DRSN4mCPred: accurately predicting sites of DNA N4-methylcytosine using deep residual shrinkage network for diagnosis and treatment of gastrointestinal cancer in the precision medicine era.

Introduction: The DNA N4-methylcytosine (4mC) site levels of those suffering from digestive system cancers were higher, and the pathogenesis of digestive system cancers may also be related to the changes in DNA 4mC levels. Identifying DNA 4mC sites is a very important step in studying the analysis of biological function and cancer prediction. Extracting accurate features from DNA sequences is the key to establishing a prediction model of effective DNA 4mC sites. This study sought to develop a new predictive model, DRSN4mCPred, which aimed to improve the performance of the predicting DNA 4mC sites. Methods: The model adopted multi-scale channel attention to extract features and used attention feature fusion (AFF) to fuse features. In order to capture features information more accurately and effectively, this model utilized Deep Residual Shrinkage Network with Channel-Wise thresholds (DRSN-CW) to eliminate noise-related features and achieve a more precise feature representation, thereby, distinguishing the sites in DNA with 4mC and non-4mC. Additionally, the predictive model incorporated an inverted residual block, a Multi-scale Channel Attention Module (MS-CAM), a Bi-directional Long Short Term Memory Network (Bi-LSTM), AFF, and DRSN-CW. Results and Discussion: The results indicated the predictive model DRSN4mCPred had extremely good performance in predicting the DNA 4mC sites across different species. This paper will potentially provide support for the diagnosis and treatment of gastrointestinal cancer based on artificial intelligence in the precise medical era.

Response to pioglitazone in non-alcoholic fatty liver disease patients with vs. without type 2 diabetes: A meta-analysis of randomized controlled trials.

Background: Pioglitazone is considered a potential therapy for non-alcoholic fatty liver disease (NAFLD). However, different effects of pioglitazone on NAFLD have been demonstrated in diabetic and non-diabetic patients. Herein, a meta-analysis of randomized, placebo-controlled trials was carried out to indirectly compare pioglitazone in NAFLD patients with vs. without type 2 diabetes. Methods: Randomized controlled trials (RCTs) of pioglitazone vs. placebo involving NAFLD patients with or without type 2 diabetes/prediabetes collected from databases were enrolled into this analysis. Methodological quality was employed to evaluate the domains recommended by the Cochrane Collaboration. The analysis covered the changes in histology (fibrosis, hepatocellular ballooning, inflammation, steatosis), liver enzymes, blood lipids, fasting blood glucose (FBS), homeostasis model assessment-IR (HOMA-IR), weight and body mass index (BMI) before and after treatment, and adverse events. Results: The review covered seven articles, with 614 patients in total, of which three were non-diabetic RCTs. No difference was found in patients with vs. without type 2 diabetes in histology, liver enzymes, blood lipids, HOMA-IR, weight, BMI, and FBS. Moreover, no significant difference was revealed in adverse effects between NAFLD patients with diabetes and without DM, except the incidence of edema that was found to be higher in the pioglitazone group than in the placebo group in NAFLD patients with diabetes. Conclusions: Pioglitazone could exert a certain effect on alleviating NAFLD, which was consistent between non-diabetic NAFLD patients and diabetic NAFLD patients in improving histopathology, liver enzymes, and HOMA-IR and reducing blood lipids. Furthermore, there were no adverse effects, except the incidence of edema which is higher in the pioglitazone group in NAFLD patients with diabetes. However, large sample sizes and well-designed RCTs are required to further confirm these conclusions.

Age, Pulse, Urea, and Albumin Score: A Tool for Predicting the Short-Term and Long-Term Outcomes of Community-Acquired Pneumonia Patients With Diabetes.

Objective: The predictive performances of CURB-65 and pneumonia severity index (PSI) were poor in patients with diabetes. This study aimed to develop a tool for predicting the short-term and long-term outcomes of CAP in patients with diabetes. Methods: A retrospective study was conducted on 531 CAP patients with type 2 diabetes. The short-term outcome was in-hospital mortality. The long-term outcome was 24-month all-cause death. The APUA score was calculated according to the levels of Age (0-2 points), Pulse (0-2 points), Urea (0-2 points), and Albumin (0-4 points). The area under curves (AUCs) were used to evaluate the abilities of the APUA score for predicting short-term outcomes. Cox regression models were used for modeling relationships between the APUA score and 24-month mortality. Results: The AUC of the APUA score for predicting in-hospital mortality was 0.807 in patients with type 2 diabetes (P<0.001). The AUC of the APUA score was higher than the AUCs of CURB-65 and PSI class (P<0.05). The long-term mortality increased with the risk stratification of the APUA score (low-risk group (0-1 points) 11.5%, intermediate risk group (2-4 points) 16.9%, high risk group (≥5 points) 28.8%, P<0.05). Compared with patients in the low-risk group, patients in the high-risk group had significantly increased risk of long-term death, HR (95%CI) was 2.093 (1.041~4.208, P=0.038). Conclusion: The APUA score is a simple and accurate tool for predicting short-term and long-term outcomes of CAP patients with diabetes.

Measurement methods of single cell drug response.

In the last decades, a wide multitude of research activity has been focused on the development of new drugs, and devoted to overcome the challenges of high cost and low efficiency in drug evaluation. The measurement of drug response at the single cell level is a quicker, more direct and more accurate way to reflect drug efficacy, which can shorten the drug development period and reduce research costs. Therefore, the single cell drug response (SCDR) measurement technology has aroused extensive attention from researchers, and has become a hot topic in the fields of drug research and cell biology. Recent years have seen the emergence of various SCDR measurement technologies that feature different working principles and different levels of measurement performance. To better examine, compare and summarize the characteristics and functions of these technologies, we select signal-to-noise ratio, throughput, content, invasion, and device complexity as the criteria to evaluate them from the drug efficacy perspective. This review aims to highlight sixteen kinds of SCDR measurement technologies, including patch-clamp technique, live-cell interferometry, capillary electrophoresis, secondary ion mass spectrometry, and more, and report widespread representative examples of SCDR measurement the recent approaches for over the past forty years. Based on their reaction principles, these technologies are classified into four categories: electrical, optical, electrochemical, and mass spectrometry, and a detailed comparison is made between them. After in-depth understanding of these technologies, it is expected to improve or integrate these technologies to propose better SCDR measurement strategies, and explore methods in new drug development and screening, as well as disease diagnosis and treatment.

A Five-Gene Signature for Recurrence Prediction of Hepatocellular Carcinoma Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies with poor prognosis. There are many selectable treatments with good prognosis in Barcelona Clinic Liver Cancer- (BCLC-) 0, A, and B HCC patients, but the most crucial factor affecting survival is the high recurrence rate after treatments. Therefore, it is of great significance to predict the recurrence of BCLC-0, BCLC-A, and BCLC-B HCC patients. AIM: To develop a gene signature to enhance the prediction of recurrence among HCC patients. MATERIALS AND METHODS: The RNA expression data and clinical data of HCC patients were obtained from the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were conducted to screen primarily prognostic biomarkers in GSE14520. Multivariate Cox regression analysis was introduced to verify the prognostic role of these genes. Ultimately, 5 genes were demonstrated to be related with the recurrence of HCC patients and a gene signature was established. GSE76427 was adopted to further verify the accuracy of gene signature. Subsequently, a nomogram based on gene signature was performed to predict recurrence. Gene functional enrichment analysis was conducted to investigate the potential biological processes and pathways. RESULTS: We identified a five-gene signature which performs a powerful predictive ability in HCC patients. In the training set of GSE14520, area under the curve (AUC) for the five-gene predictive signature of 1, 2, and 3 years were 0.813, 0.786, and 0.766. Then, the relative operating characteristic (ROC) curves of five-gene predictive signature were verified in the GSE14520 validation set, the whole GSE14520, and GSE76427, showed good performance. A nomogram comprising the five-gene signature was built so as to show a good accuracy for predicting recurrence-free survival of HCC patients. CONCLUSION: The novel five-gene signature showed potential feasibility of recurrence prediction for early-stage HCC.

Association between serum NPTX2 and cognitive function in patients with vascular dementia.

OBJECTIVE: Neuronal Pentraxin 2 (NPTX2) has recently been widely reported as a novel biomarker for Alzheimer's disease (AD), but its correlation with vascular dementia (VaD) has not been elucidated. This study aimed to explore the correlation between NPTX2 and the cognitive function of VaD patients. METHODS: 112 VaD patients and 76 healthy controls were included in the study. Upon admission, clinical baseline data for all subjects were collected. Serum NPTX2 levels were determined using enzyme-linked immunosorbent assay (ELISA). At the same time, the Montreal cognitive assessment (MoCA) scale was used to measure cognitive function. Multivariate regression analysis was used to determine the relationship between serum NPTX2 level and the cognitive function of VaD patients. RESULTS: Compared with healthy controls, VaD patients had lower serum NPTX2 levels (p < .001). The results of Spearman's correlation analysis showed that serum NPTX2 levels in VaD patients were positively correlated with MoCA scores (r = .347, p = .042). The results of multivariate regression analysis showed that after adjusting for common risk factors, serum NPTX2 levels in VaD patients were still significantly associated with MoCA scores (ß = 0.346, p = .039). CONCLUSIONS: Serum NPTX2 level was independently associated with cognitive function in patients with VaD. Serum NPTX2 level may be a novel predictor for cognitive function in VaD.

Association between thymosin beta4 and non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: non-alcoholic fatty liver disease (NAFLD) is the most common type of chronic liver injury worldwide. Some studies have shown that thymosin beta4 (Tß4) is closely related to liver diseases. Nevertheless, only a few published studies have reported the relationship between Tß4 and NAFLD. The purpose of this study was to evaluate the levels of Tß4 in patients with NAFLD compared with controls and to validate their relationship in a larger cohort. PATIENTS AND METHODS: a total of 76 NAFLD patients and 130 healthy controls were included in the study. Serum levels of Tß4, IL-6 and adiponectin were determined by ELISA. Serum glucose, insulin and lipids, as well as liver function were measured. Multivariate statistical analyses were performed via logistic regression modelling to determine the predictors with a significant relevance to NAFLD. The association between serum Tß4 and study variables was tested using correlation coefficients calculations. RESULTS: serum Tß4 content was 3.20 ± 0.98 mg/l in NAFLD patients (n = 76) and 5.53 ± 1.24 mg/l in healthy controls (n = 130); the difference between the two groups was statistically significant (p = 0.000). Multivariate logistic regression analysis identified Tß4 (OR = 0.343, 95% CI 0.240-0.491, p < 0.001), LDL (OR = 1.019, 95% CI 1.007-1.030, p = 0.001), ALT (OR = 1.021, 95% CI 1.001-1.041, p = 0.040) and IL-6 (OR = 1.443, 95% CI 1.079-1.929, p = 0.013) as independent predictors of NAFLD diagnosis. Serum Tß4 levels had a significant negative correlation with total cholesterol, TG, AST, GGT and IL-6 (p < 0.05 for all) and the correlation coefficient values were -0.163, -0.253, -0.143, -0.245 and -0.155, respectively. Serum Tß4 levels were positively correlated with serum adiponectin levels, with a correlation coefficient value of 0.143. CONCLUSION: serum Tß4 may play a defensive role in the development of NAFLD. Further studies are needed to confirm the role of Tß4 in NAFLD.

[Expression of ADAR1 isoforms in murine acute T-ALL leukemia model].

This study was purposed to investigate the expression of ADAR1 isoforms of P110 and P150 during the development of murine leukemia. A Notch1 over-expressing murine T cell acute lymphoblastic leukemia model was used to study the expression of ADAR1. BMMNC were isolated at different stages of disease and CD45.2(+)GFP(+) leukemia cells were sorted by flow cytometry at late stage. The expression of ADAR1 was detected by real time quantitative PCR. The results showed that mouse bone marrow cells from both leukemia and control groups expressed P110 and P150. Difference of P110 and P150 mRNA expression were observed during the development of leukemia. The expression of P110 dramatically increased and was significantly higher than that in control group. However, the expression level of P150 in leukemia group decreased stably and reached one-fourth of that in control group at 14 day. Furthermore, similar expression patterns could be detected in sorted CD45.2(+)GFP(+) leukemia cells. It is concluded that the mRNA expressions of P110 and P150 show diverse patterns in the development of leukemia, suggesting that RNA editing mediated by ADAR1 isoforms may play different roles in leukemia.

Abnormal expression of ADAR1 isoforms in Chinese pediatric acute leukemias.

The posttranscriptional RNA editing by the type 1 adenosine deaminase acting on RNAs (ADAR1), expressed as p110 and p150 isoforms, is important for both physiological and pathological processes. Their expression and significance in leukemias remain unknown. Here, we investigated the expression of ADAR1 in Chinese pediatric acute leukemias by real-time PCR and Western blot. The results showed that significant high expression of p110 was detected in leukemias, especially in B-ALL, whereas a slight increase of p150 could be observed. Furthermore, the decrease of p110 expression was observed in B-ALL patients achieving complete remission. Moreover, among prognostic risk groups in ALL, the highest expressions of p110 and p150 were detected in standard-risk group, whereas their lowest expressions were in high-risk group. This observation was further confirmed in comparisons between good and poor prognostic groups based on prognostic related clinical features. These results demonstrated that ADAR1 isoforms showed different expression patterns, suggesting that they might play different roles in pediatric leukemias. Our results will help us for the better understanding of RNA editing, exploring the potential target for the treatment, and making prognostic evaluation in childhood leukemias.

Abnormal expression of P2X family receptors in Chinese pediatric acute leukemias.

Nucleotides are new players in intercellular communication network. P2X family receptors are ATP-gated plasma membrane ion channels with diverse biological functions. Their distribution patterns and significance in pediatric leukemias have not been established. Here we investigated the expression of P2X receptors in BMMC samples from Chinese pediatric acute leukemias. Real-time PCR and Western blot results showed that P2X1, P2X4, P2X5 and P2X7 receptors were simultaneously over expressed in leukemias compared with controls, whereas P2X2, P2X3 and P2X6 were absent or marginally expressed in both groups. It was worth noting that the co-expression feature of them, especially between P2X4 and P2X7, could be observed and the highest expression of P2X7 was detected in relapsed patients. Moreover, concomitant decrease of P2X4, P2X5 and P2X7 expressions was observed at CR stage in a follow-up study. Functional P2X7 was also verified. These results suggested that P2X1, P2X4, P2X5 and P2X7 were hematopoiesis-related P2X receptors, and their signaling, especially for P2X7, might play important roles in pediatric leukemias. P2X receptors might co-operatively contribute to the malignant phenotype in human pediatric leukemias.

Optimization of renewal regime for improvement of polysaccharides production from Porphyridium cruentum by uniform design.

To probe the effects of renewal regime on the production of polysaccharides, Porphyridium cruentum was cultured semi-continuously in flat plate photobioreactor. Uniform design was used to optimize renewal conditions. Quadratic mathematic models related to productivity, total recovery yield of biomass and polysaccharides were set up to clarify the influence of individual factors and their interactions. According to the mathematic models, the optimal semi-continuous condition for total yield of polysaccharide was NaNO3 3.5 g/L, renewal rate 27%, renewal period 2.91 days. The optimal condition for polysaccharide output rate was NaNO3 0.5 g/L, renewal rate 5%, renewal period 7 days. With the optimal renewal regime, the maximal total recovery yields of polysaccharide achieved at 29.4 g, which was 1.57 times higher than that of batch cultivation. The maximum output rate of polysaccharide was 68.64 mg/L per day, which was 2.02 times higher than previous reported data.

Preparation of different molecular weight polysaccharides from Porphyridium cruentum and their antioxidant activities.

Hermetical microwave was used to degrade Porphyridium cruentum polysaccharides from 2918 to 256.2, 60.66 and 6.55kDa. The antioxidant properties of different molecular weight polysaccharides were evaluated by determining the scavenging ability of free radicals, inhibitory effects on lipid peroxidation in liver homogenates and hemolysis of mouse erythrocytes. Analysis of physicochemical properties confirmed that microwave degradation might not markedly change the chemical components of the polysaccharides. High-molecular-weight polysaccharides from P. cruentum had no obvious antioxidant activity, but low-molecular-weight fragments after degradation exerted an inhibitory effect on oxidative damage. The 6.55-kDa fragment had stronger antioxidant activity than the 60.66 and 256-kDa fragments.

A special linker between macrophage and hematopoietic malignant cells: membrane form of macrophage colony-stimulating factor.

The membrane form of macrophage colony-stimulating factor (mM-CSF) is an alternative splicing variant of this cytokine. Although its high expression was detected in hematopoietic malignancies, its physiologic and pathologic roles in hematopoietic system have not been established. In this report, stable transfectant clones expressing mM-CSF (Namalwa-M and Ramos-M) were obtained, which showed reduced proliferation potential in vitro. Moreover, the in vivo study showed that Namalwa-M and Ramos-M exhibited enhanced oncogenicity in tumor size in nude mice model, which could be inhibited by M-CSF monoclonal antibody. A remarkable increase in infiltrating macrophage and the vessel densities was found in tumor tissues formed by lymphoma cell lines that stably expressed mM-CSF, which suggested the involvement of macrophages in this process. The in vitro results using coculture system showed that macrophages could promote Namalwa-M and Ramos-M proliferation and activate extracellular signal-regulated kinase/mitogen-activated protein kinase signal pathway. In addition, the expression of murine origin vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor was elevated in Namalwa-M formed tumor tissues. These results suggested that mM-CSF should be a positive regulator in the development of hematopoietic malignancies by abnormally activating infiltrating macrophages, which in turn promote the malignant development. Thus, mM-CSF may be a critical linker between macrophages and malignant cells in the development of hematopoietic malignancies.