Prognostic refinement of NSMP high-risk endometrial cancers using oestrogen receptor immunohistochemistry

Background: Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement. Methods: Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n = 424), and a Dutch prospective clinical cohort called MST (n = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan-Meier method, log-rank tests and Cox's proportional hazard models were used for survival analysis. Results: In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15-0.75). Conclusions: We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

7th Drug hypersensitivity meeting: part two

No abstract availabl

Process monitoring and fault diagnosis methods using constraint suspension

SIGLEAvailable from British Library Document Supply Centre- DSC:DX77213 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Confronting mortality: faith and meaning across cultures

NoDespite advances in technology and medicine, death itself remains an immutable certainty. Indeed, the acceptance and understanding of our mortality are among the enduring metaphysical challenges that have confronted human beings from the beginning of time. How have we sought to cope with the inevitability of our mortality? How do various cultural and social representations of mortality shape and influence the way in which we understand and approach death? To what extent do personal beliefs and convictions about the meaning of life or the notion of an afterlife affect how we perceive and experience the process of death and dying? Steve Paulson, executive producer and host of To the Best of Our Knowledge, moderated a discussion on death, dying, and what lies beyond that included psychologist Lani Leary, professor of philosophy and religion Jeffrey J. Kripal, and sociologist Allan Kellehear. The following is an edited transcript of the discussion that occurred February 5, 7:00-8:30 pm, at the New York Academy of Sciences in New York City

Novel endosomal NOX2 oxidase inhibitor ameliorates pandemic influenza A virus-induced lung inflammation in mice

BACKGROUND AND OBJECTIVE:Influenza A viruses (IAV) cause respiratory tract infections that can be fatal when the virus spreads to the alveolar space (i.e. alveolitis), and this is mainly observed with highly pathogenic strains. Reactive oxygen species (ROS) production by the NOX2 NADPH oxidase in endosomes has been directly implicated in IAV pathology. Recently, we demonstrated that treatment with a novel endosome-targeted NOX2 oxidase inhibitor, cholestanol-conjugated gp91dsTAT (Cgp91ds-TAT), attenuated airway inflammation and viral replication to infection with a low pathogenic influenza A viral strain. Here, we determined whether suppression of endosome NOX2 oxidase prevents the lung inflammation following infection with a highly pathogenic IAV strain. METHODS:C57Bl/6 mice were intranasally treated with either DMSO vehicle (2%) or Cgp91ds-TAT (0.2 mg/kg/day) 1 day prior to infection with the high pathogenicity PR8 IAV strain (500 PFU/mouse). At Day 3 post-infection, mice were culled for the evaluation of airway and lung inflammation, viral titres and ROS generation. RESULTS:PR8 infection resulted in a marked degree of airway inflammation, epithelial denudation, alveolitis and inflammatory cell ROS production. Cgp91ds-TAT treatment significantly attenuated airway inflammation, including neutrophil influx, the degree of alveolitis and inflammatory cell ROS generation. Importantly, the anti-inflammatory phenotype affected by Cgp91ds-TAT significantly enhanced the clearance of lung viral mRNA following PR8 infection. CONCLUSION:Endosomal NOX2 oxidase promotes pathogenic lung inflammation to IAV infection. The localized delivery of endosomal NOX2 oxidase inhibitors is a novel therapeutic strategy against IAV, which has the potential to limit the pathogenesis caused during epidemics and pandemics.Eunice E. To, Raymond Luong, Jiayin Diao, John J. O’ Leary, Doug A. Brooks, Ross Vlahos, Stavros Selemidi

A Trust-Region Algorithm for Global Optimization

none2B. Addis; S. LeyfferAddis, Bernardetta; S., Leyffe