Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

RationaleWe recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest.ObjectivesWe now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients.MethodsWe conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test.Measurements and main resultsUrinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]).ConclusionsUrinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962)

Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes

OBJECTIVE—Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS—We genotyped 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes- associated complications. RESULTS—A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P1105. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR]1.45, P5.0107). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR 1.36, P3.1106). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR]1.33, P0.02, and HR1.32, P 0.01, respectively). We demonstrated expression of both FRMD3 and CARS in human kidney. CONCLUSIONS—We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes

Evolution of Sex-Specific Traits through Changes in HOX-Dependent doublesex Expression

Analysis in Drosophila suggests that evolutionary changes in the spatial regulation of the transcription factor doublesex play a key role in the origin, diversification, and loss of sex-specific structures

The sugar and energy in non-carbonated sugar-sweetened beverages: a cross-sectional study.

BACKGROUND: The consumption of non-carbonated sugar-sweetened beverages (NCSSBs) has many adverse health effects. However, the sugar and energy content in NCSSBs sold in China remain unknown. We aimed to investigate the sugar and energy content of NCSSBs in China and how these contents were labelled. METHODS: A cross-sectional survey was conducted in 15 supermarkets in Haidian District, Beijing from July to October 2017. The product packaging and nutrient information panels of NCSSBs were recorded to obtain type of products (local/imported), serving size, nutrient contents of carbohydrate, sugar and energy. For those NCSSBs without sugar content information, we used carbohydrate content as a replacement. RESULTS: A total of 463 NCSSBs met the inclusion criteria and were included in our analysis. The median of sugar content and energy content was 9.6 [interquartile range (IQR): 7.1-11.3] g/100 ml and 176 (IQR: 121-201) kJ/100 ml. The median of sugar contents in juice drinks, tea-based beverages, sports drinks and energy drinks were 10.4, 8.5, 5.0 and 7.4 g/100 ml. Imported products had higher sugar and energy content than local products. There were 95.2% products of NCSSBs receiving a 'red'(high) label for sugars per portion according to the UK criteria, and 81.6% products exceeding the daily free sugar intake recommendation from the World Health Organization (25 g). There were 82 (17.7%) products with sugar content on the nutrition labels and 60.2% of them were imported products. CONCLUSIONS: NCSSBs had high sugar and energy content, and few of them provided sugar content information on their nutrition labels especially in local products. Measures including developing better regulation of labelling, reducing sugar content and restricting the serving size are needed for reducing sugar intakes in China

A roadmap for gene system development in Clostridium

Clostridium species are both heroes and villains. Some cause serious human and animal diseases, those present in the microbiota contribute to health and wellbeing, while others represent useful industrial chassis for the production of chemicals and fuels. To understand, counter or exploit, there is a fundamental requirement for effective systems that may be used for directed or random genome modifications. We have formulated a simple roadmap whereby the necessary gene systems maybe developed and deployed. At its heart is the use of 'pseudo-suicide' vectors and the creation of a pyrE mutant (a uracil auxotroph), initially aided by ClosTron technology, but ultimately made using a special form of allelic exchange termed ACE (Allele-Coupled Exchange). All mutants, regardless of the mutagen employed, are made in this host. This is because through the use of ACE vectors, mutants can be rapidly complemented concomitant with correction of the pyrE allele and restoration of uracil prototrophy. This avoids the phenotypic effects frequently observed with high copy number plasmids and dispenses with the need to add antibiotic to ensure plasmid retention. Once available, the pyrE host may be used to stably insert all manner of application specific modules. Examples include, a sigma factor to allow deployment of a mariner transposon, hydrolases involved in biomass deconstruction and therapeutic genes in cancer delivery vehicles. To date, provided DNA transfer is obtained, we have not encountered any clostridial species where this technology cannot be applied. These include, Clostridium difficile, Clostridium acetobutylicum, Clostridium beijerinckii, Clostridium botulinum, Clostridium perfringens, Clostridium sporogenes, Clostridium pasteurianum, Clostridium ljungdahlii, Clostridium autoethanogenum and even Geobacillus thermoglucosidasius

Evaluation of flight efficiency for Stockholm Arlanda Airport arrivals

Analysis of punctuality of airport arrivals, as well as identification of causes of the delays within transition airspace, is an important step in evaluating performance of the Terminal Maneuvering Area (TMA) Air Navigation Services: without knowing the current performance levels, it is difficult to identify which areas could be improved. Deviations from the flight plans is one of the major reasons for arrival delays. In this work, we quantified the impact of the deviations from the flight plans on the fuel burn. One of the main reasons of fuel waste is non- optimal vertical profiles during the descent phase. We calculated how much extra fuel is wasted due to vertical flight inefficiency within Stockholm TMA.Peer ReviewedPostprint (published version

Risk factors for recurrent injurious falls that require hospitalization for older adults with dementia: a population based study

Background: Older adults with dementia are at an increased risk of falls, however, little is known about risk factors for recurrent injurious falls (a subsequent fall after the first fall has occurred) among this group. This study aimed to identify risk factors for recurrent injurious falls requiring hospitalization among adults aged 60+ years with dementia. Methods: This retrospective, whole-population cohort study was conducted using the Western Australian Hospital Morbidity Data System and Western Australian Death Registrations from 2001 to 2013. Survival analysis using a stratified conditional Cox model (type 1) was undertaken to identify risk factors for recurrent injurious falls requiring hospitalization. Results: There were 32,519 participants with an index hospital admission with dementia during the study period. Over 27 % (n = 8970) of the cohort experienced a total of 11,073 injurious falls requiring hospitalization during follow up with 7297 individuals experiencing a single fall, 1330 experiencing two falls and 343 experiencing three or more falls. The median follow-up time for each individual was 2.49 years. Females were at a significantly increased risk of 7 % for recurrent injurious falls resulting in hospitalization (adjusted hazard ratio 1.07, 95 % CI 1.01–1.12), compared to males. Increasing age, living in rural areas, and having an injurious fall in the year prior to the index hospital admission with dementia also increased the risk of recurrent injurious falls resulting in hospitalization. Conclusions: Screening those with dementia for injurious falls history could help to identify those most at risk of recurrent injurious falls. Improvement of heath care an

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin