Spatial-temporal variation in Greenland shark (Somniosus microcephalus) bycatch in the NAFO Regulatory Area

Spatial and temporal variation in Greenland shark (Somniosus microcephalus) bycatch occurrence was investigated using At-Sea Fisheries Observer data and MaxEnt, a maximum entropy species distribution model. Within the Northwest Atlantic Fisheries Organization Regulatory Area (NRA), the Flemish Pass, the slopes of the Flemish cap, and the shelf edge of Divisions 3NO contained areas of suitable habitat where Greenland shark bycatch is expected to occur. However, it should be noted that there are major areas of Greenland shark bycatch outside the NRA, in the Canadian and Greenland Exclusive Economic Zones (EEZ).En prens

High Prevalence of Abnormal Nocturnal Oximetry in Patients With Hypertrophic Cardiomyopathy

ObjectivesWe sought to determine the prevalence of nocturnal oxygen desaturation and obstructive sleep apnea (OSA) in a population of patients with hypertrophic cardiomyopathy (HCM).BackgroundThe coexistence of sleep apnea and HCM, 2 common cardiovascular conditions, has been largely unrecognized in the treatment of patients with HCM. The nocturnal hypoxia-induced hyperadrenergic state in OSA is expected to worsen hemodynamics and outcomes in HCM.MethodsOne hundred subjects with HCM between June 1, 2006, and July 14, 2008, were screened with nocturnal oximetry. Clinical variables were collected for statistical analysis. Oximetry was classified abnormal (suspicion of sleep-disordered breathing) in the presence of repetitive desaturation (≥5 events/h) followed by a rapid return to baseline oxygen saturation (SaO2) level with a decrease of ≥4% and threshold of 90%.ResultsSeventy-one (71%) patients with HCM had abnormal nocturnal oximetry (71 ± 9%, 95% confidence interval: 62% to 80%). Subjects with abnormal oximetry were older (age 59.5 ± 15.3 years) and more were hypertensive (n = 39 [55%]) than those with normal oximetry (age 45.8 ± 18.5 years, n = 9 [31%], p < 0.001, p = 0.03). Patients with HCM were more symptomatic in the presence of abnormal oximetry (New York Heart Association functional class II to III) (62% vs. 83%, p = 0.023). HCM patients had a higher prevalence of abnormal nocturnal oximetry (n = 71, 71%) compared with a control group of similar age and sex distribution (n = 49, 49%) (p = 0.001).ConclusionsAbnormal nocturnal oximetry is common in patients with HCM, suggesting that OSA is prevalent. OSA may impact hemodynamics and symptoms in HCM. Further studies are needed to determine the long-term benefit of OSA treatment on hemodynamics and disease progression in HCM

Correlation between nucleotide composition and folding energy of coding sequences with special attention to wobble bases

Background: The secondary structure and complexity of mRNA influences its accessibility to regulatory molecules (proteins, micro-RNAs), its stability and its level of expression. The mobile elements of the RNA sequence, the wobble bases, are expected to regulate the formation of structures encompassing coding sequences. Results: The sequence/folding energy (FE) relationship was studied by statistical, bioinformatic methods in 90 CDS containing 26,370 codons. I found that the FE (dG) associated with coding sequences is significant and negative (407 kcal/1000 bases, mean +/- S.E.M.) indicating that these sequences are able to form structures. However, the FE has only a small free component, less than 10% of the total. The contribution of the 1st and 3rd codon bases to the FE is larger than the contribution of the 2nd (central) bases. It is possible to achieve a ~ 4-fold change in FE by altering the wobble bases in synonymous codons. The sequence/FE relationship can be described with a simple algorithm, and the total FE can be predicted solely from the sequence composition of the nucleic acid. The contributions of different synonymous codons to the FE are additive and one codon cannot replace another. The accumulated contributions of synonymous codons of an amino acid to the total folding energy of an mRNA is strongly correlated to the relative amount of that amino acid in the translated protein. Conclusion: Synonymous codons are not interchangable with regard to their role in determining the mRNA FE and the relative amounts of amino acids in the translated protein, even if they are indistinguishable in respect of amino acid coding.Comment: 14 pages including 6 figures and 1 tabl

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p&lt;0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p&lt;0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p&lt;0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Artificial intelligence and visual analytics in geographical space and cyberspace: Research opportunities and challenges

In recent decades, we have witnessed great advances on the Internet of Things, mobile devices, sensor-based systems, and resulting big data infrastructures, which have gradually, yet fundamentally influenced the way people interact with and in the digital and physical world. Many human activities now not only operate in geographical (physical) space but also in cyberspace. Such changes have triggered a paradigm shift in geographic information science (GIScience), as cyberspace brings new perspectives for the roles played by spatial and temporal dimensions, e.g., the dilemma of placelessness and possible timelessness. As a discipline at the brink of even bigger changes made possible by machine learning and artificial intelligence, this paper highlights the challenges and opportunities associated with geographical space in relation to cyberspace, with a particular focus on data analytics and visualization, including extended AI capabilities and virtual reality representations. Consequently, we encourage the creation of synergies between the processing and analysis of geographical and cyber data to improve sustainability and solve complex problems with geospatial applications and other digital advancements in urban and environmental sciences

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P=0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P=0.028; HER2, median survival 18 vs 29 months, P=0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P=0.0197; HER2, P=0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR

Antiviral Activity Of Bacillus Sp. Isolated From The Marine Sponge Petromica Citrina Against Bovine Viral Diarrhea Virus, A Surrogate Model Of The Hepatitis C Virus

The Hepatitis C virus causes chronic infections in humans, which can develop to liver cirrhosis and hepatocellular carcinoma. The Bovine viral diarrhea virus is used as a surrogate model for antiviral assays for the HCV. From marine invertebrates and microorganisms isolated from them, extracts were prepared for assessment of their possible antiviral activity. Of the 128 tested, 2 were considered active and 1 was considered promising. The best result was obtained from the extracts produced from the Bacillus sp. isolated from the sponge Petromica citrina. The extracts 555 (500 μg/mL, SI>18) and 584 (150 μg/mL, SI 27) showed a percentage of protection of 98% against BVDV, and the extract 616, 90% of protection. All of them showed activity during the viral adsorption. 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Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas

<p>Abstract</p> <p>Background</p> <p>Advanced biliary tract carcinomas (BTCs) have poor prognosis and limited therapeutic options. Therefore, it is crucial to combine standard therapies with molecular targeting. In this study EGFR, HER2, and their molecular transducers were analysed in terms of mutations, amplifications and over-expression in a BTC case series. Furthermore, we tested the efficacy of drugs targeting these molecules, as single agents or in combination with gemcitabine, the standard therapeutic agent against BTC.</p> <p>Methods</p> <p>Immunohistochemistry, FISH and mutational analysis were performed on 49 BTC samples of intrahepatic (ICCs), extrahepatic (ECCs), and gallbladder (GBCs) origin. The effect on cell proliferation of different EGFR/HER2 pathway inhibitors as single agents or in combination with gemcitabine was investigated on BTC cell lines. Western blot analyses were performed to investigate molecular mechanisms of targeted drugs.</p> <p>Results</p> <p>EGFR is expressed in 100% of ICCs, 52.6% of ECCs, and in 38.5% of GBCs. P-MAPK and p-Akt are highly expressed in ICCs (>58% of samples), and to a lower extent in ECCs and GBCs (<46%), indicating EGFR pathway activation. HER2 is overexpressed in 10% of GBCs (with genomic amplification), and 26.3% of ECCs (half of which has genomic amplification). EGFR or its signal transducers are mutated in 26.5% of cases: 4 samples bear mutations of PI3K (8.2%), 3 cases (6.1%) in K-RAS, 4 (8.2%) in B-RAF, and 2 cases (4.1%) in PTEN, but no loss of PTEN expression is detected. EGI-1 cell line is highly sensitive to gemcitabine, TFK1 and TGBC1-TKB cell lines are responsive and HuH28 cell line is resistant. In EGI-1 cells, combination with gefitinib further increases the antiproliferative effect of gemcitabine. In TFK1 and TGBC1-TKB cells, the efficacy of gemcitabine is increased with addiction of sorafenib and everolimus. In TGBC1-TKB cells, lapatinib also has a synergic effect with gemcitabine. HuH28 becomes responsive if treated in combination with erlotinib. Moreover, HuH28 cells are sensitive to lapatinib as a single agent. Molecular mechanisms were confirmed by western blot analysis.</p> <p>Conclusion</p> <p>These data demonstrate that EGFR and HER2 pathways are suitable therapeutic targets for BTCs. The combination of gemcitabine with drugs targeting these pathways gives encouraging results and further clinical studies could be warranted.</p