Identification of novel potential homologous repair deficiency-associated genes in pancreatic adenocarcinoma via WGCNA coexpression network analysis and machine learning.

Homologous repair deficiency (HRD) impedes double-strand break repair, which is a common driver of carcinogenesis. Positive HRD status can be used as theranostic markers of response to platinum- and PARP inhibitor-based chemotherapies. Here, we aimed to fully investigate the therapeutic and prognostic potential of HRD in pancreatic adenocarcinoma (PAAD) and identify effective biomarkers related to HRD using comprehensive bioinformatics analysis. The HRD score was defined as the unweighted sum of the LOH, TAI, and LST scores, and it was obtained based on the previous literature. To characterize PAAD immune infiltration subtypes, the "ConsensusClusterPlus" package in R was used to conduct unsupervised clustering. A WGCNA was conducted to elucidate the gene coexpression modules and hub genes in the HRD-related gene module of PAAD. The functional enrichment study was performed using Metascape. LASSO analysis was performed using the "glmnet" package in R, while the random forest algorithm was realized using the "randomForest" package in R. The prognostic variables were evaluated using univariate Cox analysis. The prognostic risk model was built using the LASSO approach. ROC curve and KM survival analyses were performed to assess the prognostic potential of the risk model. The half-maximal inhibitory concentration (IC50) of the PARP inhibitors was estimated using the "pRRophetic" package in R and the Genomics of Drug Sensitivity in Cancer database. The "rms" package in R was used to create the nomogram. A high HRD score indicated a poor prognosis and an advanced clinical process in PAAD patients. PAAD tumors with high HRD levels revealed significant T helper lymphocyte depletion, upregulated levels of cancer stem cells, and increased sensitivity to rucaparib, Olaparib, and veliparib. Using WGCNA, 11 coexpression modules were obtained. The red module and 122 hub genes were identified as the most correlated with HRD in PAAD. Functional enrichment analysis revealed that the 122 hub genes were mainly concentrated in cell cycle pathways. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were screened via LASSO analysis and a random forest algorithm, and they were validated using independent validation sets. No direct association between HRD and CKS1B, HJURP, or TPX2 has not been reported in the literature so far. Thus, these findings indicated that CKS1B, HJURP, and TPX2 have potential as diagnostic and prognostic biomarkers for PAAD. We constructed a novel HRD-related prognostic model that provides new insights into PAAD prognosis and immunotherapy. Based on bioinformatics analysis, we comprehensively explored the therapeutic and prognostic potential of HRD in PAAD. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were identified through the combination of WGCNA, LASSO analysis and a random forest algorithm. A novel HRD-related risk model that can predict clinical prognosis and immunotherapeutic response in PAAD patients was constructed.

SPINT2 is involved in the proliferation, migration and phenotypic switching of aortic smooth muscle cells: Implications for the pathogenesis of thoracic aortic dissection.

Thoracic aortic dissection (TAD) is a severe and extremely dangerous cardiovascular disease. Proliferation, migration and phenotypic switching of vascular smooth muscle cells (SMCs) are major pathogenetic mechanisms involved in the development of TAD. The present study was designed to investigate the expression and potential function of serine peptidase inhibitor Kunitz type 2 (SPINT2) in TAD. The gene expression profile data for ascending aorta from patients with TAD were downloaded from the GEO database with the accession number GSE52093. Bioinformatics analysis using GEO2R indicated that the differentially expressed SPINT2 was prominently decreased in TAD. The expression levels of SPINT2 mRNA and protein in aortic dissection specimens and normal aorta tissues were measured using reverse transcription-quantitative PCR and western blotting. SPINT2 expression was downregulated in clinical samples from aortic dissection specimens of patients with TAD compared with the corresponding expression noted in tissues derived from patients without TAD. In vitro, platelet-derived growth factor BB (PDGF-BB) was applied to induce the isolated primary mouse aortic SMC phenotypic modulation (a significant upregulation in the expression levels of synthetic markers), and the SMCs were infected with the adenoviral vector, Ad-SPINT2, to construct SPINT2-overexpressed cell lines. SMC viability was detected by an MTT assay and SMC proliferation was detected via the presence of Ki-67-positive cells (immunofluorescence staining). To explore the effects of SPINT2 on SMC migration, a wound healing assay was conducted. ELISA and western blotting assays were used to measure the content and expression levels of MMP-2 and MMP-9. The expression levels of vimentin, collagen I, α-SMA and SM22α were measured using western blotting. The PDGF-BB-induced proliferation and migration of SMCs were recovered by SPINT2 overexpression. The increase in the expression levels of SPINT2 reduced the expression levels of active matrix metalloproteinases (MMPs), MMP-2 and MMP-9. Overexpression of SPINT2 suppressed SMC switching from a contractile to a synthetic type, as evidenced by decreased vimentin and collagen I expression levels along with increased α-smooth muscle actin and smooth muscle protein 22-α expression levels. Furthermore, activation of ERK was inhibited in SPINT2-overexpressing SMCs. A specific ERK agonist, 12-O-tetradecanoylphorbol-13-acetate, reversed the SPINT2-mediated inhibition of SMC migration and the phenotypic switching. Collectively, the data indicated that SPINT2 was implicated in the proliferation, migration and phenotypic switching of aortic SMCs, suggesting that it may be involved in TAD progression.

Association between iron status and incident coronary artery disease: a population based-cohort study.

Disorders of iron metabolism has been implicated in cardiovascular disease. However, the association of serum iron stores and coronary artery disease (CAD) remains inconsistent. Here, we investigated the associations of serum iron metabolism with the incidence of CAD, the severity of coronary artery stenosis, metabolic biomarkers, and the risk of major adverse cardiovascular event (MACE). A total of 643 CAD patients and 643 healthy controls were enrolled to assess the associations of serum iron status with the presence of CAD, the severity of CAD, and the risk of MACE. Serum iron metabolism and other metabolic markers were measured in all subjects. All statistical analyses were analyzed using SPSS22.0 software and STATA statistical package. Serum level of iron metabolism markers, including serum iron, unsaturated transferrin iron binding capacity (UIBC), Total iron binding capacity (TIBC) levels, in CAD groups was significantly lower than the control group (P < 0.001). UIBC and TIBC were negatively correlated with ferritin in both sexes. Each unit increase of serum iron and TIBC were found to have a protective role for CAD in women (iron: OR 0.794, 95% CI (0.647-0.973), TIBC: OR 0.891, 95% CI (0.795-0.999), P < 0.05). However, high ferritin level was significant associated the CAD incident in both sexes (OR 1.029, 95% CI (1.002-1.058) in men, OR 1.013, 95% CI (1.0-1.025) in women, P < 0.05). Serum iron metabolism markers exhibited no significant association with the severity of CAD. Increased serum level of iron and TIBC levels were found to have a protective role for CAD in women, but not in men. Elevated serum ferritin is independently and positively associated with CAD in men and women.

A versatile and low-toxicity material for photothermal therapy in deeper tissues.

The limited depth of the near infrared (NIR) response is one of the major flaws of the present photothermal therapy (PTT). In this article, thermosensitive polyurethane urea (TPUU) was synthesized by polymerization. Subsequent experiments showed that, compared with classical photosensitizers, TPUU has higher photothermal effects and lower cytotoxicity. These valuable properties could make the present PTT research provide more therapeutic options among different tissues and organs. As a practical example, TPUU was applied to regulate the intestinal flora through external NIR irradiation, which implied its promising expanded applications in deeper tissues.

Hyperthermia-triggered UK release nanovectors for deep venous thrombosis therapy.

Deep vein thrombosis (DVT) is a common and lethal complication of surgery. In the clinic, thrombolytic drugs are primarily used for treating DVT. However, the utilization of thrombolytic drugs is limited due to the risk of urokinase (UK)-related hemorrhagic complications. In this paper, a binary eutectic phase-change fatty acid composed of lauric acid and stearic acid was used to block the pores of gold-mesoporous silica core-shell nanoparticles, so as to deliver thrombolytic drugs. The eutectic mixture has a well-defined melting point at 39.2 °C, which can be used as a biocompatible phase-change material for hyperthermia-triggered drug release. The prepared system presents remarkable photothermal effects due to the gold nanoparticles and quick drug release in response to near-infrared irradiation (NIR). In addition, localized hyperthermia could also enhance the lysis of the thrombus. The thrombolytic effect of this system was evaluated in vitro and in vivo. Herein, a rabbit femoral vein thrombosis model was first built for imitating thrombolysis in vivo. The B-ultrasound was then used to monitor the changes in the thrombus after treatment. The results indicated that the reported system could be potentially used to deliver thrombotic drugs in the clinic.

Effect of Remote Ischemic Preconditioning on Patients Undergoing Elective Major Vascular Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Whether remote ischemic preconditioning (RIPC), through several cycles of ischemia-reperfusion, can generate endogenous protective substances to protect patients undergoing elective major vascular surgery remains unclear. The results derived from many randomized controlled trials (RCTs) have been discrepant. METHODS: PubMed (1966 to May 2018) and EMBASE (1966 to May 2018) databases were searched to identify all published RCTs that assessed the effect of RIPC in patients undergoing elective major vascular surgery. Then, we performed a systematic review and meta-analysis to merge the outcomes of RIPC procedures from each RCT, which included all-cause mortality, myocardial infarction (MI), acute kidney injury (AKI), and/or new-onset arrhythmia. RESULTS: A total of 909 patients were enrolled from 10 eligible studies that were conducted from 2007 through 2016. A fixed effect model was utilized in this study to pool each effect size. Pooled analyses of all RCTs showed that RIPC did not reduce the incidence of all-cause mortality (pooled risk ratio [RR] 1.36, 95% confidence interval [CI] 0.63-2.92, P = 0.56), MI (pooled RR 0.77, 95% CI 0.48-1.22, P = 0.38), AKI (pooled RR 0.93, 95% CI 0.68-1.27, P = 0.10), or new-onset arrhythmia (pooled RR 1.47, 95% CI 0.83-2.60, P = 0.52) compared with the control treatment. The publication bias detected by Begg's test was low. CONCLUSIONS: There is no prominent evidence to support the hypothesis that RIPC can provide perioperative protection to patients undergoing elective major vascular surgery. Therefore, the routine use of RIPC to reduce the incidence of perioperative complications of these operations may not be recommended.

ZnO and Hydroxyapatite-Modified Magnesium Implant with a Broad Spectrum of Antibacterial Properties and a Unique Minimally Invasive Defined Degrading Capability.

ZnO and hydroxyapatite-based membranes have been proposed to improve the antibacterial properties and anticorrosion capabilities of the magnesium implant, simultaneously. More importantly, the concept of minimally invasive surgery has been introduced to define the degradation timing of the as-modified magnesium implant. With the aid of a Kirschner wire, the as-prepared membrane could immediately change from the "protective layer" to the "degradation accelerator" of the implant material. The subsequent studies have implied that this membrane could be a promising avenue to create a biocompatible and lightweight implant material with a valuable personal customized degradable timing capability.

Rapid discrimination of malignant lesions from normal gastric tissues utilizing Raman spectroscopy system: a meta-analysis.

OBJECTIVES: To systematically analyze the diagnostic accuracy of Raman spectroscopy system (RAS) in the rapid diagnosis of gastric cancer with histopathology as the reference standard. METHODS: We searched a wide range of electronic databases for all published researches that assessed the diagnostic accuracy of RAS to detect gastric carcinoma. Full papers were obtained for potentially eligible studies and evaluated according to predefined criteria. The Quality Assessment of Diagnostic Accuracy Studies checklist was used to assess the quality of included studies. From each study, we extracted information on diagnostic performance of RAS. After exploring heterogeneity, we adopted a random effects model to pool related effect sizes. RESULTS: The initial literature search identified 257 reference articles in which 15 relevant articles with 15 data sets were selected and reviewed. The pooled sensitivity and specificity of RAS in diagnosing gastric cancer were 0.89 (95 % CI 0.84-0.92) and 0.92 (95 % CI 0.88-0.95), respectively. The positive likelihood ratio, the negative likelihood ratio, and the area under the curve were 10 (95 % CI 6.5-15.3), 0.13 (95 % CI 0.08-0.22), and 0.96 (95 % CI 0.94-0.97), respectively. All the pooled estimates, calculated by random and fixed effect models, were similar. There was no evidence of considerable publication bias. CONCLUSIONS: RAS is an objective and sensitive optical diagnostic technology for detecting gastric cancer and has advantages of being noninvasive to the body, real-time diagnosis, and ease of use. Consequently, it does deserve to be recommended.