Tumor Exosomes Reprogrammed by Low pH Are Efficient Targeting Vehicles for Smart Drug Delivery and Personalized Therapy against their Homologous Tumor.

As membrane-bound extracellular vesicles, exosomes have targeting ability for specific cell types, and the cellular environment strongly impacts their content and uptake efficiency. Inspired by these natural properties, the impacts of various cellular stress conditions on the uptake efficiency of tumor iterated exosomes are evaluated, and low-pH treatment caused increased uptake efficiency and retained cell-type specificity is found. Lipidomics analyses and molecular dynamics simulations reveal a glycerolipid self-aggregation-based mechanism for the enhanced homologous uptake. Furthermore, these low-pH reprogrammed exosomes are developed into a smart drug delivery platform, which is capable of specifically targeting tumor cells and selectively releasing diverse chemodrugs in response to the exosome rupture by the near-infrared irradiance-triggered burst of reactive oxygen species. This platform exerts safe and enhanced antitumor effects demonstrated by multiple model mice experiments. These results open a new avenue to reprogram exosomes for smart drug delivery and potentially personalized therapy against their homologous tumor.

Ebselen suppresses inflammation induced by Helicobacter pylori lipopolysaccharide via the p38 mitogen-activated protein kinase signaling pathway.

Ebselen is a seleno-organic compound that has been demonstrated to have antioxidant and anti-inflammatory properties. A previous study determined that ebselen inhibits airway inflammation induced by inhalational lipopolysaccharide (LPS), however, the underlying molecular mechanism remains to be elucidated. The present study investigated the effect of ebselen on the glutathione peroxidase (GPX)­reactive oxygen species (ROS) pathway and interleukin­8 (IL­8) expression induced by Helicobacter pylori LPS in gastric cancer (GC) cells. Cells were treated with 200 ng/ml H. pylori­LPS in the presence or absence of ebselen for various durations and concentrations (µmol/l). The expression of toll­like receptor 4 (TLR4), GPX2, GPX4, p38 mitogen­activated protein kinase (p38 MAPK), phosphorylated­p38 MAPK, ROS production and IL­8 expression were detected with western blotting or ELISA. The present study revealed that TLR4 expression was upregulated; however, GPX2 and GPX4 expression was reduced following treatment with H. pylori LPS, which led to increased ROS production, subsequently altering the IL­8 expression level in GC cells. Additionally, it was determined that ebselen prevented the reduction in GPX2/4 levels induced by H. pylori LPS, however, TLR4 expression was not affected. Ebselen may also block the expression of IL­8 by inhibiting phosphorylation of p38 MAPK. These data suggest ebselen may inhibit ROS production triggered by H. pylori LPS treatment via GPX2/4 instead of TLR4 signaling and reduce phosphorylation of p38 MAPK, resulting in altered production of IL­8. Ebselen may, therefore, be a potential therapeutic agent to mediate H. pylori LPS-induced cell damage.

The Role of Prion Protein Expression in Predicting Gastric Cancer Prognosis.

Previous reports indicated that prion protein (PrP) is involved in gastric cancer (GC) development and progression, but its role in GC prognosis has been poorly characterized. A total of 480 GC patients were recruited in this retrospective study. PrP expression in cancerous and non-cancerous gastric tissues was detected by using the tissue microarray and immunohistochemical staining techniques. Our results showed that the PrP expression in GC was significantly less frequent than that in the non-cancerous gastric tissue (44.4% vs 66.4%, P < 0.001). Cox regression analysis revealed that PrP expression was associated with TNM stage, survival status and survival time. GC patients with higher TNM stages (stages II, III and IV) had significantly lower PrP expression levels in tumors than those with lower TNM stages (stages 0 and I). Kaplan-Meier survival curves revealed that negative PrP expression was associated with poor overall survival (log-rank test: P < 0.001). The mean survival time for patients with negative PrP expression was significant lower than those with positive PrP expression (43.0±28.5m vs. 53.9±31.1m, P<0.001). In multivariate Cox hazard regression, PrP expression was an independent prognostic factor for GC survival, with a HR (hazard ratio) of 0.687 (95%CI:0.520-0.907, P=0.008). Our results revealed that negative PrP expression could independently predict worse outcome in GC and thereby could be used to guide the clinical practice.

A Meta-Analysis of C-Reactive Protein in Patients With Alzheimer's Disease.

Inflammation may be associated with Alzheimer's disease (AD). This meta-analysis aimed to compare the level of C-reactive protein (CRP) in patients having AD to healthy controls. A total of 10 cross-sectional studies (n = 2093) were identified from PubMed and EMBASE after systematic searching and evaluation. The combined standardized mean difference (SMD) of CRP level between the disease and control group was analyzed. In the meta-analysis, there was no significant difference in serum between the CRP level of patients with AD and that of healthy controls (SMD: -0.400, 95% confidence interval [CI]: -0.827 to 0.027,P= .066). However, when we stratified the studies by Mini-Mental State Examination (MMSE) scores, the level of CRP in the mild and moderate dementia subgroup (MMSE ≥ 10) was significantly lower than that in the control group (SMD: -0.582, 95% CI: -0.957 to -0.208,P= .002). Therefore, the diagnostic value of CRP for mild and moderate AD may be useful in clinical practice.

Label-Free Direct Detection of miRNAs with Poly-Silicon Nanowire Biosensors.

BACKGROUND: The diagnostic and prognostic value of microRNAs (miRNAs) in a variety of diseases is promising. The novel silicon nanowire (SiNW) biosensors have advantages in molecular detection because of their high sensitivity and fast response. In this study, poly-crystalline silicon nanowire field-effect transistor (poly-SiNW FET) device was developed to achieve specific and ultrasensitive detection of miRNAs without labeling and amplification. METHODS: The poly-SiNW FET was fabricated by a top-down Complementary Metal Oxide Semiconductor (CMOS) wafer fabrication based technique. Single strand DNA (ssDNA) probe was bind to the surface of the poly-SiNW device which was silanated and aldehyde-modified. By comparing the difference of resistance value before and after ssDNA and miRNA hybridization, poly-SiNW device can be used to detect standard and real miRNA samples. RESULTS: Poly-SiNW device with different structures (different line width and different pitch) was applied to detect standard Let-7b sample with a detection limitation of 1 fM. One-base mismatched sequence could be distinguished meanwhile. Furthermore, these poly-SiNW arrays can detect snRNA U6 in total RNA samples extracted from HepG2 cells with a detection limitation of 0.2 µg/mL. In general, structures with pitch showed better results than those without pitch in detection of both Let-7b and snRNA U6. Moreover, structures with smaller pitch showed better detection efficacy. CONCLUSION: Our findings suggest that poly-SiNW arrays could detect standard and real miRNA sample without labeling or amplification. Poly-SiNW biosensor device is promising for miRNA detection.

Prognostic role of hormone receptors in endometrial cancer: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to summarize the global predicting role of hormone receptors for survival in endometrial cancer. METHODS: Eligible studies were identified and assessed for quality through multiple search strategies. Data were collected from studies comparing overall survival (OS), cancer-specific survival (CSS), or progression-free survival (PFS) in patients with elevated levels of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) with those in patients with lower levels. The combined hazard ratios of ER, PR, and HER2 for survival were calculated. RESULTS: A total of 98 studies were included for meta-analysis (44 for ER, 38 for PR, and 16 for HER2). Higher levels of either ER or PR could significantly indicate better survival. The pooled hazard ratios (HRs) of ER for OS, CSS, and PFS were 0.75 (95% CI, 0.68-0.83), 0.45 (95% CI, 0.33-0.62), and 0.66 (95% CI, 0.52-0.85), respectively. The combined HRs of PR for OS, CSS, and PFS reached 0.63 (95% CI, 0.56-0.71), 0.62 (95% CI, 0.42-0.93), and 0.45 (95% CI, 0.30-0.68), respectively. In contrast, elevated levels of HER2 could predict worse outcome with a HR of 1.98 (95% CI, 1.49-2.62) for OS, and a HR of 2.26 (95% CI, 1.57-3.25) for PFS. CONCLUSIONS: In patients with endometrial cancer, higher level of ER and PR predicted favorable survival, and increased level of HER2 was associated with poorer survival. All of the three hormone receptors had prognostic value for survival.