A 3′UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like Kinase 1

BACKGROUND: The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. METHODS: The coding region, the 5′ and 3′UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3′UTR polymorphism. RESULTS: Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3′untranslated region (3′UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). CONCLUSION: The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors

Photometric type Ia supernova surveys in narrow band filters

We study the characteristics of a narrow band type Ia supernova survey through simulations based on the upcoming Javalambre Physics of the accelerating universe Astrophysical Survey (J-PAS). This unique survey has the capabilities of obtaining distances, redshifts, and the SN type from a single experiment thereby circumventing the challenges faced by the resource-intensive spectroscopic follow-up observations. We analyse the flux measurements signal-to-noise ratio and bias, the supernova typing performance, the ability to recover light curve parameters given by the SALT2 model, the photometric redshift precision from type Ia supernova light curves and the effects of systematic errors on the data. We show that such a survey is not only feasible but may yield large type Ia supernova samples (up to 250 supernovae at $z<0.5$ per month of search) with low core collapse contamination ($\sim 1.5$ per cent), good precision on the SALT2 parameters (average $\sigma_{m_B}=0.063$, $\sigma_{x_1}=0.47$ and $\sigma_c=0.040$) and on the distance modulus (average $\sigma_{\mu}=0.16$, assuming an intrinsic scatter $\sigma_{\mathrm{int}}=0.14$), with identified systematic uncertainties $\sigma_{\mathrm{sys}}\lesssim 0.10 \sigma_{\mathrm{stat}}$. Moreover, the filters are narrow enough to detect most spectral features and obtain excellent photometric redshift precision of $\sigma_z=0.005$, apart from $\sim$ 2 per cent of outliers. We also present a few strategies for optimising the survey's outcome. Together with the detailed host galaxy information, narrow band surveys can be very valuable for the study of supernova rates, spectral feature relations, intrinsic colour variations and correlations between supernova and host galaxy properties, all of which are important information for supernova cosmological applications.Comment: 20 pages, 12 tables and 26 figures. Version accepted by MNRAS, with results slightly different from previous on

PULSED AND CW LASER TREATMENTS OF IMPLANTED POLYSILICON SOLAR CELLS

Conventional ion implantation and unanalyzed ion bombardment have been used to elaborate the rectifying N+ contact of polycrystalline silicon (Wacker, HEM, CGE) solar cells. Two surface laser annealing in the liquid phase (Nd : YAG laser) and in the solid phase (CO2 laser) regimes have been used. The properties of the solar cells so processed have been investigated. For both doping procedures and both annealing techniques, the cells (conversion) efficiencies under AM1 illumination exceeded 11% for the various polysilicon substrates

GNAS1 T393C polymorphism and disease progression in patients with malignant melanoma

<p>Abstract</p> <p>Background</p> <p>Once metastasized, despite a variety of therapeutic options, the prognosis of patients with malignant melanoma (MM) is still poor. Therefore, the search for reliable markers to identify patients with high risk of disease progression is of high clinical importance. We have recently shown that TT genotypes of the single-nucleotide polymorphism (SNP) T393C in the gene <it>GNAS1 </it>are significantly associated with better outcome in a variety of carcinomas.</p> <p>Patients</p> <p>In the present study we assessed whether the T393C SNP is also related to the clinical course in MM. 328 patients with MM were retrospectively genotyped and genotypes were correlated with clinical outcome.</p> <p>Results</p> <p>While the allele frequency in the MM group (fC 0.52) did not significantly differ from that of healthy blood donors, the T393C SNP was associated with tumor progression of MM. Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop metastasis (HR 2.2, 95% CI 1.1-3.2, p = 0.017). Proportions of 5-year metastasis-free intervals were 87.1% for TT genotypes and 66.0% for C-allele carriers. Moreover, multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis (p = 0.012).</p> <p>Conclusions</p> <p>In summary, the <it>GNAS1 </it>T393C SNP represents a genetic host factor for predicting tumor progression also in patients with MM; genotyping of this SNP may contribute to better define patients who could benefit from an early individualized therapy.</p

EGFR inhibitors erlotinib and lapatinib ameliorate epidermal blistering in pemphigus vulgaris in a non-linear, V-shaped relationship

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PRISM II: an open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury

BACKGROUND: Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI). METHODS: Participants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C). RESULTS: The study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, -7.7 [6.1]; P < .001, 95 % CI: -8.4, -7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, -8.2 [-9.4, -7.0]) and numerically exceeds the improvement seen with placebo in that study (-5.7 [-6.8, -4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were "much" or "very much" improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related. CONCLUSIONS: DM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01799941, registered on 25 February 2013

Operations of and Future Plans for the Pierre Auger Observatory

Technical reports on operations and features of the Pierre Auger Observatory, including ongoing and planned enhancements and the status of the future northern hemisphere portion of the Observatory. Contributions to the 31st International Cosmic Ray Conference, Lodz, Poland, July 2009.Comment: Contributions to the 31st ICRC, Lodz, Poland, July 200