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Summary LncRNA PVT1 has been demonstrated to be upregulated in acute myeloid leukaemia (AML) patients and indicates a poor prognosis. Nevertheless, its role in AML remains obscure. This study investigated the regulatory role and potential mechanisms of PVT1 in the progression of AML. Expression of PVT1, miR-29 family and WAVE1 was detected by quantitative real-time polymerase chain reaction. CCK8 and EdU assays were performed to assess the proliferation of AML cells. Cell cycle and apoptosis were determined by propidium iodide (PI) staining and Annexin V/PI staining on a flow cytometer. Transwell assay was carried out to evaluate the migration and invasion abilities. The interaction between miR-29 family and PVT1/WAVE1 was confirmed by dual luciferase reporter assay and RNA immunoprecipitation assay. The protein levels of WAVE1, Bcl-2, Bax, cleaved Caspase 3, cyclin D1, and p21 were detected by western blotting. Xenograft transplantation was performed to determine the tumourigenicity of AML cell in vivo. PVT1 expression was significantly increased in AML patient samples and cells, which positively correlated with WAVE1 expression. Silencing of PVT1 restrained growth, migration and invasion, while inducing apoptosis of AML cells. Moreover, PVT1 acted as a sponge for miR-29 family to increase WAVE1 expression in AML cells. Overexpression of WAVE1 partly counteracted PVT1 knockdown-induced anti-tumour effects on AML cells in vitro and xenograft tumour in vivo. PVT1 facilitated the progression of AML via regulating miR-29 family/WAVE1 axis, which supported the conclusion that PVT1 may be a promising therapeutic target for AML.

Background: Systemic lupus erythematosus (SLE) can cause placental dysfunctions, which may result in pregnancy complications. Long noncoding RNAs (lncRNAs) are actively involved in the regulation of immune responses during pregnancy. The present study aimed to determine the lncRNA expression profiles in placentas from women with SLE to gain new insights into the underlying molecular mechanisms in SLE pregnancies.Methods: RNA sequencing (RNA-seq) analysis was performed to identify SLE-dysregulated lncRNAs and mRNAs in placentas from women with SLE and normal full-term (NT) pregnancies. Bioinformatics analysis was conducted to predict biological functions of these SLE-dysregulated lncRNAs and mRNAs. Correlation relationships between these dysregulated lncRNAs and SLE disease activity index (SLEDAI) scores were also assessed. Results: RNA-seq analysis identified 81 dysregulated lncRNAs in SLE placentas, including 53 that were up-regulated and 28 down-regulated. Additional 221 SLE-dysregulated mRNAs were also discovered, including 209 up-regulated and 12 down-regulated. Bioinformatics analysis revealed that SLE-dysregulated genes were associated with biological functions and gene networks, such as type I interferon signaling pathway, response to hypoxia, regulation of MAPK (mitogen-activated protein kinase)/JNK (c-Jun N-terminal kinase) cascade, response to steroid hormone, heparin binding, and insulin-like growth factor binding. Correlation analysis showed that lncRNA NONHSAT246155.1 was positively correlated (r = 0.333, P = 0.037) with SLEDAI score.Conclusions: This is the first report of the lncRNA profiles in placentas from SLE pregnancies. These results suggest that the aberrant expression and the potential regulatory function of lncRNAs in placentas may play comprehensive roles in the pathogenesis of SLE pregnancies. These lncRNAs, including NONHSAT246155.1 may potentially serve as novel therapeutic targets for SLE during pregnancy.

Acute myelogenous leukemia (AML) is the most common acute leukemia in adults. Despite great progress has been made in this field, the pathogenesis of AML is still not fully understood. We report here the biological role of lncRNA small nucleolar RNA host gene 5 (SNHG5) in the pathogenesis of AML and the underlying mechanisms. The results showed that lncRNA SNHG5 was highly expressed in AML cancer cell lines. In vitro studies displayed that inhibition of SNHG5 with shRNA resulted in suppression of survival, cell cycle progression, migration/invasion of AML and capacity of adhesion and angiogenesis in human umbilical vein endothelial cells. Mechanistic studies revealed a SNHG5/miR-26b/connective tissue growth factor (CTGF)/vascular endothelial growth factor A (VEGFA) axis in the regulation of AML angiogenesis. Finally, Yin Yang 1 (YY1) was found to transactivate and interact with SNHG5 promoter, leading to the upregulation of SNHG5 in AML. Collectively, upregulation of lncRNA SNHG5 mediated by YY1, activates CTGF/VEGFA via targeting miR-26b to regulate angiogenesis of AML. Our work provides new insights into the molecular mechanisms of AML.

Background Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. Results Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P P Conclusion This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426.

Introduction. Staphylococcal enterotoxin B (SEB) is an extensively studied super-antigen. A previous study by us suggested that SEB exposure during pregnancy could alter the percentage of CD4+ and CD8+ T cells in the peripheral blood of neonatal offspring rats. Aim. It is unknown whether SEB exposure during pregnancy can influence the development of regulatory T cells (Tregs) in the peripheral blood of neonatal offspring rats. Methodology. Pregnant rats at gestational day 16 were intravenously injected with 15 µg SEB. Peripheral blood was acquired from neonatal offspring rats on days 1, 3 and 5 after delivery and from adult offspring rats for determination of Treg number by cytometry, cytokines by ELISA, and FoxP3 expression by real-time PCR and western blot. Results. SEB given to pregnant rats significantly increased the absolute number of Tregs and the expression levels of FoxP3, IL-10 and TGF-β (PPPPP Conclusion. Prenatal SEB exposure attenuates the development and function of Tregs to repeated SEB exposure in the peripheral blood of adult offspring rats.

The study investigated the distribution of Epstein-Barr virus (EBV) EA-IgA, VCA-IgA, and EBVNA-IgG antibodies in a local population of Wuhan, China. Chemiluminescence immunoassay (CLIA) was used to detect EBV EA-IgA, VCA-IgA, and EBVNA-IgG antibodies in 972 subjects undergoing physical examination in Wuhan, and the results were analyzed. The detection rate of EBV was positively correlated with age. In the 972 cases, there was significant difference between different genders in the positive rate of VCA-IgA and EBVNA-IgG. Moreover, the positive rate of VCA-IgA and EBVNA-IgG was higher in men ≥ 60 years old than in those < 60 but no significant differences were found in three antibodies among various age groups. Our results suggested that the EBV infection should be intensively monitored in elderly people in Wuhan.

Preeclampsia (PE) is a hypertensive pregnancy, which is a leading cause of maternal and fetal morbidity and mortality during pregnancy. L-Tryptophan (Trp) is an essential amino acid, which can be metabolized into various biologically active metabolites. However, the levels of many circulating Trp-metabolites in human normotensive pregnancies (NT) and PE are undetermined. This study quantified the levels of Trp-metabolites in maternal and umbilical vein sera from women with NT and PE. Paired maternal and umbilical blood samples were collected from singleton pregnant patients. Twenty-five Trp-metabolites were measured in serum samples using liquid chromatography with tandem mass spectrometry. The effects of L-kynurenine (Kyn) and indole-3-lactic acid (ILA), on function of human umbilical vein endothelial cells (HUVECs), were also determined. Twenty Trp-metabolites were detected. The levels of 9 Trp-metabolites including Kyn and ILA were higher (P

23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1–5 μM) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1–10 μM) dose-dependently enhanced LDLR promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited PCSK9 (proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1α (hepatocyte nuclear factor-1α) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg · kg−1⋅ d−1, intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1α protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development.

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been found to play a major role in atherosclerotic cardiovascular disease (ASCVD) by promoting hyperlipidemia. Its inhibition has therefore emerged as a viable drug target for improving the outcome of ASCVD. However, current monoclonal antibody PCSK9 inhibitors are considered cost ineffective and there is the need to discover new effective and cheaper small molecule alternatives. Purpose The methanolic and ethanolic crude extracts of Nauclea latifolia have been shown to possess anti-hyperlipidemic activity, but the chemical component(s) responsible for this activity and the mechanism of action have remained unknown. The objective of this study was therefore to identify N. latifolia constituents with anti-hyperlipidemic activity and to investigate the inhibition of PCSK9 as a probable mechanism of action. Method In the present study, compounds were isolated from the ethanolic extract of the stem of N. latifolia. The alkaloids were evaluated for their DiI-LDL uptake promoting activity in HepG2 cell. The most active compound was further assessed for its effect on low density lipoprotein receptor (LDLR) and PCSK9 protein expressions by western blot. Results 3R-3,14-dihydroangustoline (5), showed a relatively good activity in promoting LDL uptake (1.26-fold). It further increased LDLR protein expression and decreased the protein expression of PCSK9 in a dose dependent manner (1–50 µM). Conclusion Alkaloids from N. latifolia may serve as a source of new PCSK9 inhibitors.

Aims Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. We hypothesized that nagilactone B (NLB), a small molecule extracted from the root bark of Podocarpus nagi (Podocarpaceae), suppresses atherosclerosis in an atherosclerotic mouse model. Methods and results Male apoE-deficient mice on C57BL/6J background received NLB (10 and 30 mg/kg) for 12 weeks. Compared with the model group, NLB treatment (10 and 30 mg/kg) significantly reduced en face lesions of total aorta areas. In RAW264.7 cells, NLB significantly ameliorated cholesterol accumulation in macrophages via enhancing apolipoprotein A-I and HDL-mediated cholesterol efflux. Mechanistically, NLB induced messenger RNA and protein expression of the ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 and THP-1 cells. Liver X receptor (LXR) site mutations in the mouse ABCA1 promoter abrogated NLB-mediated luciferase reporter activity. LXRα and LXRβ small interfering RNA suppressed NLB-mediated induction of ABCA1 expression. Consistent with in vitro results, NLB induced ABCA1 expression and suppressed macrophage areas in the aortic sinus. Moreover, NLB treatment did not induce the protein expression of LXR in liver. Hepatic and intestinal cholesterol accumulation was significantly alleviated on NLB treatment. Besides, NLB significantly improved plasma lipid profiles in apoE-deficient mice. Conclusion Selective LXR activation in macrophages with NLB induces ABCA1- and ABCG1-mediated cholesterol efflux while exerting minimal effects on lipogenesis and lipid accumulation in liver, resulting in regression of atherosclerosis, and therefore might be a promising strategy for therapeutics.

According to the World Health Organization,palliative care is an approach that prevents and alleviates the pain of patients with life-threatening illness and improves the quality of life of patients and their families through early identification,assessment and treatment of pain and other physical,psychosocial and spiritual problems. It is the active holistic care accomplished by multidisciplinary team. This article describes the practice of the palliative care in a patient with advanced retroperitoneal sarcoma.

Magnesium lithospermate B (MLB) is an active component of Salvia miltiorrhiza Radix, a traditional Chinese herb used in treating cardiovascular diseases. In this study, we investigated the protective effects of MLB against inflammation-induced endothelial dysfunction in vitro and in vivo, and the underlying mechanisms. Endothelial dysfunction was induced in human dermal microvascular endothelial cells (HMEC-1) in vitro by lipopolysaccharide (LPS, 1 μg/mL). We showed that pretreatment with MLB (10-100 μM) dose-dependently inhibited LPS-induced upregulation of inflammatory cytokines ICAM1, VCAM1, and TNFα, which contributed to reduced leukocytes adhesion and attenuation of endothelial hyperpermeability in HMEC-1 cells. SD rats were injected with LPS (10 mg/kg, ip) to induce endothelial dysfunction in vivo. We showed that pretreatment with MLB (25-100 mg/kg, ip) dose-dependently restored LPS-impaired endothelial-dependent vasodilation in superior mesenteric artery (SMA), attenuated leukocyte adhesion in mesenteric venules and decreased vascular leakage in the lungs. We further elucidated the mechanisms underlying the protective effects of MLB, and revealed that MLB pretreatment inhibited NF-κB activation through inhibition of IκBα degradation and subsequent phosphorylation of NF-κB p65 in vitro and in vivo. In HMEC-1 cells, MLB pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Knockdown of Nrf2 with siRNA abolished the inhibitory effects of MLB on IκBα degradation and ICAM1 up-regulation, which were mimicked by PKC inhibition (Go6983) or PI3K/Akt inhibition (LY294002). In summary, our results demonstrate that MLB inhibits NF-κB activation through PKC- and PI3K/Akt-mediated Nrf2 activation in HMEC-1 cells and protects against LPS-induced endothelial dysfunction in murine model of acute inflammation.

OBJECTIVE: To study the effect of cordycepin on cell cycle, apoptosis and autophagy of human tongue cancer TCA-8113 cells and explore the mechanism of cordycepin for inhibiting the occurrence of tongue cancer. METHODS: CCK-8 method was used to assess the inhibitory effect of cordycepin on TCA-8113 cell proliferation in vitro. The cell cycle and cell apoptosis of TCA-8113 cells treated with different concentrations of cordycepin were analyzed using flow cytometry. The expressions of apoptosis-related genes caspase-3, caspase-9, Bcl-2, and Bax were examined using quantitative real-time PCR and Western blotting, and immunohistochemistry was used to detect the expressions of autophagy-related proteins LC-3β, P62, p-mTOR, and AMPK. RESULTS: CCK-8 assay showed that cordycepin significantly inhibited the proliferation of TCA-8113 cells in a concentration-dependent manner with an IC(50) of 3.548 mg/mL at 24 h and an IC(50) of 1.185 mg/mL at 48 h. Flow cytometric analysis showed that cordycepin caused cell cycle arrest at S phase and dose-dependently increased the apoptotic rate of TCA-8113 cells. Treatment of the cells with cordycepin enhanced the expressions of Bax, caspase-3 and caspase-9 at both the mRNA and protein levels and inhibited the expression of the antiapoptotic gene Bcl-2. Immunohistochemistry demonstrated that cordycepin promoted the expression of LC-3β and AMPK and inhibited the expression of P62 and p-mTOR. CONCLUSION: Cordycepin inhibits the proliferation and induces apoptosis of HCT-116 cells through the mitochondrial pathway and induces autophagy via the AMPK/mTOR pathway.

The phytochemical study of Euphorbia helioscopia led to the isolation of 33 jatrophane diterpenoids (1-33), of which six (1-6) were new. This small jatrophane library was established to screen for potential lipid modulators. LDL-Uptake screening assay demonstrated that most of them improved LDL-Uptake rate in HepG2 cells, with compounds 16, 21 and 26 exhibiting more outstanding effects. Further exploration found that these three compounds could increase LDLR protein level in HepG2 cells dose-dependently. SAR studies suggested that substituted patterns of C-9, steric hindrance between C-14 and C-15, and the long conjugated fragment from C-5 to the carbonyl (C-9) were essential for the activity. Moreover, compound 21, a relatively abundant chemical in E. helioscopia, showed remarkable lipid-lowering effect in vivo, which makes it a promising lead for development of new lipid-lowering agents.

To explore the similarity between the iliac crest and the metacarpal bone, so as to provide an anatomical basis for the reconstruction of the metacarpal bone of the hand with the iliac crest grafting.There are 16 upper limb specimens and 10 pelvic specimens. The morphological features of the second, third, fourth and 5th metacarpal bones and iliac crest were observed. The following indexes were measured: arc height and length of metacarpal head articular surface, volar-dorsal metacarpal diameter, ulnoradial diamater, arc height and length of iliac crest, and inner and outer diameter. The obtained data were statistically analyzed to compare the morphological, structural features, arc length and diameter length of each metacarpal bone and iliac crest.The arc length of the second metacarpal head, volar-dorsal metacarpal diameter, arc height, and the ulnoradial diameter are 22.040(21.425, 23.085) mm, (14.034±0.465) mm, 4.185 (4.113, 4.598) mm, and (12.227±0.414) mm respectively. The arc length of the third metacarpal head, volar-dorsal metacarpal diameter, arc height, and the ulnoradial diameter are 23.430(22.743, 24.153)mm, (14.316±0.430) mm, 4.235(4.170, 4.670) mm, and (12.382±0.425) mm respectively. The arc length of the fourth metacarpal head, volar-dorsal metacarpal diameter, arc height, and the ulnoradial diameter are 21.960 (21.245, 22.285) mm, (12.382±0.288) mm, 4.125 (4.030, 4.305) mm, and (11.991±0.362) mm respectively. The arc length of the fifth metacarpal head, volar-dorsal metacarpal diameter, arc height, and the ulnoradial diameter are 20.030 (19.668, 20.148) mm, (11.807±0.358) mm, 4.015(3.880, 4.205) mm, and (11.659±0.399) mm respectively. The inner and outer diameter of the iliac crest is 14.350 (13.660, 14.739) mm, and the arc length and height are (22.930±0.701) mm and (4.520±0.184) mm respectively. The difference between the volar-dorsal metacarpal diameter of the second metacarpal head and the inner and outer diameter of the iliac crest has no significant; while the volar-dorsal metacarpal diameter of the third, fourth and fifth metacarpal heads are apparently longer and shorter than the inner and outer diameter of the iliac crest, respectively. The differences are statistically significant. The differences between arc length of the iliac crest and arc length of the second, fourth and fifth metacarpl head are statistically significant. However, the difference of arc length between the third metacarpal head and the ilium, as well as the difference of arc height between the second and third metacarpal heads and the iliac crest have no statistical significances, while the arc height of the fourth and fifth metacarpal heads are obviously smaller than that of the iliac crest.Autologous iliac crest is similar with metacarpal bone in anatomy, which might be a suitable donor for metacarpal bone transplantation.

Estradiol 17β (E2β) and ascorbic acid (AA) have been implicated in cancer progression. However, little is known about the actions of biologically active metabolites of E2β, 2-hydroxyestradiol (2OHE2), 4-hydroxyestradiol (4OHE2), 2-methoxyestradiol (2ME2), and 4-methoxyestradiol (4ME2) synthesized sequentially by cytochrome P450, family 1, subfamily A (CYP1A1) and B (CYP1B1), polypeptide 1, and catechol-O-methyltransferase (COMT) on ovarian cancer. Herein, we examined the expression of CYP1A1, CYP1B1, COMT, and estrogen receptor α (ERα) and β (ERβ) in human ovarian surface epithelial (IOSE-385) and cancer cell lines (OVCAR-3, SKOV-3, and OVCA-432). We also investigated the roles of E2β, 2OHE2, 4OHE2, 2ME2, and 4ME2 in cell proliferation, and their interactive effects with AA on ovarian cells. We found the expression of CYP1A1, CYP1B1, COMT, ERα, and ERβ in most cell lines tested. Treating cells with physiological concentrations of E2β and its metabolites promoted (13%-42% of the control) IOSE-385 and OVCAR-3 proliferation. The ER blockade inhibited IOSE-385 (∼76%) and OVCAR-3 (∼87%) proliferative response to E2β but not to its metabolites. The ERα blockade inhibited (∼85%) E2β-stimulated OVCAR-3 proliferation, whereas ERβ blockade attenuated (∼83%) E2β-stimulated IOSE-385 proliferation. The AA at ≥250 μmol/L completely inhibited serum-stimulated cell proliferation in all cell lines tested; however, such inhibition in IOSE-385, OVCAR-3, and OVCA-432 was partially (∼10%-20%) countered by E2β and its metabolites. Thus, our findings indicate that E2β and its metabolites promote cell proliferation and antagonize the AA-suppressed cell proliferation in a subset of ovarian cancer cells, suggesting that blocking the actions of E2β and its metabolites may enhance AA’s antiovarian cancer activity.

Objective: Crocin has been proposed as a promising candidate for cancer chemoprevention. The purpose of this investigation was to investigate the chemopreventive action and the possible mechanisms of crocin against human colon cancer cells in vitro. Methods: Cell proliferation was examined using MTT assay and the cell cycle distribution fractions were analyzed using fow cytometric analysis after propidium iodide staining. Apoptosis was detected using theTUNEL Apoptosis Detection Kit with laser scanning confocal microscope. DNA damage was assessed using the alkaline single-cell gel electrophoresis assay, while expression levels of p53, cdk2, cyclinA and P21 were examined by Western blot analysis. Results: Treatment of SW480 cells with crocetin (0.2, 0.4, 0.8 mmol/L) for 48 h signifcantly inhibited their proliferation in a concentration-dependent manner. Crocetin (0.8 mmol/L) signifcantly induced cell cycle arrest through p53-independent mechanisms accompanied by P21 induction. Crocetin (0.8 mmol/L) caused cytotoxicity in the SW480 cells by enhancing apoptosis and decreasing DNA repair capacity in a time-dependent manner. Conclusions: This report provides evidence that crocetin is a potential anticancer agent, which may be used as a chemotherapeutic drug.

Bacillary dysentery is an infectious disease caused by Shigella dysenteriae, which has a seasonal distribution. External environmental factors, including climate, play a significant role in its transmission. This paper identifies climate-related risk factors and their role in bacillary dysentery transmission. Harbin, in northeast China, with a temperate climate, and Quzhou, in southern China, with a subtropical climate, are chosen as the study locations. The least absolute shrinkage and selectionator operator is applied to select relevant climate factors involved in the transmission of bacillary dysentery. Based on the selected relevant climate factors and incidence rates, an AutoRegressive Integrated Moving Average (ARIMA) model is established successfully as a time series prediction model. The numerical results demonstrate that the mean water vapour pressure over the previous month results in a high relative risk for bacillary dysentery transmission in both cities, and the ARIMA model can successfully perform such a prediction. These results provide better explanations for the relationship between climate factors and bacillary dysentery transmission than those put forth in other studies that use only correlation coefficients or fitting models. The findings in this paper demonstrate that the mean water vapour pressure over the previous month is an important predictor for the transmission of bacillary dysentery.

G-proteins mediate cellular function upon interaction with G-protein coupled receptors. Of the 16 mammalian G-protein α subunits identified, G-protein subunit α-11 (GNA11) and -14 (GNA14) have been implicated in modulating hypertension and endothelial function. However, little is known about their expression and roles in human placentas. Here, we examined GNA11 and GNA14 protein expression in first trimester (FT), normal term (NT), and severe preeclamptic (sPE) human placentas as well as in NT human umbilical cords. We found that GNA11 and GNA14 were immunolocalized primarily in trophoblasts, villous stromal cells, and endothelial cells in placentas as well as in endothelial and/or smooth muscle cells of the umbilical cord artery and vein. Western blotting revealed that the GNA14, but not GNA11, protein levels were increased (2.5-2.9 fold; p

Retrospective and prospective studies have shown that continuous administration of trastuzumab with different chemotherapy regimens resulted in better clinical outcomes than the administration of chemotherapy alone in women with HER2-positive, trastuzumab-refractory metastatic breast cancer (MBC). However, there are limited data to evaluate the activity of trastuzumab in patients progressed after other anti-HER2 therapies, e.g. lapatinib. The aim of the present study was to evaluate retrospectively the clinical value of trastuzumab in patients with lapatinib-resistant HER2-positive advanced breast cancer treated in our center.Patients with HER2-positive MBC who experienced progression after first-line lapatinib-based regimens were assigned to receive either conventional treatment without trastuzumab or in combination with trastuzumab as second-line therapy. The efficacy end points included progression-free survival (PFS) and overall survival (OS).Thirty-five eligible patients progressed after treatment with lapatinib-based regimens were collected. None of the patients had received prior trastuzumab in either the adjuvant or metastatic setting. Twenty-two patients were assigned to receive conventional treatment without trastuzumab as second-line therapy (non-T arm) and 13 patients received conventional treatment combined with trastuzumab (T arm). There were no significant differences in the main clinical factors between the two arms, such as age, PS status, ER/PR, metastatic status, etc. Both the two cases with no disease progression after the second-line therapy were trastuzumab-treated patients, and all the other 33 cases were patients with progression despite the second-line therapy. Twenty-seven patients died due to disease progression, and eight survived (six cases of the T-arm and two cases of the non-T arm). The median PFS was 3.3 months in the non-T arm and 10.0 months in the T arm (P = 0.001). The median OS was 7.0 months in the non-T arm and 31.1 months in the T arm (P = 0.015).Trastuzumab plus conventional treatment is superior to conventional treatment in women with lapatinib-resistant HER2-positive metastatic breast cancer. Continuous anti-HER2 management can provide survival benefit to patients with HER2-positive breast cancer.

Ever since George Streisinger pioneered his research using zebrafish (Danio rerio), at the University of Oregon in 1972, the zebrafish not only has become a unique animal model in basic research, due to its fine embryonic and (molecular) genetics technique/tool developed globally, but it is also a favorite model of choice in the biomedical research, i.e., used for establishing human disease models and discovering lead drug/small chemical in the past decade. In this review, we will briefly describe the history of zebrafish research, emphasizing the well-recognized milestones, and stress how the models of leukemia, melanoma, immunity/infectious diseases and neuronal defects/neuro-degeneration diseases have been established and how pharmaceutical industry and research scientists make use of zebrafish to obtain potential therapeutic drugs. We believe that this direction of zebrafish research will lead to a better understanding of some nasty human diseases and their pathogenic mechanisms, and eventually help to achieve a better health of human beings.

AIM: To investigate mitochondrial ATP 6 and 8 polymorphisms in the colon and ileum of patients with irritable bowel syndrome with diarrhea (IBS-D). METHODS: Twenty-eight patients fulfilling the Rome III criteria for IBS-D and 28 healthy subjects were investigated. All study participants underwent screening colonoscopy and mucosal biopsies were obtained from the colon and/or terminal ileum. Genomic DNA was extracted from specimens based on standard protocols. Mitochondrial ATP (MT-ATP) 6 and 8 genes in specimens were polymerase chain reaction amplified and sequenced. Sequencing data were analyzed via Variant Reporter™ Software and compared with the reference sequence from Genbank (accession No. {"type":"entrez-nucleotide","attrs":{"text":"NC_012920","term_id":"251831106","term_text":"NC_012920"}}NC_012920) to indicate possible polymorphisms. The protocol was registered at www.clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT01028898","term_id":"NCT01028898"}}NCT01028898. RESULTS: Twenty-five polymorphic sites of MT-ATP 6 and 8 genes were detected and 12 of them were missense mutations. A median of two polymorphic sites in MT-ATP genes was found in colon specimens of controls while a median of three polymorphic sites was noted in patients with IBS-D (Mann-Whitney test, P = 0.012). The variants of the colon and ileum specimens from the same subjects were identical in all but one case. Symptom duration in IBS was not found to be a significant factor associated with the mtDNA polymorphism (Spearman correlation, P = 0.592). The mitochondrial DNA change at 8860 was present in all cases of both groups. The frequency of the 8701 polymorphism was found to be the second most frequent; however, no statistical difference was noted between the groups (χ2 test, P = 0.584). CONCLUSION: Patients with IBS-D have a higher incidence of MT-ATP 6 and 8 polymorphisms than healthy subjects, implying that the mtDNA polymorphism may play a role in IBS-D.

Background The efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer is limited by the acquired drug resistance. Identification the RNAs related to the cisplatin resistance may help to improve clinical response rates. Methods Microarray expression profiling of mRNAs, lncRNA and miRNA was undertaken in A549 cells and cisplatin resistant A549/CDDP cells. Differentially expressed mRNAs, lncRNAs and miRNAs, verified by realtime RT-PCR, were subjected to pathway analysis. Expression of NKD2 and β-catenin was assessed by realtime RT-PCR and western blot analysis. The effect of lncRNA AK126698 on cisplatin induced apoptosis was investigated by annexin-V/PI flow cytometry. Results In total, 1471 mRNAs, 1380 lncRNAs and 25 miRNAs differentially expressed in A549/CDDP and A549 cells. Among them, 8 mRNAs, 8 lncRNAs and 5 miRNAs differentially expressed in gene chip analysis were validated. High-enrichment pathway analysis identified that some classical pathways participated in proliferation, differentiation, avoidance of apoptosis, and drug metabolism were differently expressed in these cells lines. Gene co-expression network identified many genes like FN1, CTSB, EGFR, and NKD2; lncRNAs including BX648420, ENST00000366408, and AK126698; and miRNAs such as miR-26a and let-7i potentially played a key role in cisplatin resistance. Among which, the canonical Wnt pathway was investigated because it was demonstrated to be targeted by both lncRNAs and miRNAs including lncRNA AK126698. Knockdown lncRNA AK126698 not only greatly decreased NKD2 which can negatively regulate Wnt/β-catenin signaling but also increased the accumulation and nuclear translocation of β-catenin, and significantly depressed apoptosis rate induced by cisplatin in A549 cells. Conclusion Cisplatin resistance in non-small-cell lung cancer cells may relate to the changes in noncoding RNAs. Among these, AK126698 appears to confer cisplatin resistance by targeting the Wnt pathway.

Background Synaptic genes, NLGN3 and NLGN4X, two homologous members of the neuroligin family, have been supposed as predisposition loci for autism spectrum disorders (ASDs), and defects of these two genes have been identified in a small fraction of individuals with ASDs. But no such rare variant in these two genes has as yet been adequately replicated in Chinese population and no common variant has been further investigated to be associated with ASDs. Methods 7 known ASDs-related rare variants in NLGN3 and NLGN4X genes were screened for replication of the initial findings and 12 intronic tagging single nucleotide polymorphisms (SNPs) were genotyped for case-control association analysis in a total of 229 ASDs cases and 184 control individuals in a Chinese Han cohort, using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Results We found that a common intronic variant, SNP rs4844285 in NLGN3 gene, and a specific 3-marker haplotype XA-XG-XT (rs11795613-rs4844285-rs4844286) containing this individual SNP were associated with ASDs and showed a male bias, even after correction for multiple testing (SNP allele: P = 0.048, haplotype:P = 0.032). Simultaneously, none of these 7 known rare mutation of NLGN3 and NLGN4X genes was identified, neither in our patients with ASDs nor controls, giving further evidence that these known rare variants might be not enriched in Chinese Han cohort. Conclusion The present study provides initial evidence that a common variant in NLGN3 gene may play a role in the etiology of ASDs among affected males in Chinese Han population, and further supports the hypothesis that defect of synapse might involvement in the pathophysiology of ASDs.

To investigate the concordance and correlation between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) assessment for HER-2 status in breast cancer patients and analyze their relationship to clinical characteristics.A total of 128 samples of breast cancer tissue were analyzed retrospectively. FISH was employed to detect the HER-2 gene amplification. And the FISH findings were compared with IHC test results by analyzing the concordance and correlation between two results. And their relationships to the clinical characteristics were analyzed.The overall coincidence rate of IHC and FISH was 90.6% (kappa = 0.405, P = 0.000). And the discordance was mainly found in the IHC (++) group. A positive correlation was found between the two results (r = 0.655, P = 0.000). The ER (estrogen receptor) expression was negatively correlated with HER-2 gene amplification and the expression of Her-2 protein (r = -0.300, P = 0.001; r = -0.223, P = 0.011). There was a negative correlation between ER/PR status and HER-2 gene amplification (r = -0.213, P = 0.016). The similar results were found in subgroup analysis. Tumor grade was negatively correlated with the expression of Her-2 protein (r = -0.293, P = 0.008), but not with HER-2 gene amplification (P0.05).IHC is a preferred method to detect the Her-2 status in breast cancer. The strong positive expression (+++) of HER-2 protein tested by IHC is strongly consistent with HER-2 gene amplification by FISH. But HER-2 gene amplification should be further detected by FISH in patients with HER-2 positive expression (+-++) in order to guide the clinical diagnosis and treatment. ER, ER/PR (progesterone receptor) status and tumor grade are correlated with HER-2 gene amplification and/or the expression of Her-2 protein. This study helps improve the accuracy of judging HER-2 gene amplification according to the clinical and pathological features such as ER status and the results of IHC.

In 1926, Smuts put forward the concept of "holistic". Then, this concept was introduced into the field of nursing. The presentation of system theory, levels and models of people's needs, theory of solving-problem provided the theoretical base for "holistic nursing". Beginning from the definition of health provided by WHO in 1948, many scholars put forward a set of nursing concepts, such as nursing process, theory of goal attainment, holistic human body, etc. In these concepts, the concept of holistic nursing was improved gradually, and finally formed the thought and method which were focused on patients, guided by concept of modern nursing, based on the nursing process, and it applied the systematic nursing process into the clinical nursing and its administration. At present, holistic nursing has been applied widely in the world. Reviewing its history will benefit the understanding of its connotation, and its application in the clinic for further improvement.

Background The combination of chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) currently has become the hotspot issue in the treatment of non-small lung cancer (NSCLC). This systematic review was conducted to compare the efficacy and safety of the synchronous combination of these two treatments with EGFR TKIs or chemotherapy alone in advanced NSCLC. Methods EMBASE, PubMed, the Central Registry of Controlled Trials in the Cochrane Library (CENTRAL), Chinese biomedical literature database (CNKI) and meeting summaries were searched. The Phase II/III randomized controlled trials were selected by which patients with advanced NSCLC were randomized to receive a combination of EGFR TKIs and chemotherapy by synchronous mode vs. EGFR TKIs or chemotherapy alone. Results A total of six randomized controlled trials (RCTs) including 4675 patients were enrolled in the systematic review. The meta-analysis demonstrated that the synchronous combination group of chemotherapy and EGFR TKIs did not reach satisfactory results; there was no significant difference in overall survival (OS), time to progression (TTP) and objective response rate (ORR), compared with monotherapy (OS: HR = 1.05, 95%CI = 0.98–1.12; TTP: HR = 0.94, 95%CI = 0.89–1.00; ORR: RR = 1.07, 95%CI = 0.98–1.17), and no significant difference in OS and progression-free survival (PFS), compared with EGFR TKIs alone (OS: HR = 1.10, 95% CI = 0.83–1.46; PFS: HR = 0.86, 95% CI = 0.67–1.10). The patients who received synchronous combined therapy presented with increased incidences of grade 3/4 anemia (RR = 1.40, 95% CI = 1.10–1.79) and rash (RR = 7.43, 95% CI = 4.56–12.09), compared with chemotherapy, grade 3/4 anemia (RR = 6.71, 95% CI = 1.25–35.93) and fatigue (RR = 9.60, 95% CI = 2.28–40.86) compared with EGFR TKI monotherapy. Conclusions The synchronous combination of chemotherapy and TKIs is not superior to chemotherapy or EGFR TKIs alone for the first-line treatment of NSCLC.

To investigate effect of safrole oxide on cell growth and apoptosis induced by deprivation of survival factors (fibroblast growth factors, aFGF and bFGF) in vascular endothelial cells (VEC).Morphological changes were observed by light microscopy. Cell growth was determined by MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium) method. DNA fragmentation was analyzed by agarose gel electrophoresis and fluorescence microscopy. Cell cycle distribution was analyzed by flow cytometry (FCM).The cells deprived of FGF were exposed to safrole oxide 5-25 mg/L for 24 h. Cells spreading and growth were promoted (P0.01), detachment and DNA fragmentation of these cells were suppressed (P0.01), safrole oxide 10 mg/L had no obvious effect on cell cycle distribution (P0.05). When the cells were treated with safrole oxide 50-100 mg/L, detachment and DNA fragmentation of VEC were promoted (P0.01). The cell cycle was blocked at G2-M phase by safrole oxide 100 mg/L.Safrole oxide 10 mg/L inhibited, but 100 mg/L promoted apoptosis of VEC. Safrole oxide might be an important compound that affects VEC growth and apoptosis.