Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine ...the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer.
We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing.
Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% 95% CI 94·5–98·4 vs 96·6% 95·8–97·3; at 5 years: 83·8% 79·3–87·5 vs 85·0% 83·5–86·4; at 10 years: 73·4% 67·4–78·5 vs 70·1% 67·7–72·3; hazard ratio HR 0·96 95% CI 0·76–1·22; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% 95% CI 89–97 vs 91% 88–94; HR 0·59 95% CI 0·35–0·99; p=0·047) but not 5 years (81% 73–87 vs 74% 70–78; HR 1·13 0·70–1·84; p=0·62) or 10 years (72% 62–80 vs 69% 63–74; HR 2·12 0·82–5·49; p= 0·12).
Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences.
Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.
Self-reported rates of participation in sport vary by country. In the UK, about 40% of men and women aged 16 years or older participate in at least one sport every week. Although few data exist to ...assess trends for participation in sport, there is little evidence of change in the past decade among adults. Large cohort studies suggest that such participation in sport is associated with a 20–40% reduction in all-cause mortality compared with non-participation. Randomised trials and crossover clinical studies suggest that playing sport is associated with specific health benefits. Some sports have relatively high injury risk although neuromuscular training programmes can prevent various lower extremity injuries. Clinicians can influence a large number of patients through brief interventions that promote physical activity, and encouragement toward participation in sport for some physically inactive patients qualifies as evidence-based therapy. Exercise might also be considered as a fifth vital sign and should be recorded in patients' electronic medical records and routine histories.
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and ...patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human
(referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.
Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT ...cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.
In recent years, the impact of Plant Protection Products (PPPs) on insect pollinator decline has stimulated significant amounts of research, as well as political and public interest. PPP residues ...have been found in various bee-related matrices, resulting in governmental bodies worldwide releasing guidance documents on methods for the assessment of the overall risk of PPPs to different bee species. An essential part of these risk assessments are PPP residues found in pollen and nectar, as they represent a key route of exposure. However, PPP residue values in these matrices exhibit large variations and are not available for many PPPs and crop species combinations, which results in inaccurate estimations and uncertainties in risk evaluation. Additionally, residue studies on pollen and nectar are expensive and practically challenging. An extrapolation between different cropping scenarios and PPPs is not yet justified, as the behaviour of PPPs in pollen and nectar is poorly understood. Therefore, this review aims to contribute to a better knowledge and understanding of the fate of PPP residues in pollen and nectar and to outline knowledge gaps and future research needs. The literature suggests that four primary factors, the crop type, the application method, the physicochemical properties of a compound and the environmental conditions have the greatest influence on PPP residues in pollen and nectar. However, these factors consist of many sub-factors and initial effects may be disguised by different sampling methodologies, impeding their exact characterisation. Moreover, knowledge about these factors is ambiguous and restricted to a few compounds and plant species. We propose that future research should concentrate on identifying relationships and common features amongst various PPP applications and crops, as well as an overall quantification of the described parameters; in order to enable a reliable estimation of PPP residues in pollen, nectar and other bee matrices.
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•Only fragmentary datasets of pesticide residue values in pollen and nectar exist.•Poor knowledge on fate and relationship amongst different pesticides in bee products.•Extrapolation between different pesticide applications on residues is not possible.•Manifold parameters influence the pesticide residues in bee products.•Significant need for detailed research on pesticide residues in pollen and nectar.
Pesticide residue values within pollen and nectar have potentially significant consequences for the reliability of risk assessments for wild and managed bee populations, however, the reasons and mechanisms underlying variations in residues are poorly understood and require greater investigation.
Controlled human malaria infection is used to measure efficacy of candidate malaria vaccines before field studies are undertaken. Mathematical modeling using data from quantitative polymerase chain ...reaction (qPCR) parasitemia monitoring can discriminate between vaccine effects on the parasite's liver and blood stages. Uncertainty regarding the most appropriate modeling method hinders interpretation of such trials. We used qPCR data from 267 Plasmodium falciparum infections to compare linear, sine-wave, and normal-cumulative-density-function models. We find that the parameters estimated by these models are closely correlated, and their predictive accuracy for omitted data points was similar. We propose that future studies include the linear model.
Previous research indicates that a combination vaccine targeting different stages of the malaria life cycle is likely to provide the most effective malaria vaccine. This trial was the first to ...combine two existing vaccination strategies to produce a vaccine that induces immune responses to both the pre-erythrocytic and blood stages of the P. falciparum life cycle.
This was a Phase I/IIa study of a new combination malaria vaccine FFM ME-TRAP+PEV3A. PEV3A includes peptides from both the pre-erythrocytic circumsporozoite protein and the blood-stage antigen AMA-1. This study was conducted at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK. The participants were healthy, malaria naïve volunteers, from Oxford. The interventions were vaccination with PEV3A alone, or PEV3A+FFM ME-TRAP. The main outcome measure was protection from malaria in a sporozoite challenge model. Other outcomes included measures of parasite specific immune responses induced by either vaccine; and safety, assessed by collection of adverse event data.
We observed evidence of blood stage immunity in PEV3A vaccinated volunteers, but no volunteers were completely protected from malaria. PEV3A induced high antibody titres, and antibodies bound parasites in immunofluorescence assays. Moreover, we observed boosting of the vaccine-induced immune response by sporozoite challenge. Immune responses induced by FFM ME-TRAP were unexpectedly low. The vaccines were safe, with comparable side effect profiles to previous trials. Although there was no sterile protection two major observations support an effect of the vaccine-induced response on blood stage parasites: (i) Lower rates of parasite growth were observed in volunteers vaccinated with PEV3A compared to unvaccinated controls (p = 0.012), and this was reflected in the PCR results from PEV3A vaccinated volunteers. These showed early control of parasitaemia by some volunteers in this group. One volunteer, who received PEV3A alone, was diagnosed very late, on day 20 compared to an average of 11.8 days in unvaccinated controls. (ii). Morphologically abnormal parasites were present in the blood of all (n = 24) PEV3A vaccinated volunteers, and in only 2/6 controls (p = 0.001). We describe evidence of vaccine-induced blood stage efficacy for the first time in a sporozoite challenge study.
Practitioners of environmental water management (EWM) operate within complex social-ecological systems. We sought to better understand this complexity by investigating the management of environmental ...water for vegetation outcomes. We conducted an online survey to determine practitioners' perspectives on EWM for non-woody vegetation (NWV) in the Murray-Darling Basin, Australia with regards to: i) desirable outcomes and benefits; ii) influencing factors and risks; iii) challenges of monitoring and evaluation, and iv) improving outcomes. Survey participants indicated that EWM aims to achieve outcomes by improving or maintaining vegetation attributes and the functions and values these provide. Our study reveals that EWM practitioners perceive NWV management in a holistic and highly interconnected way. Numerous influencing factors as well as risks and challenges to achieving outcomes were identified by participants, including many unrelated to water. Survey responses highlighted six areas to improve EWM for NWV outcomes: (1) flow regimes, (2) vegetation attributes, (3) non-flow drivers, (4) management-governance considerations, (5) functions and values, and (6) monitoring, evaluation and research. These suggest a need for more than 'just water' when it comes to the restoration and management of NWV. Our findings indicate more integrated land-water governance and management is urgently required to address the impacts of non-flow drivers such as pest species, land-use change and climate change. The results also indicate that inherent complexity in EWM for ecological outcomes has been poorly addressed, with a need to tackle social-ecological constraints to improve EWM outcomes.
High concentrations of the most consumed pharmaceuticals, caffeine and paracetamol, have been observed globally in wastewater treatment plant discharge. Here, we assess the potential for ...photodegradation of caffeine and paracetamol residues at concentrations like those observed in treated wastewater discharges to the environment. Laboratory assays were used to measure rates of photodegradation of these two compounds both in distilled water and in natural river water with leaf litter leachate. When exposed to artificial light simulating natural sunlight, the half‐life values of caffeine and paracetamol were significantly shorter than in the dark. The presence of organic matter increased caffeine and paracetamol half‐life by lessening the photolytic effect. These results suggest that photolysis is a substantial contributor to the degradation of caffeine and paracetamol. The findings contribute to our understanding of persistence of pharmaceuticals in treated wastewater discharge.
Practitioner Points
The photodegradation of caffeine and paracetamol residues in surface water was examined.
With leaf litter leachate, caffeine and paracetamol were photodegraded in distilled and natural river water in laboratory.
Caffeine's half‐life ranged from 2.3 to 16.2 days under artificial sunlight andparacetamols from 4.3 to 12.2 days.
When incubated in the dark, the half‐life for both compounds exceeded 4 weeks.
Organic matter decreased the photolytic action of caffeine and paracetamol.
Photodegradation of caffeine and paracetamol in a stream water by artificial sunlight: Concentrations of caffeine and paracetamol were measured using HPLC, and ANCOVA was used for data analysis.
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