found that sleep deprivation can cause extensive damage to the body, including an increased incidence and mortality rate of neuropathic diseases in the brain, cardiovascular diseases, imbalances in the gut microbiota, and other multi-organ diseases. The mechanisms underlying the occurrence of multi-system and multi-organ diseases due to sleep deprivation mainly involve oxidative stress, inflammatory responses, and impaired immune function in the body. According to traditional Chinese medicine(TCM), sleep deprivation falls into the category of sleepiness, and long-term sleepiness leads to Yin-Yang imbalance, resulting in the consumption of Qi and damage to the five Zang-organs. The appropriate treatment should focus on tonifying deficiency, reinforcing healthy Qi, and harmonizing Yin and Yang. TCM is characterized by a wide variety and abundant resources, and it has minimal side effects and a broad range of applications. Numerous studies have shown that TCM drugs and prescriptions not only improve sleep but also have beneficial effects on liver nourishment, intelligence enhancement, and kidney tonification, effectively preventing and treating the body injury caused by sleep deprivation. Given the increasing prevalence of sleep deprivation and its significant impact on body health, this article reviewed sleep deprivation-mediated body injury and its mechanism, summarized and categorized TCM compound prescriptions and single drugs for preventing and treating body injury, with the aim of laying the foundation for researchers to develop effective drugs for preventing and treating body injury caused by sleep deprivation and providing references for further exploration of the molecular mechanisms underlying the body injury caused by sleep deprivation.

Irinotecan cause the side effects on development and adult physiology, and induces intestinal damage via innate immune response and oxidative damage in Drosophila.

Chemotherapy leads to significant side effects in patients, especially in the gut, resulting in various clinical manifestations and enhanced economic pressure. Until now, many of the underlying mechanisms remain poorly understood. Here, we used Drosophila melanogaster (fruit fly) as in vivo model to delineate the side effects and underlying mechanisms of Irinotecan (CPT-11). The results showed that administration of CPT-11 delayed larval development, induced imbalance of male to female ratio in offspring, shortened lifespan, impaired locomotor ability, changed metabolic capacity, induced ovarian atrophy, and increased excretion. Further, CPT-11 supplementation dramatically caused intestinal damages, including decreased intestinal length, increased crop size, disrupted gastrointestinal acid-based homeostasis, induced epithelial cell death, and damaged the ultrastructure and mitochondria structure of epithelial cells. The cross-comparative analysis between transcriptome and bioinformation results showed that CPT-11 induced intestinal damage mainly via regulating the Toll-like receptor signaling, NF-kappa B signaling, MAPK signaling, FoxO signaling, and PI3K-AKT signaling pathways. In addition, CPT-11 led to the intestinal damage by increasing ROS accumulation. These observations raise the prospects of using Drosophila as a model for the rapid and systemic evaluation of chemotherapy-induced side effects and high-throughput screening of the protective drugs.

Convergence Analysis of Online Gradient Method for High-Order Neural Networks and Their Sparse Optimization.

In this article, we investigate the boundedness and convergence of the online gradient method with the smoothing group L1/2 regularization for the sigma-pi-sigma neural network (SPSNN). This enhances the sparseness of the network and improves its generalization ability. For the original group L1/2 regularization, the error function is nonconvex and nonsmooth, which can cause oscillation of the error function. To ameliorate this drawback, we propose a simple and effective smoothing technique, which can effectively eliminate the deficiency of the original group L1/2 regularization. The group L1/2 regularization effectively optimizes the network structure from two aspects redundant hidden nodes tending to zero and redundant weights of surviving hidden nodes in the network tending to zero. This article shows the strong and weak convergence results for the proposed method and proves the boundedness of weights. Experiment results clearly demonstrate the capability of the proposed method and the effectiveness of redundancy control. The simulation results are observed to support the theoretical results.

Noninvasive Methods for Detecting Advanced Liver Fibrosis and Cirrhosis in Patients with Chronic Hepatitis B: A Single-Center Retrospective Study.

Background and Aims: The performance of noninvasive assessments to rule-in or rule-out fibrosis may improve when combined. We aimed to evaluate the efficiencies of sequential algorithms based on the aspartate aminotransferase-to-platelet ratio index (APRI), the fibrosis index based on four factors (FIB-4), and transient elastography (TE) for the assessment of advanced fibrosis (AF) and cirrhosis. Methods: This study enrolled 179 CHB subjects who underwent liver biopsy (LB) before antiviral treatment. Results: AF and cirrhosis were identified in 71 (39.7%) and 28 (15.7%) patients, respectively. Compared with TE alone, sequential FIB-4-TE and APRI-TE algorithms saved a slightly higher number of liver biopsies for the identification of advanced fibrosis (69.3% or 68.2% vs 63.7%, P=0.263 or P=0.372, respectively). For the identification of cirrhosis, sequential FIB-4-TE and APRI-TE algorithms saved a significantly higher number of liver biopsies than TE alone (83.2% or 88.3% vs 69.8%, P=0.003 or P=0.000, respectively). No significant difference was found between the sequential algorithms and TE alone in the diagnostic accuracy for the detection of AF and cirrhosis. Conclusion: The sequential algorithms could significantly reduce the need for liver biopsy with high accuracy for diagnosis of AF and cirrhosis in CHB patients, which would be optimal especially in resource-limited areas.

A comprehensive review of radioactive pollution treatment of uranium mill tailings.

Natural uranium is a crucial resource for clean nuclear energy, which has brought significant economic and social benefits to humanity. However, the development and utilization of uranium resources have also resulted in the accumulation of vast amounts of uranium mill tailings (UMTs), which pose a potential threat to human health and the ecological environment. This paper reviews the research progress on UMTs treatment technologies, including cover disposal, solidification disposal, backfilling disposal, and bioremediation methods. It is found that cover disposal is a versatile method for the long-term management of UMTs, the engineering performance and durability of the cover system can be improved by choosing suitable stabilizers for the cover layer. Solidification disposal can convert UMTs into solid waste for permanent disposal, but it produces a large amount of waste and requires high operating costs; it is necessary to explore the effectiveness and efficiency of solidification disposal for UMTs, while minimizing the bad environmental impact. Backfilling disposal realizes the resource utilization of solid waste, but the high radon exhalation rate caused by the UMTs backfilling also needs to be considered. Bioremediation methods have low investment costs and are less likely to cause secondary pollution, but the remediation efficiency is low, it can be combined with other treatment technologies to remedy the defects of a single remediation method. The article concludes with key issues and corresponding suggestions for the current UMTs treatment methods, which can provide theoretical guidance and reference for further development and application of radioactive pollution treatment of UMTs.

A synthetic cell-free 36-enzyme reaction system for vitamin B12 production.

Adenosylcobalamin (AdoCbl), a biologically active form of vitamin B12 (coenzyme B12), is one of the most complex metal-containing natural compounds and an essential vitamin for animals. However, AdoCbl can only be de novo synthesized by prokaryotes, and its industrial manufacturing to date was limited to bacterial fermentation. Here, we report a method for the synthesis of AdoCbl based on a cell-free reaction system performing a cascade of catalytic reactions from 5-aminolevulinic acid (5-ALA), an inexpensive compound. More than 30 biocatalytic reactions are integrated and optimized to achieve the complete cell-free synthesis of AdoCbl, after overcoming feedback inhibition, the complicated detection, instability of intermediate products, as well as imbalance and competition of cofactors. In the end, this cell-free system produces 417.41 µg/L and 5.78 mg/L of AdoCbl using 5-ALA and the purified intermediate product hydrogenobyrate as substrates, respectively. The strategies of coordinating synthetic modules of complex cell-free system describe here will be generally useful for developing cell-free platforms to produce complex natural compounds with long and complicated biosynthetic pathways.

A novel technique of penetrating keratoplasty to prevent intraocular contents extrusion for infectious keratitis.

PURPOSE: To evaluate the safety and the effectiveness of our novel penetrating keratoplasty for infectious keratitis. METHODS: Retrospective, noncomparative, interventional case series of patients with infectious keratitis who received the novel penetrating keratoplasty technique were analyzed. A prepared plastic sheet was located between the diseased cornea and iris-lens diaphragm. After the diseased lesions were removed, the graft was positioned on the plastic sheet and sutured to the recipient bed. The plastic sheet was pulled out from the anterior chamber before the all interrupted sutures were placed. The intra- and post-operative complications, the outcome of the graft and the number of corneal endothelial cells were analyzed. RESULTS: A total of 82 eyes of 82 patients was included. The mean follow-up period was 29 ± 16 months (range from 13 to 45 months). No intraocular content extrusion, simultaneous cataract extraction and suprachoroidal hemorrhage occurred. Direct contact between the infectious cornea and the graft was successfully avoided. Greater than expected endothelial cell reduction or complications were not found. CONCLUSIONS: This modified technique effectively prevents the extrusion of intraocular contents while avoiding the direct contact with donor endothelium during the procedure. The occurrence rate of complications such as endothelial cell loss is not higher than the conventional methods.

[Difference in liver injury induced by dictamnine between males and females: based on untargeted metabolomics].

In recent years, reports of adverse reactions related to traditional Chinese medicine(TCM) have been on the rise, especially some traditionally considered "non-toxic" TCM(such as Dictamni Cortex). This has aroused the concern of scholars. This study aims to explore the metabolomic mechanism underlying the difference in liver injury induced by dictamnine between males and females through the experiment on 4-week-old mice. The results showed that the serum biochemical indexes of liver function and organ coefficients were significantly increased by dictamnine(P<0.05), and hepatic alveolar steatosis was mainly observed in female mice. However, no histopathological changes were observed in the male mice. Furthermore, a total of 48 differential metabolites(such as tryptophan, corticosterone, and indole) related to the difference in liver injury between males and females were screened out by untargeted metabolomics and multivariate statistical analysis. According to the receiver operating characteristic(ROC) curve, 14 metabolites were highly correlated with the difference. Finally, pathway enrichment analysis indicated that disorders of metabolic pathways, such as tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis(linoleic acid metabolism and arachidonic acid metabolism), may be the potential mechanism of the difference. Liver injury induced by dictamnine is significantly different between males and females, which may be caused by the disorders of tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis pathways.

Identification of differentially expressed HERV-K(HML-2) loci in colorectal cancer.

Colorectal cancer is one of the malignant tumors with the highest mortality rate in the world. Survival rates vary significantly among patients at various stages of the disease. A biomarker capable of early diagnosis is required to facilitate the early detection and treatment of colorectal cancer. Human endogenous retroviruses (HERVs) are abnormally expressed in various diseases, including cancer, and have been involved in cancer development. Real-time quantitative PCR was used to detect the transcript levels of HERV-K(HML-2) gag, pol, and env in colorectal cancer to systematically investigate the connection between HERV-K(HML-2) and colorectal cancer. The results showed that HERV-K(HML-2) transcript expression was significantly higher than healthy controls and was consistent at the population and cell levels. We also used next-generation sequencing to identify and characterize HERV-K(HML-2) loci that were differentially expressed between colorectal cancer patients and healthy individuals. The analysis revealed that these loci were concentrated in immune response signaling pathways, implying that HERV-K impacts the tumor-associated immune response. Our results indicated that HERV-K might serve as a screening tumor marker and a target for tumor immunotherapy in colorectal cancer.

Fatal, non-fatal burden of cancer in the elderly in China, 2005-2016: a nationwide registry-based study.

BACKGROUND: As populations age, cancer burden becomes increasingly conspicuous. This study quantified the cancer burden of the elderly (≥ 60 years) in China, based on the China Cancer Registry Annual Report to provide epidemiological evidence for cancer prevention and control. METHODS: Data on cancer cases and deaths among the elderly aged ≥ 60 years were collected from the China Cancer Registry Annual Report, 2008-2019. Potential years of life lost (PYLL) and disability-adjusted life years (DALY) were calculated to analyze fatalities and the non-fatal burden. The time trend was analyzed using the Joinpoint model. RESULTS: From 2005 to 2016, the PYLL rate of cancer in the elderly was stable between 45.34‰ and 47.62‰, but the DALY rate for cancer decreased at an average annual rate of 1.18% (95% CI: 0.84-1.52%). The non-fatal cancer burden in the rural elderly was higher than that of the urban elderly. Lung, gastric, liver, esophageal, and colorectal cancers were the main cancers causing the cancer burden in the elderly, and accounted for 74.3% of DALYs. The DALY rate of lung cancer in females in the 60-64 age group increased (annual percentage change [APC] = 1.14%, 95% CI: 0.10-1.82%). Female breast cancer was one of the top five cancers in the 60-64 age group, with DALY rates that also increased (APC = 2.17%, 95% CI: 1.35-3.01%). With increasing age, the burden of liver cancer decreased, while that of colorectal cancer rose. CONCLUSIONS: From 2005 to 2016, the cancer burden in the elderly in China decreased, mainly reflected in the non-fatal burden. Female breast and liver cancer were a more serious burden in the younger elderly, while colorectal cancer burden was mainly observed in the older elderly.

Identification of Two Novel HIV-1 Second-Generation Recombinant Forms (CRF01_AE/CRF07_BC) in Men Who Have Sex with Men in Hebei, China.

In recent years, men who have sex with men (MSM) have been identified as the primary source of HIV-1 transmission in Hebei Province, China. Co-circulation of multiple subtypes in HIV-1 positive MSM populations may contribute to the emergence of the second generation of recombinant HIV-1 strains, indicating the occurrence of dual infections or superinfections in MSM populations. Thus, the discovery of new recombinant strains is important to indicate the appearance of multiple infected individuals and the prevalence caused by changes in the parent strains. In this study, we present two new unique recombinant forms (URFs) from two HIV-1-positive subjects (HB070052 and HB070056) infected through homosexual contact in Hebei Province, China. The near full-length genome of the two URFs revealed that HB070052 was divided into seven segments by six breakpoints in the gag, pol, vif, and vpr genes; HB070056 was separated into five fragments by four breakpoints, with two regions of CRF07_BC inserted into a CRF01_AE backbone's gag, pol regions. The subregion tree showed CRF01_AE segments were traced back to the cluster 4 and 6 of the CRF01_AE phylogenetic tree, which were prevalent among HIV-1 infections through MSM in China. The continued emergence of the novel CRF01_AE/CRF07_BC recombinant forms indicates the HIV-1 epidemic is complex and long-term surveillance of recombinant strains is necessary among MSM in this region.

Optimization of Hydrogenobyrinic Acid Synthesis in a Cell-Free Multienzyme Reaction by Novel S-Adenosyl-methionine Regeneration.

Hydrogenobyrinic acid, a modified tetrapyrrole composed of eight five-carbon compounds, is a key intermediate and central framework of vitamin B12. Synthesis of hydrogenobyrinic acid requires eight S-adenosyl-methionine working as the methyl group donor catalyzed by 12 enzymes including six methyltransferases, causing the great shortage of S-adenosyl-methionine and accumulation of S-adenosyl-homocysteine, which is uneconomic and unsustainable for the cascade reaction. Here, we report a cell-free synthetic system for producing hydrogenobyrinic acid by integrating 12 enzymes using 5-aminolevulininate as a substrate and develop a novel S-adenosyl-methionine regeneration system to steadily supply S-adenosyl-methionine and avoid the accumulated inhibition of S-adenosyl-homocysteine by consuming a cheaper substrate (l-methionine and polyphosphate). By combination of the reaction system optimization and S-adenosyl-methionine regeneration, the titer of hydrogenobyrinic acid was improved from 0.61 to 29.39 mg/L in a 12 h reaction period, representing an increase of 48.18-fold, raising an efficient and rapidly evolutional alternative method to produce high-value-added compounds and intermediate products.

Heme oxygenase-1 inhibits the cytotoxicity of natural killer cells to acute myeloid leukemia by downregulating human leukocyte antigen-C.

BACKGROUND AIMS: Recently, immune escape has been considered as a factor leading to relapse of acute myeloid leukemia (AML). In our previous study, heme oxygenase 1 (HO-1) proved to play an essential role in the proliferation and drug resistance of AML cells. In addition, recent studies by our group have shown that HO-1 is involved in immune escape in AML. Nevertheless, the specific mechanism by which HO-1 mediates immune escape in AML remains unclear. METHODS: In this study, we found that patients with AML and an overexpression of HO-1 had a high rate of recurrence. In vitro, overexpression of HO-1 attenuated the toxicity of natural killer (NK) cells to AML cells. Further study indicated that HO-1 overexpression inhibited human leukocyte antigen-C and reduced the cytotoxicity of NK cells to AML cells, leading to AML relapse. Mechanistically, HO-1 inhibited human leukocyte antigen-C expression by activating the JNK/C-Jun signaling pathway. RESULTS: In AML, HO-1 inhibits cytotoxicity of NK cells by inhibiting the expression of HLA-C, thus causing immune escape of AML cells. CONCLUSIONS: NK cell-mediated innate immunity is important for the fight against tumors, especially when acquired immunity is depleted and dysfunctional, and the HO-1/HLA-C axis can induce functional changes in NK cells in AML. Anti-HO-1 treatment can promote the antitumor effect of NK cells and may play an important role in the treatment of AML.

A novel pupilloplasty in crescent-shaped suturing pattern for coloboma and traumatic iris defects.

OBJECTIVE: PURPOSE: To observe the safety and effect of the C-pupilloplasty for the treatment of iris coloboma and traumatic iris defects. METHODS: A total of 21 cases (21 eyes) with iris coloboma or traumatic iris defects who underwent C-pupilloplasty (a single-pass three-throw technique) from Feb. 2016 to Mar. 2020 were analyzed retrospectively. Uncorrected visual acuity, refraction, corneal topographic keratometry and endothelial cell density were examined. RESULTS: All the patients were successfully treated, and a central and round pupil was restored. The mean follow-up duration was 8.76 ± 3.58 months (ranging from 2 to 14 months). All patients had round or round-like pupils with a diameter less than or equal to 3 mm after the C-pupilloplasty. Very slightly endothelial loss, negligible symptoms such as glare, distortion, dizziness and photophobia were observed. CONCLUSION: We introduced a new technique of pupilloplasty (C-pupilloplasty) which could be a more straight forward and more effective treatment for iris coloboma and traumatic iris defect.

Machine learning estimation of crude oil viscosity as function of API, temperature, and oil composition: Model optimization and design space.

Measurement of viscosity of crude oil is critical for reservoir simulators. Computational modeling is a useful tool for correlation of crude oil viscosity to reservoir conditions such as pressure, temperature, and fluid compositions. In this work, multiple distinct models are applied to the available dataset to predict heavy-oil viscosity as function of a variety of process parameters and oil properties. The computational techniques utilized in this work are Decision Tree (DT), MLP, and GRNN which were utilized in estimation of heavy crude oil samples collected from middle eastern oil fields. For the estimation of viscosity, the firefly algorithm (FA) was employed to optimize the hyper-parameters of the machine learning models. The RMSE error rates for the final models of DT, MLP, and GRNN are 40.52, 25.08, and 30.83, respectively. Also, the R2-scores are 0.921, 0. 978, and 0.933, respectively. Based on this and other criteria, MLP is chosen as the best model for this study in estimating the values of crude oil viscosity.