The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular ...alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets.
Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing.
MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis.
Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.
There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We ...evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow‐up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non‐significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 95% CI 0.69, 1.03) and risk of aggressive (HR: 0.88 95% CI 0.61, 1.28) and non‐aggressive tumors (HR: 0.78 95% CI 0.54, 1.14). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers.
What's new?
Urothelial cell carcinoma (UCC) is the most common form of bladder cancer. Previous studies suggested that plasma carotenoids, antioxidants found in fruit and vegetables, were associated with a decreased risk of UCC while a high intake of animal protein was associated with an increased cancer risk. Here, the authors conducted the first study to investigate the association between the Mediterranean diet, a diet rich in fresh fruits and vegetables and low in animal products, and UCC in Europe. They found that adherence to a Mediterranean diet was not significantly associated with UCC, regardless of level of tumour aggressiveness. They point out that these findings are in line with the rather weak evidence for questionnaire‐based associations between dietary factors and bladder cancer risk.
Abstract
Introduction
Resistance exercise is an effective intervention for older people at risk of, or living with, sarcopenia and frailty. Surveys of current UK practice in exercise prescription for ...these conditions found that resistance exercise was offered in only 9% of departments and was often not optimised for sarcopenia and frailty. The Benchmarking Exercise Programmes for Older People (BEPOP) project is a joint British Geriatrics Society and AGILE initiative to promote best practice in the prescription of resistance exercise for older people.
Methods
Using an online data collection tool, 10 services delivering exercise interventions to older people from across the UK submitted anonymized details of baseline assessment (including demographics), exercise prescription and progression, and outcomes, for up to 20 consecutive patients referred to their services with probable sarcopenia, frailty, falls, and reduced mobility. Descriptive data were reviewed and analysed by an expert panel comprising physiotherapists, geriatricians, and exercise specialists.
Results
Data were analysed for 188 patients with a mean age of 80 years (range 60-101). At the time of referral, 154 (83%) patients did not have a diagnosis of sarcopenia. At baseline, 115 (61%) patients received an objective assessment of muscle strength. The most common modality of resistance exercise prescribed was bodyweight exercises (n=173, 92%) followed by resistance bands (n=49, 26%). Progression of exercise programmes was predominantly through increased repetitions (n=163, 87%) rather than increased load. Forty-one (24%) patients did not undergo any review to inform progression of exercise dose. Fifty patients (30%) patients did not have re-assessment of the outcome measures recorded at baseline on completion of the prescribed exercise programme.
Conclusion
Multiple opportunities exist to improve both the diagnosis and assessment of sarcopenia, and the prescription, delivery, and monitoring of resistance exercise. BEPOP will provide individualized benchmarking reports to each site to facilitate quality improvement and local service development.
To characterize meal patterns across ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study.
Cross-sectional study utilizing ...dietary data collected through a standardized 24 h diet recall during 1995-2000. Eleven predefined intake occasions across a 24 h period were assessed during the interview. In the present descriptive report, meal patterns were analysed in terms of daily number of intake occasions, the proportion reporting each intake occasion and the energy contributions from each intake occasion.
Twenty-seven centres across ten European countries.
Women (64 %) and men (36 %) aged 35-74 years (n 36 020).
Pronounced differences in meal patterns emerged both across centres within the same country and across different countries, with a trend for fewer intake occasions per day in Mediterranean countries compared with central and northern Europe. Differences were also found for daily energy intake provided by lunch, with 38-43 % for women and 41-45 % for men within Mediterranean countries compared with 16-27 % for women and 20-26 % for men in central and northern European countries. Likewise, a south-north gradient was found for daily energy intake from snacks, with 13-20 % (women) and 10-17 % (men) in Mediterranean countries compared with 24-34 % (women) and 23-35 % (men) in central/northern Europe.
We found distinct differences in meal patterns with marked diversity for intake frequency and lunch and snack consumption between Mediterranean and central/northern European countries. Monitoring of meal patterns across various cultures and populations could provide critical context to the research efforts to characterize relationships between dietary intake and health.
Cadaveric lobar lung transplantation (CLLTx) represents a potential opportunity to address the bias against smaller recipients, especially children, on transplant waiting lists. The widespread use of ...CLLTx is hindered by the paucity of outcome data with respect to early complications and long-term lung function and survival.
We looked at the long-term outcomes in 9 patients undergoing CLLTx since May 2003, including early surgical complications, pulmonary function tests, and survival. Patients were analyzed by whether the decision to perform CLLTx was elective (made at the time of listing) or emergent (surgical decision).
The incidence of early complications in the entire group was low, with the most common being atrial arrhythmias and prolonged thoracostomy tube. Lung function at 1 and 2 years (mean forced expiratory volume in 1 second % predicted +/- standard deviation of 73 +/- 18 and 60.5 +/- 27, respectively) was equivalent to living lobar transplant results. Overall survival was similar to 199 patients who received conventional cadaveric LTx during the same period.
This study suggests that CLLTx has a low complication rate with acceptable lung function and long-term survival, especially in cases where consideration has been given to CLLTx at the time of listing. CLLTx warrants consideration more often for patients of smaller physique to improve their chance of receiving LTx.
Glioblastoma multiforme (GBM) tumours are diffusely infiltrative making surgical resection virtually impossible. Invasion of brain parenchyma is facilitated by cell migration and degradation of the ...extracellular matrix (ECM). Invadopodia are actin-rich organelles that protrude from the ventral side of the plasma membrane in direct contact with the ECM and play an important role in mesenchymal cell invasion. We have characterized the 'invasive potential' of a panel of established GBM cell lines (n = 9) using QCM gelatin invadopodia assay (Millipore) and performed comparative, quantitative membrane mass spectrometry-based proteomic analyses of highly invasive vs. less-invasive cell lines. All GBM cells produced invadopodia, and there was a significant difference between the most invasive (U87MG) and least invasive (LN229) cells (65%, percentage of total cell area; p = 0.0001). Overall, 1667 quantifiable proteins were identified from duplicate analyses, of which 76% mapped to membrane structures using the David bioinformatics database (http://david.abcc.ncifcrf.gov). The differential abundance of 38 proteins significantly correlated with the degree of invasion (r2 > 0.45 or r2 < -0.45; n greater than or equal to 5; p < 0.05) and are predominantly involved in cellular movement and cell-cell and interactions. Fluorescence microscopy demonstrates co-localisation of novel proteins to invadopodia structures and siRNA knockdown of a target protein confirmed its role in invadopodia-formation. Invadopodia-associated membrane proteins could be novel targets for anti-invasive GBM therapies.
Drugs that impair tumour angiogenesis, i.e. therapeutic antibody anti-vascular endothelial growth factor, bevacizumab (BEV), are becoming standard therapy for recurrent GBM, despite having no impact ...on overall survival times. Resistance to BEV is fatal, and mechanisms are largely unexplored. With access to exceedingly rare fresh-frozen serial GBM tumours, we performed comprehensive quantitative proteome analyses to identify important mechanisms of BEV escape and tumour recurrence. Tumour tissues from three patients primary (n = 2), recurrent (n = 2) and post-BEV recurrent (n = 3) were homogenised, clarified (1,000 x g, 4 degree C) and ultracentrifuged (100,000 x g, 4 degree C) to isolate the soluble (SOL) proteome supernatant from the microsomal (MEM) pellet. Digested SOL and MEM proteomes were analysed by two independent quantitative MS/MS approaches; Label-free quantitation performed on spectra obtained in triplicate using an Orbitrap Velos (Thermo Electron) and 4-plex iTRAQ-labelling coupled ERLIC-RP MS/MS analysis using a 5600 TripleTOF registered (AB Sciex; single run for MEM; duplicate run for SOL). Spectra were processed using Mascot Distiller, Progenesis, Scaffold and ProteinPilot(TM) softwares. This multi-centre proteomics project has achieved a number of highly reproducible and comprehensive quantitative proteome datasets (average of 1760 MEM proteins and 2334 SOL proteins identified at 95% confidence levels) from precious serial GBM specimens. Significant differentially abundant proteins include those involved in Rho regulation of actin-based motility and cytoskeleton and endocytosis signalling. Bioinformatics analyses with captured whole exome sequencing data are underway to define novel mechanisms of evasive resistance to BEV in recurrent GBM.
Abstract The triple-taper cemented femoral stem was developed to promote proximal femoral and calcar loading to minimize periprosthetic bone loss and aseptic loosening. Periprosthetic changes in bone ...mineral density in Gruen zones 1 to 7 were analyzed in 103 patients over a 2-year period using dual x-ray absorptiometry. There was a statistically significant decrease in bone mineral density in all Gruen zones, but was most marked in zones 1 and 7. Periprosthetic bone density was reduced significantly in the first 3 to 9 months, after which recovery of bone density occurred. Greater calcar bone loss was seen in women, patients with a low preoperative bone density, and patients with poor postoperative mobility. Age at surgery did not effect calcar bone loss.
Objective To assess the association between consumption of fried foods and risk of coronary heart disease.Design Prospective cohort study.Setting Spanish cohort of the European Prospective ...Investigation into Cancer and Nutrition.Participants 40 757 adults aged 29-69 and free of coronary heart disease at baseline (1992-6), followed up until 2004.Main outcome measures Coronary heart disease events and vital status identified by record linkage with hospital discharge registers, population based registers of myocardial infarction, and mortality registers.Results During a median follow-up of 11 years, 606 coronary heart disease events and 1135 deaths from all causes occurred. Compared with being in the first (lowest) quarter of fried food consumption, the multivariate hazard ratio of coronary heart disease in the second quarter was 1.15 (95% confidence interval 0.91 to 1.45), in the third quarter was 1.07 (0.83 to 1.38), and in the fourth quarter was 1.08 (0.82 to 1.43; P for trend 0.74). The results did not vary between those who used olive oil for frying and those who used sunflower oil. Likewise, no association was observed between fried food consumption and all cause mortality: multivariate hazard ratio for the highest versus the lowest quarter of fried food consumption was 0.93 (95% confidence interval 0.77 to 1.14; P for trend 0.98).Conclusion In Spain, a Mediterranean country where olive or sunflower oil is used for frying, the consumption of fried foods was not associated with coronary heart disease or with all cause mortality.
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