BACKGROUND: Chronic periodontitis, an inflammation-related disorder affecting global populations, has been revealed to be linked to diverse cancers. Numerous epidemiological studies have not shown a link between chronic periodontitis and blood cancers in Taiwan. METHODS: This study included 601,628 patients, diagnosed with newly chronic periodontitis by the ICD-9-CM classification, who were enrolled from 2001 to 2021 in the National Health Insurance Research Database (NHIRD) in Taiwan. In this study, we employed comprehensive statistical analyses to investigate the association between chronic periodontitis and hematologic cancers. Initially, we calculated incidence density and used a Poisson regression to analyze relative risk. Subsequently, we compared the cumulative incidence of hematological cancer in both chronic and non-chronic periodontitis groups using the Kaplan-Meier method. RESULTS: The results revealed a significantly lower cumulative incidence of hematologic cancer in individuals with non-chronic periodontitis over a 12-year follow-up period. To further explore the risk factors, a Cox proportional hazard regression analysis was conducted. Being male (adjusted hazard ratio [aHR] = 1.21, 95% CI: 1.04 to 1.42; p = 0.014) and having hypertension (aHR = 1.34, 95% CI: 1.06 to 1.69; p = 0.015) were demonstrated to be associated with an increased risk of hematologic cancers, respectively. In addition, in a subtype multivariate analysis for categorizing hematologic cancers into lymphoma and leukemia, the aHR for leukemia was 1.48 (95% CI: 1.13 to 1.93; p = 0.004) and aHR for lymphoma was 1.15 (95% CI: 0.96 to 1.37; p = 0.140). CONCLUSIONS: This study found that being male and having hypertension were the significant risk factors for hematological malignancies. Moreover, the association between chronic periodontitis and specific subtypes of hematologic cancers was confirmed.
Background: Whether the estimated pulse wave velocity (ePWV) in Chinese patients with hypertension can serve as an independent predictor of cardiovascular and all-cause mortality remains unknown. Therefore, this study investigated the associations between ePWV and cardiovascular and all-cause mortalities and explored potential effect modifiers influencing these relationships. Finally, we compared the ePWV with the brachial-ankle pulse wave velocity (baPWV) to determine which parameter better predicts mortality. Methods: The population of this longitudinal cohort study was selected from the China H-type Hypertension Registry Study. The exposure and outcome variables were ePWV and all-cause and cardiovascular mortalities, respectively. The Cox proportional hazard regression model was applied to assess the associations between ePWV and all-cause and cardiovascular mortalities. The performances of ePWV and baPWV in predicting death were compared using the receiver operating characteristic (ROC) curve area, net reclassification improvement index (NRI), and integrated discrimination improvement index (IDI). Results: This prospective study enrolled 14,232 patients with hypertension. Following an average follow-up of 48 months, 806 individuals succumbed to all-cause mortality, with 397 cases specifically attributed to cardiovascular diseases. The Cox proportional regression analysis revealed a significant association between a 1â m/s increase in ePWV and a 37% higher risk of all-cause mortality (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.31-1.43) as well as a 52% higher risk of cardiovascular mortality (HR: 1.52, 95% CI: 1.43-1.62) in the fully adjusted model. The findings for ePWV according to quartile demonstrated hazard ratios for all-cause mortality for Q2 (10.25 < ePWV < 11.32), Q3 (11.32 < ePWV < 12.40), and Q4 (ePWV ≥ 12.40) of 1.50 (HR: 1.50, 95% CI: 1.07-2.10), 2.34 (HR: 2.34, 95% CI: 1.73-3.18), and 4.09 (HR: 4.09, 95% CI: 3.05-5.49), respectively, compared with Q1 (ePWV < 10.25). The risk of cardiovascular death also increased in proportion to the rise in ePWV. The results of the area under the ROC curve, NRI, and IDI all indicated that ePWV outperformed baPWV in predicting mortality. The results of the subgroup analysis demonstrated that body mass index (BMI) and hypoglycemic drug use modified the association between ePWV and mortality. Conclusions: The performance of ePWV in predicting all-cause and cardiovascular mortalities was superior to that of baPWV alone. Patients who were overweight or obese with higher ePWV values exhibited a significantly increased risk of all-cause death. The correlation between elevated ePWV and the risk of cardiovascular death was more pronounced in patients who had not received hypoglycemic drugs.
In this paper, a precise and efficient method to optimize corrugated tube heat exchangers is proposed by combining computational fluid dynamics simulation with optimization. The optimization of tubular heat exchangers involves contradictory Colburn coefficient j, and the friction coefficient f, so it is a multi-objective optimization problem. The approximate model is obtained by an extreme learning machine, and the structure parameter of the heat exchanger is optimized by the nondominated sorting genetic algorithm-â ¡. Compared to the results between the original and optimized tube, the optimized structure Colburn coefficient increased by 5.1 % and the friction coefficient decreased by 9.3 %. Finally, the internal flow field is compared qualitatively from temperature, pressure, and velocity. The optimization effect is further emphasized by using the field synergy theory.
BACKGROUND: Ubiquitin-conjugating enzyme E2 N (UBE2N) is recognized in the progression of some cancers; however, little research has been conducted to describe its role in prostate cancer. The purpose of this paper is to explore the function and mechanism of UBE2N in prostate cancer cells. METHODS: UBE2N expression was detected in Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data, prostate cancer tissue microarrays, and prostate cancer cell lines, respectively. UBE2N knockdown or overexpression was used to analyze its role in cell viability and glycolysis of prostate cancer cells and tumor growth. XAV939 or Axin1 overexpression was co-treated with UBE2N overexpression to detect the involvement of the Wnt/ß-catenin signaling and Axin1 in the UBE2N function. UBE2N interacting with Axin1 was analyzed by co-immunoprecipitation assay. RESULTS: UBE2N was upregulated in prostate cancer and the UBE2N-high expression correlated with the poor prognosis of prostate cancer. UBE2N knockdown inhibited cell viability and glycolysis in prostate cancer cells and restricted tumor formation in tumor-bearing mice. Wnt/ß-catenin inhibition and Axin1 overexpression reversed the promoting viability and glycolysis function of UBE2N. UBE2N promoted Axin1 ubiquitination and decreased Axin1 protein level.
Axin Protein , Cell Survival , Glycolysis , Prostatic Neoplasms , Ubiquitin-Conjugating Enzymes , Ubiquitination , Animals , Humans , Male , Mice , Axin Protein/metabolism , Axin Protein/genetics , Cell Line, Tumor , Mice, Nude , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/genetics , Ubiquitin-Conjugating Enzymes/metabolism , Ubiquitin-Conjugating Enzymes/genetics , Wnt Signaling Pathway
Rose black spot disease, caused by Marssonina rosae (syn. Diplocarpon rosae), is one of the most widespread diseases of field-grown roses worldwide. Pathogens have been found to interfere with or stimulate plant immune response through the secreted effectors. However, the molecular mechanism involved in inhibition of rose immune response by M. rosae effectors remains poorly understood. In this study, we identified the effector MrSEP43, which played a pivotal role in promoting the virulence of M. rosae and enhancing rose susceptibility by reducing callose deposition, H2O2 accumulation, and the expression of defense genes in jasmonic acid signaling pathway. Through Y2H, BiFC, and LUC assays, MrSEP43 was proved to interact with the rose orphan protein RcBROG. RcBROG, which was a positive regulator of defense against M. rosae, enhanced rose resistance by increasing callose deposition, H2O2 accumulation, and expression of RcERF1 in the ethylene signaling pathway. Overall, our findings suggested that the virulence effector MrSEP43 from M. rosae specifically targeted the orphan protein RcBROG to suppress rose immune response to M. rosae. These results provided new insight into how M. rosae manipulated and successfully colonized rose leaves, and were essential for preventing the breakdown of resistance to rose black spot disease.
An unprecedented 1,5-addition/N-1,4-addition cascade reaction is established via palladium hydride catalysis. A variety of polysubstituted dihydropyrrole skeletons are constructed in high yield and with exclusively >20:1 diastereoselectivity. An enantioselective protocol of this design is also developed to provide a novel access to enantioenriched dihydropyrroles.
Rosehips are a prominent source of numerous bioactive compounds. However, despite their extensive potential, the metabolic profiles among different rosehip species have not been fully elucidated. In this study, 523 secondary metabolites from rosehips of 12 Rosa species were identified using ultra-high-performance liquid chromatography-tandem mass spectrometry. They were primarily composed of flavonoids and phenolic acids. A K-means analysis revealed the characteristic metabolites in different rosehips. For example, R. persica contained a more abundant supply of phenolic acids, while R. roxburghii harbored a richer array of terpenoids. A total of 73 key active ingredients were screened from traditional Chinese medicine databases, and they indicated that R. persica is more promising for use in functional foods or health supplements compared with the other fruits. Moreover, a differential analysis identified 47 compounds as potential contributors to the astringent taste of rosehips, including ellagic acid 4-O-glucoside and cadaverine. This study provides valuable information to develop new functional foods of rosehips and improve the quality of their fruits.
The average life of a dog is generally maintained at ten to fifteen years, and tumours are the predominant reason that leads to the death of dogs, especially canine mammary carcinoma. Therefore, early diagnosis of tumours is very important. In this study, tumor size, morphology, and texture could be seen through general clinical examination, tumor metastasis could be seen through imaging examination, inflammatory reactions could be seen through hematological examination, and abnormal cell morphology could be seen through cytological and histopathological examination. In the 269 malignant cases and 179 benign cases, we randomly selected 30 cases each, and an additional 30 healthy dogs were selected for the experiment (healthy dogs: dogs in good physical condition without any tumor or other diseases). We used RT-qPCR and ELISA to determine the relative expression of vascular endothelial growth factor (VEGF), tumor protein P53 (P53), serum ferritin (SF), and NOD-like receptor protein 3 (NLRP3) in 30 healthy dogs, 30 dogs with benign mammary tumours, and 30 dogs with malignant mammary tumours. In the results, the same expression trend was obtained both in serum and tissues, and the expression of the four markers was the highest in malignant mammary tumours, with highly significant differences compared with the benign and healthy/paracancerous groups. By plotting the ROC curves, it was found that the results of combined tests were better than a single test and the combination of the four markers was the best for the early diagnosis. In conclusion, this can assist the clinical early diagnosis to a certain extent, and also provides some references and assistance for the development of tumor detection kits in clinical practice.
Vascular endothelial cells play a critical role in maintaining the health of blood vessels, but dysfunction can lead to cardiovascular diseases. The impact of arsenite exposure on cardiovascular health is a significant concern due to its potential adverse effects. This study aims to explore how NBR1-mediated autophagy in vascular endothelial cells can protect against oxidative stress and apoptosis induced by arsenite. Initially, our observations revealed that arsenite exposure increased oxidative stress and triggered apoptotic cell death in human umbilical vein endothelial cells (HUVECs). However, treatment with the apoptosis inhibitor Z-VAD-FMK notably reduced arsenite-induced apoptosis. Additionally, arsenite activated the autophagy pathway and enhanced autophagic flux in HUVECs. Interestingly, inhibition of autophagy exacerbated arsenite-induced apoptotic cell death. Our findings also demonstrated the importance of autophagy receptor NBR1 in arsenite-induced cytotoxicity, as it facilitated the recruitment of caspase 8 to autophagosomes for degradation. The protective effect of NBR1 against arsenite-induced apoptosis was compromised when autophagy was inhibited using pharmacological inhibitors or through genetic knockdown of essential autophagy genes. Conversely, overexpression of NBR1 facilitated caspase 8 degradation and reduced apoptotic cell death in arsenite-treated HUVECs. In conclusion, our study highlights the vital role of NBR1-mediated autophagic degradation of caspase 8 in safeguarding vascular endothelial cells from arsenite-induced oxidative stress and apoptotic cell death. Targeting this pathway could offer a promising therapeutic approach to mitigate cardiovascular diseases associated with arsenite exposure.
Apoptosis , Arsenites , Autophagy , Caspase 8 , Human Umbilical Vein Endothelial Cells , Oxidative Stress , Humans , Arsenites/toxicity , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Apoptosis/drug effects , Autophagy/drug effects , Caspase 8/metabolism , Caspase 8/genetics , Oxidative Stress/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Proteolysis/drug effects , Cells, Cultured
As the population continues to age, there is a growing need for elderly care services. In China, home care is widely embraced as a preferred method of caring for the elderly, and it has a promising commercial outlook. The strategic allocation of Elderly Care Service Personnel (ECSP) is a crucial component of the operational procedures for home care services. By strategically assigning elderly service personnel, it is possible to enhance the satisfaction and simultaneously minimize expenses. The issue of rationalizing the assignment of ECSP in the face of restricted resources is a genuine challenge that requires a solution, given the many types of elderly service demands and the skill requirements and time limits of certain projects. This study presents a strategy for assigning personnel on an hourly basis, taking into account time frame limits. This method involves several steps. Firstly, it involves assessing the specific service needs of the elderly, including the required door-to-door service time, service level, and gender preferences. Secondly, it calculates the service satisfaction and service operation cost of the Home Care Service Platform (HCSP) separately. Finally, it constructs a multi-objective elderly service personnel assignment method. This method aims to minimize the ECSP 's travel time and wasted time, maximize the satisfaction of the elderly by considering priority levels and ECSP scores, and minimize the operation cost of the HCSP. A model is developed to assign ECSP for elderly individuals, with the goal of minimizing travel time and wasted time, maximizing elderly satisfaction by considering priority and service personnel rating, and minimizing operating costs for the HCSP. Additionally, if there are unserved elderly individuals, an optimized path model is constructed using a cross-modified genetic algorithm to obtain the optimal matching result. Ultimately, an arithmetic example is employed to demonstrate the practicality and efficiency of the strategy put forth in this research. The findings demonstrate that the model presented in this research possesses distinct advantages in comparison to other conventional models.
The redox mediated photoelectrochemical (PEC) or electrochemical (EC) alkene oxidation process is a promising method to produce high value-added epoxides. However, due to the competitive reaction of water oxidation and overoxidation of the mediator, the utilization of the electricity is far below the ideal value, where the loss of epoxidation's faradaic efficiency (FE) is ≈50%. In this study, a Br-/HOBr-mediated method is developed to achieve a near-quantitative selectivity and ≈100% FE of styrene oxide on α-Fe2O3, in which low concentration of Br- as mediator and locally generated acidic micro-environment work together to produce the higher active HOBr species. A variety of styrene derivatives are investigated with satisfied epoxidation performance. Based on the analysis of local pH-dependent epoxidation FE and products distribution, the study further verified that HOBr serves as the true active mediator to generate the bromohydrin intermediate. It is believed that this strategy can greatly overcome the limitation of epoxidation FE to enable future industrial applications.
This study aimed to investigate the knowledge about, attitudes toward, and acceptance and predictors of receiving the mpox vaccine among Chinese cancer patients. Patients were selected using a convenience sampling method. A web-based self-report questionnaire was developed to assess cancer patients' knowledge, attitudes, and acceptance regarding the mpox vaccine. Multivariate logistic regression analysis was used to determine predictors of acceptance of the mpox vaccine. A total of 805 cancer patients were included in this study, with a vaccine hesitancy rate of 27.08%. Approximately 66% of the patients' information about mpox and the vaccine came from the mass media, and there was a significant bias in the hesitant group's knowledge about mpox and the vaccine. Multivariable logistic regression analysis suggested that retirement; chemotherapy; the belief that the mpox vaccine could prevent disease, that vaccination should be compulsory when appropriate and that the mpox vaccine prevents mpox and reduces complications; the willingness to pay for the mpox vaccine; the willingness to recommend that friends and family receive the mpox vaccine; and the belief that the mpox vaccine should be distributed fairly and equitably were factors that promoted vaccination. The belief that mpox worsens tumor prognosis was a driving factor for vaccine hesitancy. This study investigated the knowledge of cancer patients about mpox and the vaccine, evaluated the acceptance and hesitancy rates of the mpox vaccine and examined the predictors of vaccination intention. We suggest that the government scientifically promote the vaccine and develop policies such as free vaccination and personalized vaccination to increase the awareness and acceptance rate of the mpox vaccine.
Health Knowledge, Attitudes, Practice , Neoplasms , Patient Acceptance of Health Care , Humans , Male , Female , China , Cross-Sectional Studies , Middle Aged , Neoplasms/psychology , Adult , Patient Acceptance of Health Care/psychology , Surveys and Questionnaires , Aged , Cancer Vaccines , Vaccination Hesitancy/psychology , Vaccination Hesitancy/statistics & numerical data , Vaccination/psychology , Vaccination/statistics & numerical data , Intention , Young Adult
Background: The associations of body fat parameters with arterial stiffness measured by brachial-ankle pulse wave velocity in hypertensive patients were scarce. Methods: This cross-sectional study analyzed 4322 hypertensive adults. The correlations between the anthropometric indexes (body mass index [BMI], waist circumference, waist-tohip ratio [WHR], waist-to-height ratio [WHtR], a body shape index [ABSI], body round index [BRI]) and ba-PWV values were analyzed using multivariable linear regression model. Results: In both sex categories, linear regression models showed that BMI levels were inversely related to baPWV (adjusted-ß per SD increase in male: -0.51, 95% CI -0.66 to -0.36, P < 0.001; female: -0.50, 95% CI -0.63 to -0.37, P < 0.001). Waist circumference positively correlated with baPWV only in male hypertensive individuals. BaPWV positively correlated to WHR or WHtR levels (adjusted-ß per SD increase: 0.32, 95% CI 0.21 to 0.43, P < 0.001; 0.64, 95% CI 0.47 to 0.82, P < 0.001; respectively), ABSI (adjusted-ß per SD increase for ABSI × 100: 0.27, 95% CI 0.18 to 0.36, P < 0.001) and BRI (adjusted-ß per SD increase: 0.64, 95% CI 0.46 to 0.81, P < 0.001) levels. The relationship between anthropometric indices and arterial stiffness based on baPWV values were also consistent. ABSI had the highest predictive power of arterial stiffness (area under the curve, 0.594; P < 0.001). Conclusion: In Chinese adults with hypertension, BMI was inversely related to baPWV, while WHR, WHtR, ABSI and BRI were positively related. Waist circumference positively correlated with baPWV only in male hypertensive individuals.
MAIN CONCLUSION: IAA cooperates with JA to inhibit SA and negatively regulates rose black spot disease resistance. Black spot disease caused by the fungus Marssonina rosae is the most prevalent and severe ailment in rose cultivation, leading to the appearance of black spots on leaves and eventual leaf fall, significantly impacting the utilization of roses in gardens. Salicylic acid (SA) and jasmonic acid (JA) are pivotal hormones that collaborate with indole-3 acetic acid (IAA) in regulating plant defense responses; however, the detailed mechanisms underlying the induction of black spot disease resistance by IAA, JA, and SA remain unclear. In this study, transcript analysis was conducted on resistant (R13-54) and susceptible (R12-26) lines following M. rosae infection. In addition, the impact of exogenous interference with IAA on SA- and JA-mediated disease resistance was examined. The continuous accumulation of JA, in synergy with IAA, inhibited activation of the SA signaling pathway in the early infection stage, thereby negatively regulating the induction of effective resistance to black spot disease. IAA administration alleviated the inhibition of SA on JA to negatively regulate the resistance of susceptible strains by further enhancing the synthesis and accumulation of JA. However, IAA did not contribute to the negative regulation of black spot resistance when high levels of JA were inhibited. Virus-induced gene silencing of RcTIFY10A, an inhibitor of the JA signaling pathway, further suggested that IAA upregulation led to a decrease in disease resistance, a phenomenon not observed when the JA signal was inhibited. Collectively, these findings indicate that the IAA-mediated negative regulation of black spot disease resistance relies on activation of the JA signaling pathway.
Disease Resistance , Salicylic Acid , Salicylic Acid/metabolism , Disease Resistance/genetics , Cyclopentanes/metabolism , Oxylipins/metabolism , Signal Transduction , Acetates/pharmacology , Plant Diseases/microbiology , Gene Expression Regulation, Plant
Background/purpose: Local anesthesia (LA) training is an essential clinical skill in dental education. However, the traditional teaching method of student-to-student injection has ethical concerns. This study investigated whether a flipped classroom (FC) teaching model with instructional videos improves students' skills in administering LA. Materials and methods: Fourth-year dental students in 2017 (traditional teaching, n = 70) and 2018 (FC model, n = 79) were assessed for their ability to perform an inferior alveolar nerve block and lingual nerve block. The FC group watched pre-recorded videos prior to a hands-on training session. Skills were evaluated using a 24-item checklist converted to letter grades. Perceptions of the FC approach were also surveyed. Results: The FC group showed statistically significantly higher final grades than the traditional teaching group (P < 0.05). Most FC students agreed that the videos improved clarity and learning objectives. Conclusion: The FC teaching model with procedural video instruction improved skills and confidence in administering LA over traditional teaching methods. Videos can be a beneficial supplement in pre-clinical dental training.
BACKGROUND: The prognostic value of carbohydrate antigen 19-9 (CA19-9) is known to be affected by elevated bilirubin levels in patients with gallbladder carcinoma (GBC). The clinical significance of changes in the ratio of CA19-9 levels to total bilirubin (TB) levels in patients with GBC after curative-intent resection remains unknown. The aim of this study was to determine the prognostic value of changes in preoperative and postoperative CA19-9/TB ratio in these patients. METHODS: Prospectively colleced data on consecutive patients who underwent curative-intent resection for GBC between January 2015 and December 2020 stored in a multicenter database from 10 hospitals were analysed in this retrospective cohort study. Based on the adjusted CA19-9 defined as the ratio of CA19-9 to TB, and using 2×103 U/µmol as the upper normal value, patients were divided into a normal group (with normal preoperative and postoperative adjusted CA19-9), a normalization group (with abnormal preoperative but normal postoperative adjusted CA19-9), and a non-normalization group (with abnormal postoperative adjusted CA19-9). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare OS and RFS among the groups. The Cox regression model was used to determine factors independently associated with OS and RFS. RESULTS: The normal group (n=179 patients) and the normalization group (n=73 patients) had better OS and RFS than the non-normalization group (n=65 patients) (the 3-year OS rates 72.0%, 58.4% and 24.2%, respectively; the RFS rates 54.5%, 25.5% and 11.8%, respectively; both P<0.001). There were no significant differences between the normal and the normalization groups in OS and RFS (OS, P=0.255; RFS, P=0.130). Cox regression analysis confirmed that the non-normalization group was independently associated with worse OS and RFS. Subgroup analysis revealed that the non-normalization group of patients who received adjuvant therapy had significantly improved OS and RFS as compared to those who did not receive adjuvant therapy (OS, P=0.025; RFS, P=0.003). CONCLUSIONS: Patients with GBC who underwent curative-intent surgical resection with postoperative abnormal levels of adjusted CA19-9 (the CA19-9/TB ratio) were associated with poorer long-term survival outcomes. Adjuvant therapy after surgery improved the long-term outcomes of these patients.
OBJECTIVE: This study evaluates the effectiveness of incorporating the Chat Generative Pre-trained Transformer (ChatGPT) into the clinical teaching of hepatobiliary surgery for undergraduate medical students. MATERIALS AND METHODS: A group of 61 medical undergraduates from the Affiliated Hospital of Guizhou Medical University, undergoing hepatobiliary surgery training, were randomly assigned to either an experimental group (31 students) using ChatGPT-based blended teaching or a control group (30 students) with traditional teaching methods. The evaluation metrics included final exam scores, teaching satisfaction, and teaching effectiveness ratings, analyzed using SPSS 26.0 (SPSS Inc., Chicago, IL) with t-tests and χ2 tests. RESULTS: The experimental group significantly outperformed the control group in final exam theoretical scores (86.44 ± 5.59 vs. 77.86 ± 4.16, p < .001) and clinical skills scores (83.84 ± 6.13 vs. 79.12 ± 4.27, p = .001). Additionally, the experimental group reported higher teaching satisfaction (17.23 ± 1.33) and self-evaluation of teaching effectiveness (9.14 ± 0.54) compared to the control group (15.38 ± 1.5 and 8.46 ± 0.70, respectively, p < .001). CONCLUSIONS: The integration of ChatGPT into hepatobiliary surgery education significantly enhances theoretical knowledge, clinical skills, and overall satisfaction among medical undergraduates, suggesting a beneficial impact on their educational development.
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by challenges in treatment, including drug resistance and frequent relapse. Recent research highlights the crucial roles of tumor microenvironment (TME) in assisting tumor cell immune escape and promoting tumor aggressiveness. This study delves into the interplay between AML and TME. Through the exploration of potential driver genes, we constructed an AML prognostic index (AMLPI). Cross-platform data and multi-dimensional internal and external validations confirmed that the AMLPI outperforms existing models in terms of areas under the receiver operating characteristic curves, concordance index values, and net benefits. High AMLPIs in AML patients were indicative of unfavorable prognostic outcomes. Immune analyses revealed that the high-AMLPI samples exhibit higher expression of HLA-family genes and immune checkpoint genes (including PD1 and CTLA4), along with lower T cell infiltration and higher macrophage infiltration. Genetic variation analyses revealed that the high-AMLPI samples associate with adverse variation events, including TP53 mutations, secondary NPM1 co-mutations, and copy number deletions. Biological interpretation indicated that ALDH2 and SPATS2L contribute significantly to AML patient survival, and their abnormal expression correlates with DNA methylation at cg12142865 and cg11912272. Drug response analyses revealed that different AMLPI samples tend to have different clinical selections, with low-AMLPI samples being more likely to benefit from immunotherapy. Finally, to facilitate broader access to our findings, a user-friendly and publicly accessible webserver was established and available at http://bioinfor.imu.edu.cn/amlpi. This server provides tools including TME-related AML driver genes mining, AMLPI construction, multi-dimensional validations, AML patients risk assessment, and figures drawing.
Leukemia, Myeloid, Acute , Nucleophosmin , Humans , Prognosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , DNA Methylation , Tumor Microenvironment , Aldehyde Dehydrogenase, Mitochondrial/genetics , Aldehyde Dehydrogenase, Mitochondrial/metabolism
Hepatocellular carcinoma (HCC) is a common type of cancer that ranks first in cancer-associated death worldwide. Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are the key components of the pyrimidine pathway, which promotes cancer development. However, the function of CAD in HCC needs to be clarified. In this study, the clinical and transcriptome data of 424 TCGA-derived HCC cases were analyzed. The results demonstrated that high CAD expression was associated with poor prognosis in HCC patients. The effect of CAD on HCC was then investigated comprehensively using GO annotation analysis, KEGG enrichment analysis, Gene Set Enrichment Analysis (GSEA), and CIBERSORT algorithm. The results showed that CAD expression was correlated with immune checkpoint inhibitors and immune cell infiltration. In addition, low CAD levels in HCC patients predicted increased sensitivity to anti-CTLA4 and PD1, while HCC patients with high CAD expression exhibited high sensitivity to chemotherapeutic and molecular-targeted agents, including gemcitabine, paclitaxel, and sorafenib. Finally, the results from clinical sample suggested that CAD expression increased remarkably in HCC compared with non-cancerous tissues. Loss of function experiments demonstrated that CAD knockdown could significantly inhibit HCC cell growth and migration both in vitro and in vivo. Collectively, the results indicated that CAD is a potential oncogene during HCC metastasis and progression. Therefore, CAD is recommended as a candidate marker and target for HCC prediction and treatment.
