Targeted gene therapy of nasopharyngeal cancer in vitro and in vivo by enhanced thymidine kinase expression driven by human TERT promoter and CMV enhancer

<p>Abstract</p> <p>Background/Aim</p> <p>To explore the therapeutic effects of thymidine kinase (TK) expressed by enhanced vector pGL3-basic- hTERTp-TK-EGFP-CMV driven by human telomerase reverse transcriptase promoter (hTERTp) as well as cytomegalovirus immediate early promoter enhancer (CMV).</p> <p>Materials/Methods</p> <p>Enhanced TK-EGFP expression was confirmed by fluorescent microscopy, real time PCR and telomerase activity. Its effects were examined by survival of tumor cells NPC 5-8F and MCF-7, index of xenograft implanted in nude mice and histology.</p> <p>Results</p> <p>Compared with non-enhanced vector pGL3-basic-TK-hTERTp-EGFP, TK expressed by the enhanced vector significantly decreased NPC 5-8F and MCF-7 cell survival rates after ganciclovir (GCV) treatment (p < 0.001) and tumor progress in nude mice with NPC xenograft and treated with GCV, without obvious toxicity to mouse liver and kidney.</p> <p>Conclusion</p> <p>The enhanced TK expression vector driven by hTERTp with CMV enhancer has brighter clinical potentials in nasopharyngeal carcinoma therapy than the non-enhanced vector.</p

Maternal care in rural China: a case study from Anhui province

<p>Abstract</p> <p>Background</p> <p>Studies on prenatal care in China have focused on the timing and frequency of prenatal care and relatively little information can be found on how maternal care has been organized and funded or on the actual content of the visits, especially in the less developed rural areas. This study explored maternal care in a rural county from Anhui province in terms of care organization, provision and utilization.</p> <p>Methods</p> <p>A total of 699 mothers of infants under one year of age were interviewed with structured questionnaires; the county health bureau officials and managers of township hospitals (n = 10) and county level hospitals (n = 2) were interviewed; the process of the maternal care services was observed by the researchers. In addition, statistics from the local government were used.</p> <p>Results</p> <p>The county level hospitals were well staffed and equipped and served as a referral centre for women with a high-risk pregnancy. Township hospitals had, on average, 1.7 midwives serving an average population of 15,000 people. Only 10–20% of the current costs in county level hospitals and township hospitals were funded by the local government, and women paid for delivery care. There was no systematic organized prenatal care and referrals were not mandatory. About half of the women had their first prenatal visit before the 13th gestational week, 36% had fewer than 5 prenatal visits, and about 9% had no prenatal visits. A major reason for not having prenatal care visits was that women considered it unnecessary. Most women (87%) gave birth in public health facilities, and the rest in a private clinic or at home. A total of 8% of births were delivered by caesarean section. Very few women had any postnatal visits. About half of the women received the recommended number of prenatal blood pressure and haemoglobin measurements.</p> <p>Conclusion</p> <p>Delivery care was better provided than both prenatal and postnatal care in the study area. Reliance on user fees gave the hospitals an incentive to put more emphasis on revenue generating activities such as delivery care instead of prenatal and postnatal care.</p

Transcriptome profiling of immune responses to cardiomyopathy syndrome (CMS) in Atlantic salmon

<p>Abstract</p> <p>Background</p> <p>Cardiomyopathy syndrome (CMS) is a disease associated with severe myocarditis primarily in adult farmed Atlantic salmon (<it>Salmo salar </it>L.), caused by a double-stranded RNA virus named piscine myocarditis virus (PMCV) with structural similarities to the <it>Totiviridae </it>family. Here we present the first characterisation of host immune responses to CMS assessed by microarray transcriptome profiling.</p> <p>Results</p> <p>Unvaccinated farmed Atlantic salmon post-smolts were infected by intraperitoneal injection of PMCV and developed cardiac pathology consistent with CMS. From analysis of heart samples at several time points and different tissues at early and clinical stages by oligonucleotide microarrays (SIQ2.0 chip), six gene sets representing a broad range of immune responses were identified, showing significant temporal and spatial regulation. Histopathological examination of cardiac tissue showed myocardial lesions from 6 weeks post infection (wpi) that peaked at 8-9 wpi and was followed by a recovery. Viral RNA was detected in all organs from 4 wpi suggesting a broad tissue tropism. High correlation between viral load and cardiac histopathology score suggested that cytopathic effect of infection was a major determinant of the myocardial changes. Strong and systemic induction of antiviral and IFN-dependent genes from 2 wpi that levelled off during infection, was followed by a biphasic activation of pathways for B cells and MHC antigen presentation, both peaking at clinical pathology. This was preceded by a distinct cardiac activation of complement at 6 wpi, suggesting a complement-dependent activation of humoral Ab-responses. Peak of cardiac pathology and viral load coincided with cardiac-specific upregulation of T cell response genes and splenic induction of complement genes. Preceding the reduction in viral load and pathology, these responses were probably important for viral clearance and recovery.</p> <p>Conclusions</p> <p>By comparative analysis of gene expression, histology and viral load, the temporal and spatial regulation of immune responses were characterised and novel immune genes identified, ultimately leading to a more complete understanding of host-virus responses and pathology and protection in Atlantic salmon during CMS.</p

Stereological Analysis of Neuron, Glial and Endothelial Cell Numbers in the Human Amygdaloid Complex

Cell number alterations in the amygdaloid complex (AC) might coincide with neurological and psychiatric pathologies with anxiety imbalances as well as with changes in brain functionality during aging. This stereological study focused on estimating, in samples from 7 control individuals aged 20 to 75 years old, the number and density of neurons, glia and endothelial cells in the entire AC and in its 5 nuclear groups (including the basolateral (BL), corticomedial and central groups), 5 nuclei and 13 nuclear subdivisions. The volume and total cell number in these territories were determined on Nissl-stained sections with the Cavalieri principle and the optical fractionator. The AC mean volume was 956 mm3 and mean cell numbers (x106) were: 15.3 neurons, 60 glial cells and 16.8 endothelial cells. The numbers of endothelial cells and neurons were similar in each AC region and were one fourth the number of glial cells. Analysis of the influence of the individuals’ age at death on volume, cell number and density in each of these 24 AC regions suggested that aging does not affect regional size or the amount of glial cells, but that neuron and endothelial cell numbers respectively tended to decrease and increase in territories such as AC or BL. These accurate stereological measures of volume and total cell numbers and densities in the AC of control individuals could serve as appropriate reference values to evaluate subtle alterations in this structure in pathological conditions

Altering a Histone H3K4 Methylation Pathway in Glomerular Podocytes Promotes a Chronic Disease Phenotype

Methylation of specific lysine residues in core histone proteins is essential for embryonic development and can impart active and inactive epigenetic marks on chromatin domains. The ubiquitous nuclear protein PTIP is encoded by the Paxip1 gene and is an essential component of a histone H3 lysine 4 (H3K4) methyltransferase complex conserved in metazoans. In order to determine if PTIP and its associated complexes are necessary for maintaining stable gene expression patterns in a terminally differentiated, non-dividing cell, we conditionally deleted PTIP in glomerular podocytes in mice. Renal development and function were not impaired in young mice. However, older animals progressively exhibited proteinuria and podocyte ultra structural defects similar to chronic glomerular disease. Loss of PTIP resulted in subtle changes in gene expression patterns prior to the onset of a renal disease phenotype. Chromatin immunoprecipitation showed a loss of PTIP binding and lower H3K4 methylation at the Ntrk3 (neurotrophic tyrosine kinase receptor, type 3) locus, whose expression was significantly reduced and whose function may be essential for podocyte foot process patterning. These data demonstrate that alterations or mutations in an epigenetic regulatory pathway can alter the phenotypes of differentiated cells and lead to a chronic disease state

Search for a light exotic particle in J/psi radiative decays

Using a data sample containing 1.06x10^8 psi' events collected with the BESIII detector at the BEPCII electron-positron collider, we search for a light exotic particle X in the process psi' -> pi^+ pi^- J/psi, J/psi -> gamma X, X -> mu^+ mu^-. This light particle X could be a Higgs-like boson A^0, a spin-1 U boson, or a pseudoscalar sgoldstino particle. In this analysis, we find no evidence for any mu^+mu^- mass peak between the mass threshold and 3.0 GeV/c^2. We set 90%-confidence-level upper limits on the product-branching fractions for J/psi -> gamma A^0, A^0 -> mu^+ mu^- which range from 4x10^{-7} to 2.1x10^{-5}, depending on the mass of A^0, for M(A^0)<3.0 GeV/c^2. Only one event is seen in the mass region below 255 MeV/c^2 and this has a mu^+mu^- mass of 213.3 MeV/c^2 and the product branching fraction upper limit 5x10^{-7}.Comment: 7 pages, 3 figures, submitted to Physical Review

Serum screening with Down's syndrome markers to predict pre-eclampsia and small for gestational age: Systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Reliable antenatal identification of pre-eclampsia and small for gestational age is crucial to judicious allocation of monitoring resources and use of preventative treatment with the prospect of improving maternal/perinatal outcome. The purpose of this systematic review was to determine the accuracy of five serum analytes used in Down's serum screening for prediction of pre-eclampsia and/or small for gestational age.</p> <p>Methods</p> <p>The data sources included Medline, Embase, Cochrane library, Medion (inception to February 2007), hand searching of relevant journals, reference list checking of included articles, contact with experts. Two reviewers independently selected the articles in which the accuracy of an analyte used in Downs's serum screening before the 25^thgestational week was associated with the occurrence of pre-eclampsia and/or small for gestational age without language restrictions. Two authors independently extracted data on study characteristics, quality and results.</p> <p>Results</p> <p>Five serum screening markers were evaluated. 44 studies, testing 169,637 pregnant women (4376 pre-eclampsia cases) and 86 studies, testing 382,005 women (20,339 fetal growth restriction cases) met the selection criteria. The results showed low predictive accuracy overall. For pre-eclampsia the best predictor was inhibin A>2.79MoM positive likelihood ratio 19.52 (8.33,45.79) and negative likelihood ratio 0.30 (0.13,0.68) (single study). For small for gestational age it was AFP>2.0MoM to predict birth weight < 10^thcentile with birth < 37 weeks positive likelihood ratio 27.96 (8.02,97.48) and negative likelihood ratio 0.78 (0.55,1.11) (single study). A potential clinical application using aspirin as a treatment is given as an example.</p> <p>There were methodological and reporting limitations in the included studies thus studies were heterogeneous giving pooled results with wide confidence intervals.</p> <p>Conclusion</p> <p>Down's serum screening analytes have low predictive accuracy for pre-eclampsia and small for gestational age. They may be a useful means of risk assessment or of use in prediction when combined with other tests.</p

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe