Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

Background We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinical efficacy of the combination. Methods Twenty-two participants with histologically confirmed glioblastoma in first relapse were treated every 2 weeks with RO5323441 (625 mg, 1250 mg, or 2500 mg) plus bevacizumab (10 mg/kg). A standard 3 + 3 dose-escalation trial design was used. Results RO5323441 combined with bevacizumab was generally well tolerated, and the maximum tolerated dose was not reached. Two participants experienced dose-limiting toxicities (grade 3 meningitis associated with spinal fluid leak [1250 mg] and grade 3 cerebral infarction [2500 mg]). Common adverse events included hypertension (14 participants, 64%), headache (12 participants, 55%), dysphonia (11 participants, 50%) and fatigue (6 participants, 27%). The pharmacokinetics of RO5323441 were linear, over-the-dose range, and bevacizumab exposure was unaffected by RO5323441 coadministration. Modulation of plasmatic angiogenic proteins, with increases in VEGFA and decreases in FLT4, was observed. Dynamic contrast-enhanced/diffusion-weighted MRI revealed large decreases in vascular parameters that were maintained through the dosing period. Combination therapy achieved an overall response rate of 22.7%, including one complete response, and median progression-free and overall survival of 3.5 and 8.5 months, respectively. Conclusion The toxicity profile of RO5323441 plus bevacizumab was acceptable and manageable. The observed clinical activity of the combination does not appear to improve on that obtained with single-agent bevacizumab in patients with recurrent glioblastom

Quantum Non-Demolition Detection of Strongly Correlated Systems

Preparation, manipulation, and detection of strongly correlated states of quantum many body systems are among the most important goals and challenges of modern physics. Ultracold atoms offer an unprecedented playground for realization of these goals. Here we show how strongly correlated states of ultracold atoms can be detected in a quantum non-demolition scheme, that is, in the fundamentally least destructive way permitted by quantum mechanics. In our method, spatially resolved components of atomic spins couple to quantum polarization degrees of freedom of light. In this way quantum correlations of matter are faithfully mapped on those of light; the latter can then be efficiently measured using homodyne detection. We illustrate the power of such spatially resolved quantum noise limited polarization measurement by applying it to detect various standard and "exotic" types of antiferromagnetic order in lattice systems and by indicating the feasibility of detection of superfluid order in Fermi liquids.Comment: Published versio

Candidate Genes Detected in Transcriptome Studies Are Strongly Dependent on Genetic Background

Whole genome transcriptomic studies can point to potential candidate genes for organismal traits. However, the importance of potential candidates is rarely followed up through functional studies and/or by comparing results across independent studies. We have analysed the overlap of candidate genes identified from studies of gene expression in Drosophila melanogaster using similar technical platforms. We found little overlap across studies between putative candidate genes for the same traits in the same sex. Instead there was a high degree of overlap between different traits and sexes within the same genetic backgrounds. Putative candidates found using transcriptomics therefore appear very sensitive to genetic background and this can mask or override effects of treatments. The functional importance of putative candidate genes emerging from transcriptome studies needs to be validated through additional experiments and in future studies we suggest a focus on the genes, networks and pathways affecting traits in a consistent manner across backgrounds

Methods for biogeochemical studies of sea ice: The state of the art, caveats, and recommendations

AbstractOver the past two decades, with recognition that the ocean’s sea-ice cover is neither insensitive to climate change nor a barrier to light and matter, research in sea-ice biogeochemistry has accelerated significantly, bringing together a multi-disciplinary community from a variety of fields. This disciplinary diversity has contributed a wide range of methodological techniques and approaches to sea-ice studies, complicating comparisons of the results and the development of conceptual and numerical models to describe the important biogeochemical processes occurring in sea ice. Almost all chemical elements, compounds, and biogeochemical processes relevant to Earth system science are measured in sea ice, with published methods available for determining biomass, pigments, net community production, primary production, bacterial activity, macronutrients, numerous natural and anthropogenic organic compounds, trace elements, reactive and inert gases, sulfur species, the carbon dioxide system parameters, stable isotopes, and water-ice-atmosphere fluxes of gases, liquids, and solids. For most of these measurements, multiple sampling and processing techniques are available, but to date there has been little intercomparison or intercalibration between methods. In addition, researchers collect different types of ancillary data and document their samples differently, further confounding comparisons between studies. These problems are compounded by the heterogeneity of sea ice, in which even adjacent cores can have dramatically different biogeochemical compositions. We recommend that, in future investigations, researchers design their programs based on nested sampling patterns, collect a core suite of ancillary measurements, and employ a standard approach for sample identification and documentation. In addition, intercalibration exercises are most critically needed for measurements of biomass, primary production, nutrients, dissolved and particulate organic matter (including exopolymers), the CO2 system, air-ice gas fluxes, and aerosol production. We also encourage the development of in situ probes robust enough for long-term deployment in sea ice, particularly for biological parameters, the CO2 system, and other gases.This manuscript is a product of SCOR working group 140 on Biogeochemical Exchange Processes at Sea-Ice Interfaces (BEPSII); we thank BEPSII chairs Jacqueline Stefels and Nadja Steiner and SCOR executive director Ed Urban for their practical and moral support of this endeavour. This manuscript was first conceived at an EU COST Action 735 workshop held in Amsterdam in April 2011; in addition to COST 735, we thank the other participants of the “methods” break-out group at that meeting, namely Gerhard Dieckmann, Christoph Garbe, and Claire Hughes. Our editors, Steve Ackley and Jody Deming, and our reviewers, Mats Granskog and two anonymous reviewers, provided invaluable advice that not only identified and helped fill in some gaps, but also suggested additional ways to make what is by nature a rather dry subject (methods) at least a bit more interesting and accessible. We also thank the librarians at the Institute of Ocean Sciences for their unflagging efforts to track down the more obscure references we required. Finally, and most importantly, we thank everyone who has braved the unknown and made the new measurements that have helped build sea-ice biogeochemistry into the robust and exciting field it has become.This is the final published article, originally published in Elementa: Science of the Anthropocene, 3: 000038, doi: 10.12952/journal.elementa.00003

Translational selection on SHH genes

Codon usage bias has been observed in various organisms. In this study, the correlation between SHH genes expression in some tissues and codon usage features was analyzed by bioinformatics. We found that translational selection may act on compositional features of this set of genes

Coping with unpredictability: Dopaminergic and neurotrophic responses to omission of expected reward in Atlantic salmon (Salmo salar L.).

Comparative studies are imperative for understanding the evolution of adaptive neurobiological processes such as neural plasticity, cognition, and emotion. Previously we have reported that prolonged omission of expected rewards (OER, or 'frustrative nonreward') causes increased aggression in Atlantic salmon (Salmo salar). Here we report changes in brain monoaminergic activity and relative abundance of brain derived neurotrophic factor (BDNF) and dopamine receptor mRNA transcripts in the same paradigm. Groups of fish were initially conditioned to associate a flashing light with feeding. Subsequently, the expected food reward was delayed for 30 minutes during two out of three meals per day in the OER treatment, while the previously established routine was maintained in control groups. After 8 days there was no effect of OER on baseline brain stem serotonin (5-HT) or dopamine (DA) activity. Subsequent exposure to acute confinement stress led to increased plasma cortisol and elevated turnover of brain stem DA and 5-HT in all animals. The DA response was potentiated and DA receptor 1 (D1) mRNA abundance was reduced in the OER-exposed fish, indicating a sensitization of the DA system. In addition OER suppressed abundance of BDNF in the telencephalon of non-stressed fish. Regardless of OER treatment, a strong positive correlation between BDNF and D1 mRNA abundance was seen in non-stressed fish. This correlation was disrupted by acute stress, and replaced by a negative correlation between BDNF abundance and plasma cortisol concentration. These observations indicate a conserved link between DA, neurotrophin regulation, and corticosteroid-signaling pathways. The results also emphasize how fish models can be important tools in the study of neural plasticity and responsiveness to environmental unpredictability

Blood culture status and mortality among patients with suspected community-acquired bacteremia: a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Comparison of mortality among patients with positive and negative blood cultures may indicate the contribution of bacteremia to mortality. This study (1) compared mortality among patients with community-acquired bacteremia with mortality among patients with negative blood cultures and (2) determined the effects of bacteremia type and comorbidity level on mortality among patients with positive blood cultures.</p> <p>Methods</p> <p>This cohort study included 29,273 adults with blood cultures performed within the first 2 days following hospital admission to an internal medical ward in northern Denmark during 1995-2006. We computed product limit estimates and used Cox regression to compute adjusted mortality rate ratios (MRRs) within 0-2, 3-7, 8-30, and 31-180 days following admission for bacteremia patients compared to culture-negative patients.</p> <p>Results</p> <p>Mortality in 2,648 bacteremic patients and 26,625 culture-negative patients was 4.8% vs. 2.0% 0-2 days after admission, 3.7% vs. 2.7% 3-7 days after admission, 5.6% vs. 5.1% 8-30 days after admission, and 9.7% vs. 8.7% 31-180 days after admission, corresponding to adjusted MRRs of 1.9 (95% confidence interval (CI): 1.6-2.2), 1.1 (95% CI: 0.9-1.5), 0.9 (95% CI: 0.8-1.1), and 1.0 (95% CI: 0.8-1.1), respectively. Mortality was higher among patients with Gram-positive (adjusted 0-2-day MRR 1.9, 95% CI: 1.6-2.2) and polymicrobial bacteremia (adjusted 0-2-day MRR 3.5, 95% CI: 2.2-5.5) than among patients with Gram-negative bacteremia (adjusted 0-2-day MRR 1.5, 95% CI 1.2-2.0). After the first 2 days, patients with Gram-negative bacteremia had the same risk of dying as culture-negative patients (adjusted MRR 0.8, 95% CI: 0.5-1.1). Only patients with polymicrobial bacteremia had increased mortality within 31-180 days following admission (adjusted MRR 1.3, 95% CI: 0.8-2.1) compared to culture-negative patients. The association between blood culture status and mortality did not differ substantially by level of comorbidity.</p> <p>Conclusions</p> <p>Community-acquired bacteremia was associated with an increased risk of mortality in the first week of medical ward admission. Higher mortality among patients with Gram-positive and polymicrobial bacteremia compared with patients with Gram-negative bacteremia and negative cultures emphasizes the prognostic importance of these infections.</p

Is the health of people living in rural areas different from those in cities? Evidence from routine data linked with the Scottish Health Survey

<p>Abstract</p> <p>Background</p> <p>To examine the association between rurality and health in Scotland, after adjusting for differences in individual and practice characteristics.</p> <p>Methods</p> <p>Design: Mortality and hospital record data linked to two cross sectional health surveys. Setting: Respondents in the community-based 1995 and 1998 Scottish Health Survey who consented to record-linkage follow-up. Main outcome measures: Hypertension, all-cause premature mortality, total hospital stays and admissions due to coronary heart disease (CHD).</p> <p>Results</p> <p>Older age and lower social class were strongly associated with an increased risk of each of the four health outcomes measured. After adjustment for individual and practice characteristics, no consistent pattern of better or poorer health in people living in rural areas was found, compared to primary cities. However, individuals living in remote small towns had a lower risk of a hospital admission for CHD and those in very remote rural had lower mortality, both compared with those living in primary cities.</p> <p>Conclusion</p> <p>This study has shown how linked data can be used to explore the possible influence of area of residence on health. We were unable to find a consistent pattern that people living in rural areas have materially different health to that of those living in primary cities. Instead, we found stronger relationships between compositional determinants (age, gender and socio-economic status) and health than contextual factors (including rurality).</p

Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight

BACKGROUND: It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population-based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age. METHODOLOGY/PRINCIPAL FINDINGS: We followed 65,212 children born in Denmark from 1970-1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08-2.61) at 12 years of age and 1.63 (95% CI 1.00-2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71-6.42 at age 12, and OR 2.31, 95% CI 1.08-4.97 at age 13). CONCLUSIONS/SIGNIFICANCE: Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood