MAX transcriptionally enhances PD-L1 to inhibit CD8+ T cell-mediated killing of lung adenocarcinoma cells.

Immune checkpoint blockade (ICB) therapies, such as monoclonal antibodies against the PD-1/PD-L1 immune checkpoint pathway, have been a major breakthrough in the treatment of lung cancer especially lung adenocarcinoma (LUAD), but their effectiveness is limited. High expression of PD-L1 in tumor cells is one of the key reasons evading immune surveillance, yet the mechanisms that regulate PD-L1 expression are not fully understood. By analyzing the chromatin immunoprecipitation sequencing data of MYC-associated X-factor (MAX) based on lung cancer cell lines, we found that the transcriptional regulator MAX is able to bind to the promoter region of the PD-L1 gene. Further, we performed several molecular biology experiments to determine that MAX promotes PD-L1 transcription in LUAD cells, which in turn assists LUAD cells to evade killing by CD8+ T cells, an effect that can be reversed by anti-PD-L1 antibody. In LUAD, the expression of MAX is positively correlated with PD-L1 and the infiltration of CD8+ T cells. Importantly, we further identified that high expression of the MAX/PD-L1 axis is associated with poor overall survival and fist progression of patients with LUAD. Thus, this study sheds light on the mechanism by which MAX inhibits CD8+ T cell-mediated killing of LUAD cells by activating PD-L1 transcription, and MAX may serve as a potential combinatorial target for ICB therapies that block the PD-1/PD-L1 pathway in LUAD.

Advanced machine learning algorithms to evaluate the effects of the raw ingredients on flowability and compressive strength of ultra-high-performance concrete.

The estimation of concrete characteristics through artificial intelligence techniques is come out to be an effective way in the construction sector in terms of time and cost conservation. The manufacturing of Ultra-High-Performance Concrete (UHPC) is based on combining numerous ingredients, resulting in a very complex composite in fresh and hardened form. The more ingredients, along with more possible combinations, properties and relative mix proportioning, results in difficult prediction of UHPC behavior. The main aim of this research is the development of Machine Learning (ML) models to predict UHPC flowability and compressive strength. Accordingly, sophisticated and effective artificial intelligence approaches are employed in the current study. For this purpose, an individual ML model named Decision Tree (DT) and ensembled ML algorithms called Bootstrap Aggregating (BA) and Gradient Boosting (GB) are applied. Statistical analyses like; Determination Coefficient (R2), Root Mean Square Error (RMSE), and Mean Absolute Error (MAE) are also employed to evaluate algorithms' performance. It is concluded that the GB approach appropriately forecasts the UHPC flowability and compressive strength. The higher R2 value, i.e., 0.94 and 0.95 for compressive and flowability, respectively, of the DT technique and lesser error values, have higher precision than other considered algorithms with lower R2 values. SHAP analysis reveals that limestone powder content and curing time have the highest SHAP values for UHPC flowability and compressive strength, respectively. The outcomes of this research study would benefit the scholars of the construction industry to quickly and effectively determine the flowability and compressive strength of UHPC.

Expressions of EZH2 and NOTCH3 pathway in osteosarcoma and their roles in osteosarcoma stem cells.

Osteosarcoma (OS) is the most common malignant bone tumour; however, the underlying mechanisms are mainly unknown. Enhancer of zeste homologue 2 (EZH2) and NOTCH pathway are important molecular signals related to carcinogenesis and tumour progression, but they are not fully understand in OS. Enhancer of zeste homologue 2, Notch3, HES1, and Nanog were detected on OS samples and statistically analysed. Expressions of these genes were investigate, and stem-like phenotype was verified in OS cells. This study found that higher EZH2 expression, Notch3 pathway, or Nanog were associated with tumour relapse and metastasis and a significantly shorter survival time. Moreover, the Notch3 pathway was activated in osteosarcoma stem cells. Enhancer of zeste homologue 2 overexpression could activate the Notch3 pathway and increase HES1 expression, leading to upregulated stem cell-related gene expression and self-renewal of OS cells. Our study demonstrates that EZH2, Notch3, and Nanog are important prognostic factors. Enhancer of zeste homologue 2 could maintain the self-renewal of OS cells, where the Notch3 pathway activation may be involved.

Angiotensin receptor blockers and breast cancer risk: a meta-analysis.

INTRODUCTION: Some studies reported that angiotensin receptor blockers (ARBs) reduced the risk of breast cancer. However, other studies did not show similar results. EVIDENCE ACQUISITION: The PubMed and EMBASE databases were searched. The strength of the association between ARBs and the risk of breast cancer was measured by odds ratio (OR) and 95% confidence interval (CI). EVIDENCE SYNTHESIS: Eight eligible studies with 1,994,880 individuals were considered for this meta-analysis. ARBs was not associated with the risk of breast cancer (OR=0.93; 95% CI: 0.81-1.06; I2=86%). In the subgroup analysis of race, a significantly decreased breast cancer risk were observed in Asians (OR=0.62; 95% CI: 0.53-0.73; I2=0%). However, a significantly increased breast cancer risk were observed in Caucasians (OR=1.08; 95% CI: 1.02-1.13; I2=28%). CONCLUSIONS: This study provided evidence that ARBs was associated with decreased breast cancer in Asians and increased risk of breast cancer in Caucasians.

The effect of prediabetes on hepatocellular carcinoma risk: a systematic review and meta-analysis.

INTRODUCTION: Some studies suggested an increased risk of hepatocellular carcinoma (HCC) risk in subjects with prediabetes, whereas other studies have reported negative results. Therefore, we did this meta-analysis to assess the role of prediabetes on HCC risk. EVIDENCE ACQUISITION: We searched studies from PubMed, Embase, and Web of Science databases. The strength of association between prediabetes and HCC risk was assessed by calculating hazard ratio (HR) with 95% CI. EVIDENCE SYNTHESIS: A total of 8 cohort studies and 1 case-control study with 1384594 individuals were included. Patients with prediabetes showed an increased HCC risk (HR=1.21; 95% CI, 1.13-1.30; P<0.00001). Subgroup analyses were performed according to race and gender. The results showed that both Asians with prediabetes (HR=1.19; 95% CI, 1.11-1.28; P<0.00001) and Caucasians with prediabetes (HR=2.12; 95% CI, 1.36-3.31; P=0.001 were significantly associated with increased risk of HCC, respectively. In the subgroup analysis by gender, both male patients with prediabetes (HR=1.49; 95% CI, 1.03-2.15; P=0.03) and female patients with prediabetes (HR=1.24; 95% CI, 1.01-1.52; P=0.04) showed increased risk of HCC, respectively. CONCLUSIONS: In conclusion, this meta-analysis demonstrated that prediabetes might be a risk factor of HCC.

Angiotensin-converting enzyme I/D polymorphism is a genetic biomarker of diabetic peripheral neuropathy: evidence from a meta-analysis.

The Angiotensin-converting enzyme (ACE) I/D polymorphism has been indicated to be correlated with peripheral neuropathy (PN) susceptibility, but study results are still debatable. Thus, a meta-analysis was conducted. Databases including PubMed, Embase and CNKI were searched. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Eight studies with 1430 cases and 1873 controls were included in this meta-analysis. The association between ACE I/D polymorphism and PN risk was significant (OR = 1.25; 95% CI 1.05-1.48; P = 0.01). When stratified by ethnicity, the significantly increased PN risk was observed in Caucasians (OR = 1.24; 95% CI 1.05-1.47; P = 0.01). In conclusion, this meta-analysis suggested that ACE I/D polymorphism was a risk factor for PN.

[Prevalence and clinical characteristics of orthostatic hypotension in the elderly and retired population].

OBJECTIVE: To determine the prevalence and clinical characteristics of orthostatic hypotension (OH) in the elderly and retired population. METHODS: A total of 1174 elderly and retired people underwent health screening physical examination in Guangzhou military region were included. The orthostatic blood pressure and heart rate were measured in supine position after resting for more than 5 minutes and at 0 and 2 min after standing. Subjects were divided into OH positive group and OH negative group. Orthostatic hypotension was defined as 20 mm Hg (1 mm Hg = 0.133 kPa) or greater decrease in SBP and/or 10 mm Hg or greater decrease in DBP after standing. RESULTS: The prevalence of OH in this cohort was 25.6% at either 0 or 2 min after standing (21.6% or 20.7% respectively). Incidence of hypertension, myocardial infarction (MI), heart failure (HF), ischemic stroke and diabetes was significantly higher in OH positive group than in OH negative group (all P < 0.05), however, antihypertensive medication was similar between the two groups. CONCLUSIONS: Orthostatic hypotension is common in the elderly and retired population and is associated with increased risk of hypertension, diabetes mellitus and cardiovascular disease.