Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study.

BACKGROUND Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. METHODS We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. FINDINGS Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4·5 [95% CI 2·1-9·8]; p=0·00013; area under the receiver operator curve [AUC] 0·70 [95% CI 0·65-0·76]) and radical prostatectomy (4·0 [1·6-9·7]; p=0·0024; AUC 0·57 [0·52-0·61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 [1·2-12]; p=0·019; AUC 0·67 [0·61-0·73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 [95% CI 2·0-19]; p=0·0015; AUC 0·74 [95% CI 0·65-0·83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 [95% CI 1·4-6·0]; p=0·0039; AUC 0·68 [95% CI 0·63-0·73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. INTERPRETATION This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. FUNDING Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society.

Recovery of large carnivores in Europe's modern human-dominated landscapes.

The conservation of large carnivores is a formidable challenge for biodiversity conservation. Using a data set on the past and current status of brown bears (Ursus arctos), Eurasian lynx (Lynx lynx), gray wolves (Canis lupus), and wolverines (Gulo gulo) in European countries, we show that roughly one-third of mainland Europe hosts at least one large carnivore species, with stable or increasing abundance in most cases in 21st-century records. The reasons for this overall conservation success include protective legislation, supportive public opinion, and a variety of practices making coexistence between large carnivores and people possible. The European situation reveals that large carnivores and people can share the same landscape.

Consecutive series of 226 journey bicruciate substituting total knee replacements: early complication and revision rates

BACKGROUND The Journey bicruciate substituting (BCS) total knee replacement (TKR) is intended to improve knee kinematics by more closely approximating the surfaces of a normal knee. The purpose of this analysis was to address the safety of Journey BCS knees by studying early complication and revision rates in a consecutive case series. METHODS Between December 2006 and May 2011, a single surgeon implanted 226 Journey BCS total knee prostheses in 191 patients (124 women, 67 men) who were eligible for study. Mean age at surgery was 68 years (41-85 years).Outcome measures were early complications and minor and major revision rates. All complications were considered, irrespective of whether conservative treatment or revision was required. RESULTS The average implantation time was 3.5 years (range 1.3-5.8 years). Thirty-three complications (14.6% of 226 knees) required minor or major revision surgery in 25 patients. The remaining eight patients were treated conservatively. Sixteen minor revisions were performed in 12 patients. Thirteen major revisions were required in 13 patients, which results in a rate of 1.65 major revisions per 100 component years. The linear trend of the early complication rate by treatment year was not significant (p = .22).Multivariate logistic regression showed no significant predictors for the occurrence of a complication or for revision surgery. A tendency towards higher complication rates was observed in female patients, although it was not significant (p = .066). CONCLUSIONS The complication and revision rates of the Journey BCS knee implant are high in comparison with those reported for other established total knee systems. Caution is advised when using this implant, particularly for less experienced knee surgeons.

Five-year results of lumbar disc prostheses in the SWISSspine registry

PURPOSE The Swiss Federal Office of Public Health demanded a nationwide HTA registry for lumbar total disc arthroplasty (TDA), to decide about its reimbursement. The goal of the SWISS spine registry is to generate evidence about the safety and efficiency of lumbar TDA. METHODS Two hundred forty-eight cases treated between 3-2005 and 6-2006, who were eligible for the 5-year follow-up were included in the study. Follow-up rates for 3-6 months, 1, 2 and 5 years were 85.9, 77.0, 44.0 and 51.2 %, respectively. Outcome measures were back and leg pain, medication consumption, quality of life, intraoperative and postoperative complication and revision rates. Additionally, segmental mobility, ossification, adjacent and distant segment degeneration were analysed at the 5-year follow-up. RESULTS There was a significant, clinically relevant and lasting reduction of back (preop/postop 73/29 VAS points) and leg pain (preop/postop VAS 55/22) and a consequently decreased analgesics consumption and quality of life improvement (preop/postop 0.30/0.76 EQ-5D score points) until 5 years after surgery. The rates for intraoperative and early postoperative complications were 4.4 and 3.2 %, respectively. The overall complication rate during five postoperative years was 23.4 %, and the adjacent segment degeneration rate was 10.7 %. In 4.4 % of patients, a revision surgery was performed. Cumulative survivorship probability for a revision/re-intervention-free 5-year postoperative course was 90.4 %. At the 5-year follow-up, the average range of motion of the mobile segments (86.8 %) was 9.7°. In 43.9 % of patients, osteophytes at least potentially affecting the range of motion were seen. CONCLUSIONS Lumbar TDA appeared as efficient in long-term pain alleviation, consequent reduction of pain medication consumption and improvement of quality of life. The procedure also appeared sufficiently safe, but surgeons have to be aware of a list of potential adverse events. The outcome is stable over the 5-year postoperative period. The vast majority of treated segments remained mobile after 5 years, although almost half of patients showed osteophytes.

In vivo compatibility of Dynesys(®) spinal implants: a case series of five retrieved periprosthetic tissue samples and corresponding implants

PURPOSE To determine whether particulate debris is present in periprosthetic tissue from revised Dynesys(®) devices, and if present, elicits a biological tissue reaction. METHODS Five Dynesys(®) dynamic stabilization systems consisting of pedicle screws (Ti alloy), polycarbonate-urethane (PCU) spacers and a polyethylene-terephthalate (PET) cord were explanted for pain and screw loosening after a mean of 2.86 years (1.9-5.3 years). Optical microscopy and scanning electron microscopy were used to evaluate wear, deformation and surface damage, and attenuated total reflectance Fourier transform infrared spectroscopy to assess surface chemical composition of the spacers. Periprosthetic tissue morphology and wear debris were determined using light microscopy, and PCU and PET wear debris by polarized light microscopy. RESULTS All implants had surface damage on the PCU spacers consistent with scratches and plastic deformation; 3 of 5 exhibited abrasive wear zones. In addition to fraying of the outer fibers of the PET cords in five implants, one case also evidenced cord fracture. The pedicle screws were unremarkable. Patient periprosthetic tissues around the three implants with visible PCU damage contained wear debris and a corresponding macrophage infiltration. For the patient revised for cord fracture, the tissues also contained large wear particles (>10 μm) and giant cells. Tissues from the other two patients showed comparable morphologies consisting of dense fibrous tissue with no inflammation or wear debris. CONCLUSIONS This is the first study to evaluate wear accumulation and local tissue responses for explanted Dynesys(®) devices. Polymer wear debris and an associated foreign-body macrophage response were observed in three of five cases.

Improved relapse-free survival after autologous stem cell transplantation does not translate into better quality of life in chronic lymphocytic leukemia: lessons from the randomized European Society for Blood and Marrow Transplantation-Intergroup study

In chronic lymphocytic leukemia (CLL) medical progress is driven by clinical studies with relapse-free survival (RFS) as the primary endpoint. The randomized EBMT-Intergroup trial compared high-dose therapy and autologous stem cell transplantation (ASCT) to observation and demonstrated a substantial improvement of RFS without showing improved overall survival for the transplant arm. Here we report quality of life (QoL) information of the first 3 years following randomization from that study. The main objective was to assess the impact of treatment on QoL over time. Two secondary analyses were performed to further investigate the impact of ASCT and relapse on QoL. In the primary analysis, we demonstrate an adverse impact of ASCT on QoL which was largest at 4 months and continued throughout the first year after randomization. Further, we demonstrated a sustained adverse impact of relapse on QoL which worsened over time. Despite better disease control by ASCT the side effects thus turned the net effect towards inferior QoL in the first year and comparable QoL in the following 2 years after randomization. This study emphasizes the importance of information concerning QoL impacts when patients are counseled about treatments aimed at improving RFS in the absence of a survival benefit.

Synthesis and Properties of 6′-Fluoro-tricyclo-DNA

The synthesis of the two fluorinated tricyclic nucleosides 6?-F-tc-T and 6?-F-tc-5MeC, as well as the corresponding building blocks for oligonucleotide assembly, was accomplished. An X-ray analysis of N4-benzoylated 6?-F-tc-5MeC reavealed a 2?-exo (north) conformation of the furanose ring, characterizing it as an RNA mimic. In contrast to observations in the bicyclo-DNA series, no short contact between the fluorine atom and the H6 of the base, reminiscent of a nonclassical F···H hydrogen bond, could be observed. Tm measurements of modified oligodeoxynucleotides with complementary RNA showed slightly sequence-dependent duplex stabilization profiles with maximum ?Tm/mod values of +4.5 °C for 6?-F-tc-5MeC and +1 °C for 6?-F-tc-T. In comparison with parent tc-modified oligonucleotides, no relevant changes in Tm were detected, attributing the fluorine substituent a neutral role in RNA affinity. A structural analysis of duplexes with DNA and RNA by CD-spectroscopy revealed a shift from B- to A-type conformation induced by the 6?-F-tc-nucleosides. This is not a specific ?fluorine effect?, as the same is also observed for the parent tc-modifications. The two fluorinated tc-nucleosides were also incorporated into a pure tricyclo-DNA backbone and showed no discrimination in Tm with complementary RNA, demonstrating that 6?-F substitution is also compatible within fully modified tc-oligonucleotides.

Measuring the mechanical properties of plant cells by combining micro-indentation with osmotic treatments

Growth in plants results from the interaction between genetic and signalling networks and the mechanical properties of cells and tissues. There has been a recent resurgence in research directed at understanding the mechanical aspects of growth, and their feedback on genetic regulation. This has been driven in part by the development of new micro-indentation techniques to measure the mechanical properties of plant cells in vivo. However, the interpretation of indentation experiments remains a challenge, since the force measures results from a combination of turgor pressure, cell wall stiffness, and cell and indenter geometry. In order to interpret the measurements, an accurate mechanical model of the experiment is required. Here, we used a plant cell system with a simple geometry, Nicotiana tabacum Bright Yellow-2 (BY-2) cells, to examine the sensitivity of micro-indentation to a variety of mechanical and experimental parameters. Using a finite-element mechanical model, we found that, for indentations of a few microns on turgid cells, the measurements were mostly sensitive to turgor pressure and the radius of the cell, and not to the exact indenter shape or elastic properties of the cell wall. By complementing indentation experiments with osmotic experiments to measure the elastic strain in turgid cells, we could fit the model to both turgor pressure and cell wall elasticity. This allowed us to interpret apparent stiffness values in terms of meaningful physical parameters that are relevant for morphogenesis.

The effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study.

BACKGROUND Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channelling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. METHODS We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. RESULTS 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient years). In a conventional Cox model, recent - but not cumulative - exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past four years increased the risk of a CVD event (hazard ratio 2.06, 95% confidence interval 1.43-2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6 to 36 months caused the greatest increase in risk. CONCLUSIONS Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study.

BACKGROUND Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING European Commission and the Wellcome Trust.

Exploring Growth Variability and Crown Vitality of Sessile Oak (Quercus Petraea) in the Czech Republic

Unraveling climatic effects on growth of oak - Europe’s most ecologically and economically important forest species - has been the subject of many recent studies; however, more insight based on field data is necessary to better understand the relationship between climate and tree growth and to adapt forest management strategies to future climate change. In this report, we explore the influence of temperature, precipitation and drought variability on the productivity and vitality of oak stands in the Czech Highlands. We collected 180 cores from mature oaks (Quercus petraea) at four forest stands in the Czech Drahany Highlands. Standard dendromethods were used for sample preparation, ring width measurements, cross-dating, chronology development, and the assessment of growth-climate response patterns. Crown vitality was also evaluated, using the modified ICP Forests methodology. Late spring precipitation totals between May and June as well as the mean July temperature for the year of ring formation were found to be the most important factors for oak growth, whereas crown condition was significantly affected by spring and summer drought. This study is rep-resentative for similar bio-ecological habitats across Central Europe and can serve as a dendroclima-tological blueprint for earlier periods for which detailed meteorological information is missing .