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Management of early-stage breast cancer in young women with mutations in BRCA1 or BRCA2 remains controversial. This study assessed the long-term risks of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast-conserving surgery followed by radiotherapy. Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy at our hospital. We recruited 127 of these women for complete sequencing of BRCA1 and BRCA2. Demographic, clinical, pathological, and outcome data were recorded. The primary endpoints were rates of ipsilateral and contralateral breast cancer, in relation to germline BRCA1/2 status. 105 women were classified as having sporadic disease (94 with wild-type or known polymorphisms and 11 with variants of unclear significance) and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] or BRCA2 [seven]). At 12 years of follow-up, the genetic group had significantly higher rates of ipsilateral (49% vs 21%, p=0·007) and contralateral events (42% vs 9%, p=0·001) than the sporadic group. The majority of events were classified as second primary tumours. No patient in the genetic group had undergone oophorectomy or was taking prophylactic agents such as tamoxifen. Patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours. With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable. Alternatively, bilateral mastectomy may be considered, to minimise the risk of second tumours in the breasts.

The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package (‘Mykrobe predictor’) that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S . aureus , the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n =470). For M . tuberculosis , our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n =1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes. The clinical application of new sequencing techniques is expected to accelerate pathogen identification. Here, Bradley et al . present a clinician-friendly software package that uses sequencing data for quick and accurate prediction of antibiotic resistance profiles for S. aureus and M. tuberculosis .

Multiple myeloma (MM) is an incurable blood cancer that primarily affects older adults. Several frailty tools have been developed to address the heterogeneity of aging in this population. Uptake of these measures has been variable, leading to a gap in knowledge regarding the proportion of enrolled trial participants considered frail and uncertainty in the treatment-related effects and outcomes among this high-risk population. We performed a systematic review of therapeutic interventional MM clinical trials reporting on frailty. We included 43 clinical trials (24 randomized controlled trials and 19 non-randomized trials) which met eligibility criteria. Frailty was increasingly incorporated in studies in more recent years with 41.9% of included studies being reported in the last two years. Commonly used frailty tools included the International Myeloma Working Group (IMWG) frailty index (41.8%), and the simplified frailty score (39.5%). Frailty status was categorized with 3 levels as (frail, intermediate fit, or fit) in 51.2% of the studies and dichotomized (frail, non-frail) in 18.6% of studies. Frailty prevalence greatly varied across trials ranging from 17.2% to 73.6% of the cohort. Of the included studies, 72.0% conducted subgroup analysis (planned or post-hoc) based on frailty status. Most studies demonstrated a consistent benefit of MM interventions among the frail and non-frail populations, however in general, frail patients had worse outcomes compared to the fit. Although frailty is increasingly being incorporated in MM clinical trials, due to the variation in both the definition and categorization of frailty, there remains heterogeneity in the prevalence of frailty and its potential associated impact on outcomes.

The public health threat posed by a looming ‘post-antibiotic’ era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature’s control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N -terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the ‘vancapticins’, possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to ‘revitalise’ antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors. The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.

Background The poor prognosis and rising incidence of esophageal adenocarcinoma highlight the need for improved detection methods. The potential for circulating microRNAs (miRNAs) as biomarkers in other cancers has been shown, but circulating miRNAs have not been well characterized in esophageal adenocarcinoma. We investigated whether circulating exosomal miRNAs have potential to discriminate individuals with esophageal adenocarcinoma from healthy controls and non-dysplastic Barrett’s esophagus. Methods Seven hundred fifty-eight miRNAs were profiled in serum circulating exosomes from a cohort of 19 healthy controls, 10 individuals with Barrett’s esophagus, and 18 individuals with locally advanced esophageal adenocarcinoma. MiRNA expression was assessed using all possible permutations of miRNA ratios per individual. Four hundred eight miRNA ratios were differentially expressed in individuals with cancer compared to controls and Barrett’s esophagus (Mann-Whitney U test, P  < 0.05). The 179/408 ratios discriminated esophageal adenocarcinoma from healthy controls and Barrett’s esophagus (linear regression, P  < 0.05; area under receiver operating characteristic (ROC) > 0.7, P  < 0.05). A multi-biomarker panel (RNU6-1/miR-16-5p, miR-25-3p/miR-320a, let-7e-5p/miR-15b-5p, miR-30a-5p/miR-324-5p, miR-17-5p/miR-194-5p) demonstrated enhanced specificity and sensitivity (area under ROC = 0.99, 95 % CI 0.96–1.0) over single miRNA ratios to distinguish esophageal adenocarcinoma from controls and Barrett’s esophagus. Conclusions This study highlights the potential for serum exosomal miRNAs as biomarkers for the detection of esophageal adenocarcinoma.

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no ‘druggable’ driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease. Treating malignant pleural mesothelioma (MpM) is challenging due to a lack of druggable genes, but other molecular features could be clinically useful. Here the authors profile mRNA translation dysregulation in MpM cell lines using polysome profiling, and identify mTORC1 and 2 as potential pharmacological targets.

Two screening approaches converge on capzimin, a first-in-class inhibitor of the Rpn11 protease component of the 19S proteasome. Capzimin stabilizes polyubiquitinated substrates, induces the unfolded protein response, and blocks proliferation of cancer cells. The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

The Southern Ocean plays a critical role in regulating global climate as a major sink for atmospheric carbon dioxide (CO2), and in global ocean biogeochemistry by supplying nutrients to the global thermocline, thereby influencing global primary production and carbon export. Biogeochemical processes within the Southern Ocean regulate regional primary production and biological carbon uptake, primarily through iron supply, and support ecosystem functioning over a range of spatial and temporal scales. Here we assimilate existing knowledge and present new data to examine the biogeochemical cycles of iron, carbon and major nutrients, their key drivers and their responses to, and roles in, contemporary climate and environmental change. Projected increases in iron supply, coupled with increases in light availability to phytoplankton through increased near-surface stratification and longer ice-free periods, are very likely to increase primary production and carbon export around Antarctica. Biological carbon uptake is likely to increase for the Southern Ocean as a whole, whilst there is greater uncertainty around projections of primary production in the Sub-Antarctic and basin-wide changes in phytoplankton species composition, as well as their biogeochemical consequences. Phytoplankton, zooplankton, higher trophic level organisms and microbial communities are strongly influenced by Southern Ocean biogeochemistry, in particular through nutrient supply and ocean acidification. In turn, these organisms exert important controls on biogeochemistry through carbon storage and export, nutrient recycling and redistribution, and benthic-pelagic coupling. The key processes described in this paper are summarised in the graphical abstract. Climate-mediated changes in Southern Ocean biogeochemistry over the coming decades are very likely to impact primary production, sea-air CO2 exchange and ecosystem functioning within and beyond this vast and critically important ocean region.

Caribbean coral reefs are experiencing a shift to algal dominance at the expense of stony corals. Determining the factors leading to algal phase shifts is crucial for assuring the survival of Caribbean coral reefs. In this study, factors controlling the growth of the abundant brown macroalgae Dictyota spp. were investigated by varying herbivory pressure (caging) and nutrients (fertilizer addition) on coral reefs near St. Thomas (US Virgin Islands). Experiment 1 measured Dictyota heights and percent cover at 3 sites (11–20 m depth) and showed no growth response to nutrient addition and a weak negative response to herbivory. To confirm results of Experiment 1, a caging and nutrient manipulation (Experiment 2) was conducted at one site (14 m depth) using the dependent variable Dictyota biomass. A strong negative response of growth to nutrient addition was shown, presumably because of nutrient inhibition, and an equally negative response to herbivory (loss of ∼50% biomass over 21 d). The inhibitory effect of fertilization on growth was confirmed in a third experiment that showed increasing biomass loss over 4 treatment levels of increasing fertilizer addition (0 [ambient], 5, 10, 20 g). Overall, Dictyota was not nutrient limited at any sites, and was weakly controlled by herbivore populations. Factors responsible for Dictyota abundance on Caribbean reefs may reflect decreased herbivory caused by overfishing and reductions in coral cover and do not appear to be affected by recent changes in nitrogen or phosphorus load. This study reinforces the need for conservation and management of herbivores in coral reef ecosystems, to mitigate the effects from anthropogenic stressors.

The multiphase optimization strategy (MOST) is a new methodological approach for building, optimizing, and evaluating multicomponent interventions. Conceptually rooted in engineering, MOST emphasizes efficiency and careful management of resources to move intervention science forward steadily and incrementally. MOST can be used to guide the evaluation of research evidence, develop an optimal intervention (the best set of intervention components), and enhance the translation of research findings, particularly type II translation. This article uses an ongoing study to illustrate the application of MOST in the evaluation of diverse intervention components derived from the phase-based framework reviewed in the companion article by Baker et al. (Ann Behav Med, in press, 2011 ). The article also discusses considerations, challenges, and potential benefits associated with using MOST and similar principled approaches to improving intervention efficacy, effectiveness, and cost-effectiveness. The applicability of this methodology may extend beyond smoking cessation to the development of behavioral interventions for other chronic health challenges.