Stress Constraints From Shear-Wave Analysis in Shallow Sediments at an Actively Seeping Pockmark on the W-Svalbard Margin

Mechanisms related to sub-seabed fluid flow processes are complex and inadequately understood. Petrophysical properties, availability of gases, topography, stress directions, and various geological parameters determine the location and intensity of leakage which change over time. From tens of seafloor pockmarks mapped along Vestnesa Ridge on the west-Svalbard margin, only six show persistent present-day seepage activity in sonar data. To investigate the causes of such restricted gas seepage, we conducted a study of anisotropy within the conduit feeding one of these active pockmarks (i.e., Lunde Pockmark). Lunde is ∼400–500 m in diameter, and atop a ∼300–400 m wide seismic chimney structure. We study seismic anisotropy using converted S-wave data from 22 ocean-bottom seismometers (OBSs) located in and around the pockmark. We investigate differences in symmetry plane directions in anisotropic media using null energy symmetries in transverse components. Subsurface stress distribution affects fault/fracture orientations and seismic anisotropy, and we use S-wave and high-resolution 3D seismic data to infer stress regimes in and around the active seep site and study the effect of stresses on seepage. We observe the occurrence of changes in dominant fault/fracture and horizontal stress orientations in and around Lunde Pockmark and conclude minimum (NE-SW) and maximum (SE-NW) horizontal stress directions. Our analysis indicates a potential correlation between hydrofractures and horizontal stresses, with up to a ∼32% higher probability of alignment of hydrofractures and faults perpendicular to the inferred minimum horizontal stress direction beneath the Lunde Pockmark area

Sedimentary deformation relating to episodic seepage in the last 1.2 million years: a multi-scale seismic study from the Vestnesa Ridge, eastern Fram Strait

Seafloor hydrocarbon seepage is a natural fluid release process that occurs worldwide on continental shelves, slopes, and in deep oceanic basins. The Vestnesa sedimentary ridge in the eastern Fram Strait hosts a deep-water gas hydrate system that became charged with hydrocarbons ~2.7 Ma and has experienced episodic seepage along the entire ridge until a few thousand years ago, when seepage activity apparently ceased in the west but persisted in the east. Although it has been documented that faults and fractures play a key role in feeding the seeps with thermogenic gases, the mechanisms controlling seepage periodicity remain poorly understood. Here we integrate highresolution P-cable 3D seismic and Chirp data to investigate the spatial and temporal evolution of high-resolution fractures and fluid flow features in the west of the Vestnesa Ridge. We characterize sediment deformation using a fracture density seismic attribute workflow revealing two highly deformed stratigraphic intervals and associated small-scale pockmarks (<20 m diameter). Chronostratigraphic constraints from the region show that these two highly deformed intervals are influenced by at least three major climatic and oceanic events during the last 1.2 million years: the Mid-Pleistocene Transition (~1.25–0.7 Ma), the penultimate deglaciation (~130 ka) and the last deglaciation (Heinrich Stadial 1: ~16 ka). These periods of deformation appear associated with seismic anomalies potentially correlated with buried methane-derived authigenic carbonate and have been sensitive to shifts in the boundary of the free gas-gas hydrate interface. Our results show shifts (up to ~30 m) in the depth of the base of the gas hydrate stability zone (GHSZ) associated with major changes in ocean bottom water temperatures. This ocean-driven effect on the base of the GHSZ since the Last Glacial Maximum coincides with the already highly deformed Mid-Pleistocene Transition sedimentary interval and likely enhanced deformation and gas leakage along the ridge. Our results have implications for understanding how glacial cycles impact fracture formation and associated seepage activity

Spatial Changes in Gas Transport and Sediment Stiffness Influenced by Regional Stress: Observations From Piezometer Data Along Vestnesa Ridge, Eastern Fram Strait

Gas transport through sediments to the seabed and seepage occurs via advection through pores, faults, and fractures, and as solubility driven gas diffusion. The pore pressure gradient is a key factor in these processes. Yet, in situ measurements for quantitative studies of fluid dynamics and sediment deformation in deep ocean environments remain scarce. In this study, we integrate piezometer data, geotechnical tests, and sediment core analyses to study the pressure regime that controls gas transport along the Vestnesa Ridge in the eastern Fram Strait. The data show a progressive westward decrease in induced pore pressure (i.e., from c. 180 to c. 50 kPa) upon piezometer penetration and undrained shear strength of the sediments, interpreted as a decrease in sediment stiffness. In addition, the data suggest that the upper c. 6 m of sediments may be mechanically damaged due to variations in gas diffusion rates and exsolution. Background pore pressures are mostly at hydrostatic conditions, but localized excess pore pressures (i.e., up to 10 kPa) exist and point toward external controls. When analyzed in conjunction with observations from geophysical data and sediment core analyses, the pore pressure data suggest a spatial change from an advection dominated to a diffusion dominated fluid flow system, influenced by the behavior of sedimentary faults. Understanding gas transport mechanisms and their effect on fine-grained sediments of deep ocean settings is critical for constraining gas hydrate inventories, seepage phenomena and sub-seabed sediment deformations and instabilities

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society