Trastuzumab aggravates radiation induced cardiotoxicity in mice.

Some breast cancer patients with overexpression of human epidermal growth factor receptor 2 need both chest radiotherapy and targeted therapy with trastuzumab (TRZ). The cardiotoxicity associated with combined treatment potentially restricts the clinical benefits of antitumor therapy. There is no consensus on whether and how chest radiotherapy can be given in concurrent with TRZ at present, considering the cardiotoxicity. This study intends to establish an in vitro and in vivo heart injury model by irradiation and TRZ, analyze whether there is a synergistic effect in heart, and to explore the molecular changes. First, an in vitro irradiation model of H9C2 cardiomyocytes was established. The effects of TRZ and radiation on cardiomyocyte injury were observed by cell flow cytometry, CCK-8 test, Western blot, γ-H2AX fluorescence focus formation and cell Reactive Oxygen Species (ROS) content test. Second, the mouse heart injury model was set up by X-ray cardiac irradiation combined with TRZ. Six months later, the cardiac function was analyzed by small animal ultrasound and 18FDG-micro PET/CT. The morphological changes of heart tissue were assessed by histological section. We found that concurrent TRZ aggravates the injury effect of irradiation on cardiomyocytes in vitro. The influence of TRZ might be consequence of inhibiting Akt phosphorylation, promoting the excessive accumulation of ROS in cells and promoting intracellular DNA damage. In animal experiments, the dysfunction of diastolic and myocardial ischemia of mouse heart was observed by echocardiography and 18FDG-micro PET/CT, respectively; myocardial fibrosis and cardiomyocyte apoptosis were also observed. Therefore, our in vitro and in vivo experiments have revealed that TRZ combined irradiation caused more cardiotoxicity than irradiation or TRZ alone. These results suggested that the concurrent management of TRZ and radiotherapy should be carefully made in clinical practice, and more attention is needed on cardiac safety.

Proximity effect of a two-dimensional van der Waals magnet Fe3GeTe2 on nickel films.

Recent advances in two-dimensional van der Waals (2D vdW) magnets provide new platforms to study their magnetism in reduced dimensions. However, most of the studies performed to date have been limited to low temperatures. Here, we report the proximity effect of a 2D vdW magnet Fe3GeTe2 (FGT) on nickel (Ni) films at room temperature. Ferromagnetic resonance measurements show that FGT can increase the perpendicular magnetic anisotropy (PMA) and magnetic damping of the adjacent Ni film. Such an interfacial effect is observed at room temperature, and becomes more pronounced as the temperature decreases. A similar effect is also achieved in another 2D heterostructure of Cr2Ge2Te6/Ni, implying its universality in a variety of 2D magnetic materials. Our work provides a new approach for utilizing 2D magnets in spintronics at room temperature.

Identification of novel candidate pathogenic genes in pituitary stalk interruption syndrome by whole-exome sequencing.

Pituitary stalk interruption syndrome (PSIS) is a type of congenital malformation of the anterior pituitary, which leads to isolated growth hormone deficiency or multiple hypothalamic-pituitary deficiencies. Many genetic factors have been explored, but they only account for a minority of the genetic aetiology. To identify novel PSIS pathogenic genes, we conducted whole-exome sequencing with 59 sporadic PSIS patients, followed by filtering gene panels involved in pituitary development, holoprosencephaly and midline abnormality. A total of 81 heterozygous variants, distributed among 59 genes, were identified in 50 patients, with 31 patients carrying polygenic variants. Fourteen of the 59 pathogenic genes clustered to the Hedgehog pathway. Of them, PTCH1 and PTCH2, inhibitors of Hedgehog signalling, showed the most frequent heterozygous mutations (22%, seven missense and one frameshift mutations were identified in 13 patients). Moreover, five novel heterozygous null variants in genes including PTCH2 (p.S391fs, combined with p.L104P), Hedgehog acyltransferase (p.R280X, de novo), MAPK3 (p.H50fs), EGR4 (p.G22fs, combined with LHX4 p.S263N) and SPG11 (p.Q1624X), which lead to truncated proteins, were identified. In conclusion, genetic mutations in the Hedgehog signalling pathway might underlie the complex polygenic background of PSIS, and the findings of our study could extend the understanding of PSIS pathogenic genes.

ITGBL1 promotes cell migration and invasion through stimulating the TGF-ß signalling pathway in hepatocellular carcinoma.

OBJECTIVES: Integrin beta-like 1 (ITGBL1) is involved in the migration and invasion of several cancers; however, its roles in the development and progression of hepatocellular carcinoma (HCC) remain largely unknown. MATERIALS AND METHODS: Immunohistochemistry staining was used to investigate the expression pattern of ITGBL1 and its prognostic values in HCC patients. The transwell, wound-healing assays, xenograft and orthotopic mouse models were employed to determine the effects of ITGBL1 on HCC cell migration and invasion in vitro and in vivo. The biological mechanisms involved in cell migration and invasion caused by ITGBL1 were determined with Western blotting and RT-PCR methods. RESULTS: ITGBL1 expression was significantly increased in HCC tissues compared to adjacent normal tissues. Patients with higher ITGBL1 expression were associated with more reduced overall survival. ITGBL1 overexpression promoted migration and invasion in SMMC-7721 and HepG2 cells in vitro and in vivo, whereas knockdown or knockout ITGBL1 in CSQT-2 cells significantly reduced cell migration and invasion abilities. In SMMC-7721 cells, ITGBL1 overexpression stimulated TGF-ß/Smads signalling pathway, along with the KRT17 and genes involved in the epithelial-mesenchymal transition (EMT). In contrast, ITGBL1 knockout inhibited the TGF-ß/Smads signalling pathway in CSQT-2 cells. CONCLUSIONS: These findings suggested that ITGBL1 promoted migration and invasion in HCC cells by stimulating the TGF-ß/Smads signalling pathway. ITGBL1 could be a promising prognostic biomarker, as well as a potential therapeutic target in HCC.

Enhanced Broad-band Radio Frequency Detection in Nanoscale Magnetic Tunnel Junction by Interface Engineering.

Broad-band radio frequency (RF) detection is of great interest for its potential applications in wireless charging and energy harvesting. Here, we demonstrate that the bandwidth of broad-band RF detection in spin-torque diodes based on magnetic tunnel junctions (MTJs) can be enhanced through engineering the interface perpendicular magnetic anisotropy (PMA) between the CoFeB free layer and the MgO tunnel barrier. An ultrawide RF detection bandwidth of over 3 GHz is observed in the MTJs, and the broad-band RF detection behavior can be modulated by tuning the free layer PMA. Furthermore, a wide RF detection bandwidth (about 1.8 GHz) can be realized even without any external bias field for free layers with a thickness of about 1.65 nm. Finally, the dependence of the broad-band RF detection bandwidth on external magnetic field and RF power is discussed. Our results pave the way for RF energy harvesting for future portable nanoelectronics.

Genome-wide methylation study of whole blood cells DNA in men with congenital hypopituitarism disease.

Congenital hypopituitarism (CH) is a relatively rare disease that is characterized by the deficiency of one or more hormones secreted by the pituitary gland, which leads to metabolic disorders, amenorrhea and infertility. However, the underlying molecular mechanisms of CH have not yet been fully elucidated. The present study evaluated the genome­wide methylation level of whole blood DNA in 12 patients with CH and 12 age­matched controls using Illumina Human Methylation 450 array, in order to determine the roles of epigenetic regulation in the pathogenesis of CH. The results demonstrated that the methylation levels of 51 CpG sites were significantly different between the patients with CH and the controls. Functional enrichment analysis identified that the aberrant methylated genes were enriched in gene sets associated with metabolic or cellular process, immune system process and reproduction. In addition, two CpG sites on genes LIM domain kinase 2 (LIMK2) and piwi­like RNA­mediated gene silencing 2 (PIWIL2), which are involved in spermatogenesis and/or testicular development, were identified to be hypermethylated in male patients with CH. The hypermethylation of these sites was further validated in another 40 patients with CH and 40 matched controls with a quantitative bisulfite pyrosequencing method, and the methylation levels of these two loci demonstrated promising diagnostic capacities for CH. The present results suggested that aberrant methylation of genes may be involved in the pathogenesis of CH, and hypermethylation of LIMK2 and PIWIL2 may contribute to the infertility of male patients with CH. Further studies are required to elucidate the underlying mechanisms of the epigenetic regulation of these genes.

MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin.

The long non-coding RNA maternally expressed gene 3 (MEG3) is frequently dysregulated in human cancers; however, its roles in colorectal cancer (CRC) development are largely unknown. Here, we reported that MEG3 was down-regulated in CRC tissues and CRC patients with lower MEG3 showed poorer overall survival and disease-free survival than those with higher MEG3 level. MEG3 over-expression represses CRC cells proliferation and migration in vivo and in vitro, while MEG3 knockdown leads to the enhanced proliferation and metastasis of CRC cells. In CRC cells, MEG3 over-expression is related to decreased Clusterin mRNA and the corresponding protein levels, and it also directly binds to Clusterin protein through its 732-1174 region. In further, Clusterin over-expression rescues the compromised abilities of proliferation and metastasis induced by MEG3 over-expression, suggesting that MEG3 inhibits the CRC progression through regulating the Clusterin activities. Additionally, we found that 1α,25-(OH)2D and vitamin D receptor (VDR) stimulate MEG3 expression in CRC cells through directly binding to its promoter. These results suggested that MEG3 functions as a tumor suppressor in CRC via regulating the Clusterin activities and may underlie the anticancer activities of vitamin D on CRC cells. The VDR/MEG3/Clusterin signaling pathway may serve as potential therapeutic targets and prognosis biomarkers for CRC patients in future.

Body mass index had different effects on premenopausal and postmenopausal breast cancer risks: a dose-response meta-analysis with 3,318,796 subjects from 31 cohort studies.

BACKGROUND: There is sufficient evidence supporting a relationship between increased body mass index (BMI) and an increased risk for breast cancer among postmenopausal women. However, most studies have found a decreased risk for premenopausal breast cancer. This study was conducted to find out the different effects of BMI on the risk of breast cancer among premenopausal and postmenopausal women, and explore the potential factors that influence the associations. METHODS: A dose-response meta-analysis with 3,318,796 participants from 31 articles was conducted. Cohort studies that included BMI and corresponding breast cancer risk were selected through various databases including PubMed, Medline, Web of Science, the China National Knowledge Infrastructure (CNKI) and Chinese Scientific Journals (VIP). Random effects models were used for analyzing the data. RESULTS: The summary relative risks (RRs) were 1.33 (95%CI: 1.20-1.48) and 0.94(95%CI: 0.80-1.11) among postmenopausal and premenopausal women, respectively. The dose-response meta-analysis indicated a positive non-linear association between BMI and breast cancer risk among postmenopausal women, and compared to the mean level of the normal BMI category (21.5 kg/m2) the RR in total postmenopausal women were1.03 (95% CI: 1.02-1.05) per 1 kg/m2 increment. However, no statistically significant association among total premenopausal women was detected. In subgroup analysis among European premenopausal women, the summary RR was 0.79(95%CI: 0.70-0.88). The non-linear relationship showed a negative non-linear association between BMI and breast cancer risk among European premenopausal women. When compared to the mean level of the normal BMI category, the RRs were 0.98 (95%CI: 0.96-1.00) per 1 kg/m2 increment, respectively. CONCLUSIONS: In line with previous studies BMI had different effects on pre-menopausal and postmenopausal breast cancer risk. However, contrary to previous studies, a high BMI was not associated with decreased risk in total pre-menopausal women. More research is needed to better understand these differences.

Positive Helicobacter pylori status is associated with better overall survival for gastric cancer patients: evidence from case-cohort studies.

Helicobacter pylori (H. pylori) infection increases the gastric cancer risk; however, the influences of H. pylori infection status on the outcomes for gastric cancer patients have not yet clearly defined. Herein, we systematically assessed the epidemiological studies regarding the associations between the H.pylori infection status at diagnosis and the prognosis for gastric cancer patients with the meta-analysis methods. Thirty-three eligibility studies with 8,199 participants that had determined the H.pylori infection status and the outcomes for gastric cancer patients were identified through searching the PubMed and MEDLINE databases updated to March 1st, 2017. The random-effects model suggested that positive H. pylori infection was associated with better overall survival with the pooled hazard ratio (HR) was 0.79 [95% confidence interval (CI) = 0.66-0.93; Q = 134.86, df = 32, P-heterogeneity < 0.001; I2 = 76.3%] compared to negative patients. The association was found to be more prominent in studies with higher quality, longer following-up time and more sensitive detection methods. An inverse but not statistically significant association between the H.pylori status and the disease-free survival of the patients (pooled HR = 0.84, 95% CI = 0.61-1.05;Q = 30.48, df = 11, P-heterogeneity = 0.001; I2 = 63.9%) was found, while no significant association was noticed in any subgroup analyses. These results suggested that gastric cancer patients with positive H.pylori infection status at diagnosis have better overall survival compared to negative; however, more studies are warranted to confirm the results and elucidate the underlying mechanisms.

Prognostic Biomarker Identification Through Integrating the Gene Signatures of Hepatocellular Carcinoma Properties.

Many molecular classification and prognostic gene signatures for hepatocellular carcinoma (HCC) patients have been established based on genome-wide gene expression profiling; however, their generalizability is unclear. Herein, we systematically assessed the prognostic effects of these gene signatures and identified valuable prognostic biomarkers by integrating these gene signatures. With two independent HCC datasets (GSE14520, N=242 and GSE54236, N=78), 30 published gene signatures were evaluated, and 11 were significantly associated with the overall survival (OS) of postoperative HCC patients in both datasets. The random survival forest models suggested that the gene signatures were superior to clinical characteristics for predicting the prognosis of the patients. Based on the 11 gene signatures, a functional protein-protein interaction (PPI) network with 1406 nodes and 10,135 edges was established. With tissue microarrays of HCC patients (N=60), we determined the prognostic values of the core genes in the network and found that RAD21, CDK1, and HDAC2 expression levels were negatively associated with OS for HCC patients. The multivariate Cox regression analyses suggested that CDK1 was an independent prognostic factor, which was validated in an independent case cohort (N=78). In cellular models, inhibition of CDK1 by siRNA or a specific inhibitor, RO-3306, reduced cellular proliferation and viability for HCC cells. These results suggest that the prognostic predictive capacities of these gene signatures are reproducible and that CDK1 is a potential prognostic biomarker or therapeutic target for HCC patients.