Design of Machine Learning Algorithms and Internal Validation of a Kidney Risk Prediction Model for Type 2 Diabetes Mellitus.

Objective: This study aimed to explore specific biochemical indicators and construct a risk prediction model for diabetic kidney disease (DKD) in patients with type 2 diabetes (T2D). Methods: This study included 234 T2D patients, of whom 166 had DKD, at the First Hospital of Jilin University from January 2021 to July 2022. Clinical characteristics, such as age, gender, and typical hematological parameters, were collected and used for modeling. Five machine learning algorithms [Extreme Gradient Boosting (XGBoost), Gradient Boosting Machine (GBM), Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF)] were used to identify critical clinical and pathological features and to build a risk prediction model for DKD. Additionally, clinical data from 70 patients (nT2D = 20, nDKD = 50) were collected for external validation from the Third Hospital of Jilin University. Results: The RF algorithm demonstrated the best performance in predicting progression to DKD, identifying five major indicators: estimated glomerular filtration rate (eGFR), glycated albumin (GA), Uric acid, HbA1c, and Zinc (Zn). The prediction model showed sufficient predictive accuracy with area under the curve (AUC) values of 0.960 (95% CI: 0.936-0.984) and 0.9326 (95% CI: 0.8747-0.9885) in the internal validation set and external validation set, respectively. The diagnostic efficacy of the RF model (AUC = 0.960) was significantly higher than each of the five features screened with the highest feature importance in the RF model. Conclusion: The online DKD risk prediction model constructed using the RF algorithm was selected based on its strong performance in the internal validation.

Safety, Tolerability, and Pharmacokinetics of the Novel Hepatitis B Virus Expression Inhibitor GST-HG131 in Healthy Chinese Subjects: a First-in-Human Single- and Multiple-Dose Escalation Trial.

GST-HG131, a novel dihydroquinolizinone (DHQ) compound, has been shown to reduce circulating levels of HBsAg in animals. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetic profile of GST-HG131 in healthy Chinese subjects. This was a double-blind, randomized, placebo-controlled phase Ia clinical trial that was conducted in two parts. Part A was a single-ascending-dose (SAD; GST-HG131 10 30, 60, 100, 150, 200, 250 or 300 mg or placebo) study, which also assessed the food effect of GST-HG131 100 mg. Part B was a multiple-ascending-dose (MAD; GST-HG131 30, 60 or 100 mg or placebo BID) study. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. PK analyses were conducted in blood, urine, and fecal samples. Single doses of GST-HG131 ≤ 300 mg and multiple doses of GST-HG131 ≤ 60 mg were generally safe and well tolerated; however, multiple dosing was stopped at GST-HG131 100 mg, as pre-defined stopping rules specified in the protocol were met (Grade II drug related AEs of nausea and dizziness in >50% of subjects). In the SAD study, median tmax of GST-HG131 was 1-6 h, and t1/2 ranged from 3.88 h to 14.3 h. PK parameters were proportional to dose. Exposure was reduced after food intake. In the MAD study, steady-state was attained on day 4, and there was no apparent plasma accumulation of GST-HG131 on day 7 (Racc < 1.5). In conclusion, GST-HG131 exhibited an acceptable safety profile in healthy subjects at single doses ranging from 10-300 mg and multiple doses (BID) ranging from 30-60 mg, and the MAD doses (30 mg and 60 mg BID) that potentially meet the therapeutic AUC requirements. These findings imply GST-HG131 has potential as a therapeutic option for CHB infection. (This study has been registered at ClinicalTrials.gov under identifier NCT04499443.).

Signature RNAS and related regulatory roles in type 1 diabetes mellitus based on competing endogenous RNA regulatory network analysis.

BACKGROUND: Our study aimed to investigate signature RNAs and their potential roles in type 1 diabetes mellitus (T1DM) using a competing endogenous RNA regulatory network analysis. METHODS: Expression profiles of GSE55100, deposited from peripheral blood mononuclear cells of 12 T1DM patients and 10 normal controls, were downloaded from the Gene Expression Omnibus to uncover differentially expressed long non-coding RNAs (lncRNAs), mRNAs, and microRNAs (miRNAs). The ceRNA regulatory network was constructed, then functional and pathway enrichment analysis was conducted. AT1DM-related ceRNA regulatory network was established based on the Human microRNA Disease Database to carry out pathway enrichment analysis. Meanwhile, the T1DM-related pathways were retrieved from the Comparative Toxicogenomics Database (CTD). RESULTS: In total, 847 mRNAs, 41 lncRNAs, and 38 miRNAs were significantly differentially expressed. The ceRNA regulatory network consisted of 12 lncRNAs, 10 miRNAs, and 24 mRNAs. Two miRNAs (hsa-miR-181a and hsa-miR-1275) were screened as T1DM-related miRNAs to build the T1DM-related ceRNA regulatory network, in which genes were considerably enriched in seven pathways. Moreover, three overlapping pathways, including the phosphatidylinositol signaling system (involving PIP4K2A, INPP4A, PIP4K2C, and CALM1); dopaminergic synapse (involving CALM1 and PPP2R5C); and the insulin signaling pathway (involving CBLB and CALM1) were revealed by comparing with T1DM-related pathways in the CTD, which involved four lncRNAs (LINC01278, TRG-AS1, MIAT, and GAS5-AS1). CONCLUSION: The identified signature RNAs may serve as important regulators in the pathogenesis of T1DM.

Overexpression of the long non-coding RNA Oprm1 alleviates apoptosis from cerebral ischemia-reperfusion injury through the Oprm1/miR-155/GATA3 axis.

Numerous differentially expressed long non-coding RNAs (lncRNAs) have been identified in cerebral ischemia-reperfusion (I/R) injury using RNA-Seq analysis. However, little is known about whether and how lncRNAs are involved in cerebral I/R injury. In this study, we investigated the function of the lncRNA Oprm1 in cerebral I/R injury and explored the underlying mechanism. An oxygen-glucose deprivation model in N2a cells was utilized to mimic cerebral I/R injury in vitro. Trypan blue staining, terminal deoxytransferase-mediated dUTP-biotin nick end labelling and caspase-3 were measured to evaluate apoptosis. Middle cerebral artery occlusion was performed in mice to evaluate the function of lncRNA Oprm1 in vivo. Real-time PCR and western blotting were used to measure the expression levels of lncRNA Opmr1, caspase-3, miR-155, GATA binding protein 3 (GATA3) and nuclear factor (NF)-κB. lncRNA Oprm1 was mainly located in the cytoplasm. Overexpression of lncRNA Oprm1 alleviated the apoptosis induced by oxygen-glucose deprivation and significantly reduced cleaved caspase-3 levels. Infarct size was distinctly decreased in the lncRNA Oprm1-overexpression group. The neurological score was also improved. Our findings showed that the lncRNA Oprm1/miR-155/GATA3 axis plays an important role in cerebral I/R injury. lncRNA Oprm1 may attenuate cerebral injury through the NF-κB pathway. lncRNA Oprm1 may serve as a potential target for new therapeutic interventions in patients with ischemic stroke.

Inhibition of C-X-C Motif Chemokine 10 (CXCL10) Protects Mice from Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease characterized by long-term breathing problems and poor airflow. COPD can progress to persistent decline of pulmonary function. This study explored the effect of CXCL10 on COPD induced by cigarette smoke (CS) and its underlying mechanism. MATERIAL AND METHODS Wild-type (WT) mice were randomly assigned into 3 groups: the control group, the CS group, and the intervention group. Mice in the CS group were exposed to CS and mice in the CXCL10 group were exposed to CS and CXCL10 neutralizing antibody. At 24 h after the last CS exposure, body weight and lung functions of each mouse were recorded. Mice were then anesthetized for collecting bronchoalveolar lavage fluid (BALF) and lung tissues. Levels of interleukin-6 (IL-6), keratinocyte chemotactic factor (KC), and monocyte chemoattractant protein-1 (MCP-1) in supernatant and lung homogenate were detected by ELISA and real-time PCR (RT-PCR), respectively. For in vitro experiments, human bronchial epithelial cells 16HBE were stimulated with different concentrations of cigarette smoke extract (CSE) and CXCL10. Cell viability and levels of inflammatory cytokines in the cell supernatant were detected by Cell Counting Kit-8 (CCK-8) and ELISA assay, respectively. RESULTS Our data showed significant weight loss and reduction of lung functions in mice in the CS group compared with those in the control group and intervention group. Increased levels of IL-6, KC, and MCP-1 in BALF and lung homogenate were observed in mice in the model group compared to those in the control group and intervention group. In vitro experiments also confirmed that CXCL10-neutralizing antibody can inhibit CSE-induced cell necrosis and activation of inflammatory cytokines. CONCLUSIONS Inhibited CXCL10 protects against COPD progression by decreasing secretion of inflammatory factors, which provides a new direction for the clinical prevention and treatment of COPD.

Endothelial nitric oxide synthase gene polymorphisms and risk of erectile dysfunction: An updated meta-analysis of genetic association studies.

PURPOSE: Endothelial nitric oxide synthase (eNOS) polymorphisms have been implicated as risk factors for erectile dysfunction (ED), but the results of genetic association studies are inconclusive. We performed a meta-analysis of published studies investigating the association between ED and three eNOS polymorphisms, intron 4 VNTR, G894T and T786C in humans. METHODS: The PubMed, Web of Science, CNKI and Google Scholar databases were searched for relevant studies published up to November 2017. Association studies with case-control design were included. For each study with genotype information we calculated odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The search identified 13 eligible studies. The G894T and T786C polymorphisms showed a significant association with ED risk in Caucasians (GT + TT versus GG for G894T: OR = 2.13, 95% CI = 1.08-4.19; CC versus CT + TT for T786C: OR = 3.29, 95% CI = 2.30-4.72) and Asians (GT + TT versus GG for G894T: OR = 2.08, 95% CI = 1.53-2.84; CC + CT versus TT for T786C: OR = 3.13, 95% CI = 1.35-7.25). In addition, the intron 4 VNTR polymorphism was associated with ED risk only among Caucasian subjects (aa versus bb + ab: OR = 2.38, 95% CI = 1.15-4.93). We found no evidence of publication bias. The robustness of overall analyses was ensured in sensitivity analyses excluding studies deviating from Hardy-Weinberg equilibrium. CONCLUSION: Our findings suggest that common genetic polymorphisms in the eNOS gene contribute to risk of ED, presumably by effects on eNOS activity and NO availability.

Establishment of age- and gender-specific pediatric reference intervals for liver function tests in healthy Han children.

BACKGROUND: The development and growth of children influence values of liver function tests. This study aims to establish age- and gender-specific pediatric reference intervals of liver function among Han children in Changchun, China. METHODS: A total of 1394 healthy Han children, aged 2-14 years, were recruited from communities and schools with informed parental consent in Changchun. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), total bilirubin (TBIL) and direct bilirubin (DBIL) were measured on Hitachi 7600-210 automatic biochemical analyzer. The age- and gender-specific reference intervals were partitioned using Harris and Boyd's test and calculated using nonparametric rank method. The pediatric reference intervals were validated in five representative hospitals located in different areas in Changchun. RESULTS: All the analytes required some levels of age partitioning. Proteins (TP, ALB) and bilirubins (TBIL, DBIL) required no gender partitioning. In contrast, considerable gender partitioning was required for serum ALT, AST, GGT, and ALP. TP, TBIL, and DBIL showed steady increases, and AST showed apparent decreases over time, whereas ALT, GGT, ALP, and ALB demonstrated complex trends of change. ALT and GGT increased sharply in males from 11 to 14 years old. However, ALP declined in females from 13 to 14 years. All five laboratories passed the validation of reference intervals. CONCLUSIONS: There were apparent age or gender variations of the reference intervals for liver function. When establishing pediatric reference intervals, partitioning according to age and gender is necessary.

Knockdown of TRIM44 Inhibits the Proliferation and Invasion in Prostate Cancer Cells.

Tripartite motif 44 (TRIM44), a member of the TRIM protein family, has been shown to play a role in tumor development and progression. However, the potential involvement of TRIM44 in prostate cancer has not been fully explored. Therefore, in the present study, we analyzed the expression of TRIM44 in prostate cancer and assessed the role of TRIM44 in the progression of prostate cancer. Our results showed that the expression of TRIM44 was significantly upregulated in human prostate cancer cell lines. In addition, knockdown of TRIM44 significantly inhibited the proliferation, migration, and invasion of prostate cancer cells in vitro, as well as attenuated the tumor growth in vivo. Mechanistic studies showed that knockdown of TRIM44 significantly reduced the levels of phosphorylated PI3K and Akt in PC-3 cells. In conclusion, this study provided evidence that knockdown of TRIM44 inhibited proliferation and invasion in prostate cancer cells, at least in part, through the inactivation of the PI3K/Akt signaling pathway. These results suggest that TRIM44 may be a potential therapeutic target for the treatment of prostate cancer.

Associations of serum and urinary magnesium with the pre-diabetes, diabetes and diabetic complications in the Chinese Northeast population.

The effect of magnesium (Mg) deficiency on the prevalence of diabetes and diabetic complications has received a great attention. The present study investigated the association of Mg level in the serum or urine of the patients, lived in the Northeast areas of China, with either pre-diabetes or diabetes with and without complications. From January 2010 to October 2011, patients with type 1 diabetes (T1D, n = 25), type 2 diabetes (T2D, n = 137), impaired fasting glucose (IFG, n = 12) or impaired glucose tolerance (IGT, n = 15), and age/gender matched control (n = 50) were enrolled in the First Hospital of Jilin University. In T2D group, there were 24, 34, and 50 patients with nephropathy, retinopathy or peripheral neuropathy. Serum Mg levels in the patients with IGT, IFG, T2D, and T1D were significantly lower than that of control. The urinary Mg levels were significantly increased only in T2D and T1D patients compared to control. There was no difference for these two changes among T2D with and without complications; In addition, there was a significantly positive correlation of serum Mg levels with serum Ca levels only in T2D patients, and also a significantly positive correlation of urinary Mg levels with urinary Ca levels in control, IGT patients, and T2D patients. Simvastatin treatment in T2D patients selectively reduced serum Ca levels and urinary Mg levels. These results suggest that the potential impact of Mg deficiency on metabolic syndrome, diabetes and diabetic complications needs to be received special attention.