Organic Geochemistry of a Hydrocarbon-rich Calcarenite from the Chicxulub Scientific Drilling Program

The organic geochemistry of hydrocarbon-rich core material recovered by the CSDP is examined to establish whether hydrocarbons are associated with the migration and emplacement of organic matter by post-impact hydrothermal activity

Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication

The evolutionarily conserved DNA topoisomerase II beta-binding protein 1 (TopBP1) functions in DNA replication, DNA damage response, and cell survival. We analyzed the role of TopBP1 in human and bovine papillomavirus genome replication. Consistent with prior reports, TopBP1 co-localized in discrete nuclear foci and was in complex with papillomavirus E2 protein. Similar to E2, TopBP1 is recruited to the region of the viral origin of replication during G1/S and early S phase. TopBP1 knockdown increased, while over-expression decreased transient virus replication, without affecting cell cycle. Similarly, using cell lines harboring HPV-16 or HPV-31 genome, TopBP1 knockdown increased while over-expression reduced viral copy number relative to genomic DNA. We propose a model in which TopBP1 serves dual roles in viral replication: it is essential for initiation of replication yet it restricts viral copy number

p53 represses human papillomavirus type 16 DNA replication via the viral E2 protein

<p>Abstract</p> <p>Background</p> <p>Human papillomavirus (HPV) DNA replication can be inhibited by the cellular tumour suppressor protein p53. However, the mechanism through which p53 inhibits viral replication and the role that this might play in the HPV life cycle are not known. The papillomavirus E2 protein is required for efficient HPV DNA replication and also regulates viral gene expression. E2 represses transcription of the HPV E6 and E7 oncogenes and can thereby modulate indirectly host cell proliferation and survival. In addition, the E2 protein from HPV 16 has been shown to bind p53 and to be capable of inducing apoptosis independently of E6 and E7.</p> <p>Results</p> <p>Here we use a panel of E2 mutants to confirm that mutations which block the induction of apoptosis via this E6/E7-independent pathway, have little or no effect on the induction of apoptosis by the E6/E7-dependent pathway. Although these mutations in E2 do not affect the ability of the protein to mediate HPV DNA replication, they do abrogate the repressive effects of p53 on the transcriptional activity of E2 and prevent the inhibition of E2-dependent HPV DNA replication by p53.</p> <p>Conclusion</p> <p>These data suggest that p53 down-regulates HPV 16 DNA replication via the E2 protein.</p

A new family of covalent inhibitors block nucleotide binding to the active site of pyruvate kinase

PYK (pyruvate kinase) plays a central role in the metabolism of many organisms and cell types, but the elucidation of the details of its function in a systems biology context has been hampered by the lack of specific high-affinity small-molecule inhibitors. High-throughput screening has been used to identify a family of saccharin derivatives which inhibit LmPYK (Leishmania mexicana PYK) activity in a time- (and dose-) dependent manner, a characteristic of irreversible inhibition. The crystal structure of DBS {4-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfanyl]benzoic acid} complexed with LmPYK shows that the saccharin moiety reacts with an active-site lysine residue (Lys335), forming a covalent bond and sterically hindering the binding of ADP/ATP. Mutation of the lysine residue to an arginine residue eliminated the effect of the inhibitor molecule, providing confirmation of the proposed inhibitor mechanism. This lysine residue is conserved in the active sites of the four human PYK isoenzymes, which were also found to be irreversibly inhibited by DBS. X-ray structures of PYK isoforms show structural differences at the DBS-binding pocket, and this covalent inhibitor of PYK provides a chemical scaffold for the design of new families of potentially isoform-specific irreversible inhibitors

Population comparison of right whale body condition reveals poor state of the North Atlantic right whale

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Christiansen, F., Dawson, S. M., Durban, J. W., Fearnbach, H., Miller, C. A., Bejder, L., Uhart, M., Sironi, M., Corkeron, P., Rayment, W., Leunissen, E., Haria, E., Ward, R., Warick, H. A., Kerr, I., Lynn, M. S., Pettis, H. M., & Moore, M. J. Population comparison of right whale body condition reveals poor state of the North Atlantic right whale. Marine Ecology Progress Series, 640, (2020): 1-16, doi:10.3354/meps13299.The North Atlantic right whale Eubalaena glacialis (NARW), currently numbering <410 individuals, is on a trajectory to extinction. Although direct mortality from ship strikes and fishing gear entanglements remain the major threats to the population, reproductive failure, resulting from poor body condition and sublethal chronic entanglement stress, is believed to play a crucial role in the population decline. Using photogrammetry from unmanned aerial vehicles, we conducted the largest population assessment of right whale body condition to date, to determine if the condition of NARWs was poorer than 3 seemingly healthy (i.e. growing) populations of southern right whales E. australis (SRWs) in Argentina, Australia and New Zealand. We found that NARW juveniles, adults and lactating females all had lower body condition scores compared to the SRW populations. While some of the difference could be the result of genetic isolation and adaptations to local environmental conditions, the magnitude suggests that NARWs are in poor condition, which could be suppressing their growth, survival, age of sexual maturation and calving rates. NARW calves were found to be in good condition. Their body length, however, was strongly determined by the body condition of their mothers, suggesting that the poor condition of lactating NARW females may cause a reduction in calf growth rates. This could potentially lead to a reduction in calf survival or an increase in female calving intervals. Hence, the poor body condition of individuals within the NARW population is of major concern for its future viability.North Atlantic: NOAA NA14OAR4320158; Australia: US Office of Naval Research Marine Mammals Program (Award No. N00014-17-1-3018), the World Wildlife Fund for Nature Australia and a Murdoch University School of Veterinary and Life Sciences Small Grant Award; New Zealand: New Zealand Antarctic Research institute (NZARI 2016-1-4), Otago University and NZ Whale and Dolphin Trust; Argentina: National Geographic Society (Grant number: NGS-379R-18)

Correlation between Subtypes of Cryptosporidium parvum in Humans and Risk

Multilocus microsatellite analysis discriminates among C. parvum strains and is a potential tool for identifying anthroponotic or zoonotic transmission

Strategies to Improve Recruitment to a De-escalation Trial:a Mixed-methods Study of the OPTIMA Prelim Trial in Early Breast Cancer

Aims: De-escalation trials are challenging and sometimes may fail due to poor recruitment. The OPTIMA Prelim randomised controlled trial (ISRCTN42400492) randomised patients with early stage breast cancer to chemotherapy versus ‘test-directed’ chemotherapy, with a possible outcome of no chemotherapy, which could confer less treatment relative to routine practice. Despite encountering challenges, OPTIMA Prelim reached its recruitment target ahead of schedule. This study reports the root causes of recruitment challenges and the strategies used to successfully overcome them. Materials and methods: A mixed-methods recruitment intervention (QuinteT Recruitment Intervention) was used to investigate the recruitment difficulties and feedback findings to inform interventions and optimise ongoing recruitment. Quantitative site-level recruitment data, audio-recorded recruitment appointments (n = 46), qualitative interviews (n = 22) with trialists/recruiting staff (oncologists/nurses) and patient-facing documentation were analysed using descriptive, thematic and conversation analyses. Findings were triangulated to inform a ‘plan of action’ to optimise recruitment. Results: Despite best intentions, oncologists' routine practices complicated recruitment. Discomfort about deviating from the usual practice of recommending chemotherapy according to tumour clinicopathological features meant that not all eligible patients were approached. Audio-recorded recruitment appointments revealed how routine practices undermined recruitment. A tendency to justify chemotherapy provision before presenting the randomised controlled trial and subtly indicating that chemotherapy would be more/less beneficial undermined equipoise and made it difficult for patients to engage with OPTIMA Prelim. To tackle these challenges, individual and group recruiter feedback focussed on communication issues and vignettes of eligible patients were discussed to address discomforts around approaching patients. ‘Tips’ documents concerning structuring discussions and conveying equipoise were disseminated across sites, together with revisions to the Patient Information Sheet. Conclusions: This is the first study illuminating the tension between oncologists' routine practices and recruitment to de-escalation trials. Although time and resources are required, these challenges can be addressed through specific feedback and training as the trial is underway

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