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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.dsr.2007.07.001 Byline: A.R. Baker (a), K. Weston (a), S.D. Kelly (b), M. Voss (c), P. Streu (d), J.N. Cape (e) Keywords: SOLAS; North Atlantic; Nutrients; Atmospheric deposition; Productivity; Nitrogen fixation; M55 Abstract: Atmospheric deposition fluxes of soluble nutrients (N, P, Si, Fe, Co, Zn) to the tropical North Atlantic were determined during cruise M55 of the German SOLAS programme. Nutrient fluxes were highest in the east of the section along 10[degrees]N, owing to the proximity of source regions in West Africa and Europe, and lowest in the west, for both dry and wet deposition modes. In common with other recent studies, atmospheric P and Si inputs during M55 were strongly depleted relative to the stoichiometry of phytoplankton Fe, N, P and Si requirements. Atmospheric N inputs were equivalent to 0.1-4.7% of observed primary productivity during the cruise. Atmospheric nutrient supply was also compared to observed nitrogen fixation rates during M55. While atmospheric Fe supply may have been sufficient to support N fixation (depending on the relationship between our simple Fe leaching experiment and aerosol Fe dissolution in seawater), atmospheric P supply was well below the required rate. The stable nitrogen isotope composition of nitrate-N in aerosol and rain was also determined. Results of a simple model indicate that atmospheric deposition and nitrogen fixation introduce similar amounts of isotopically light nitrogen into surface waters of the study region. This implies that nitrogen isotope-based methods would overestimate nitrogen fixation here by a factor of 2, if atmospheric inputs were not taken into account. Author Affiliation: (a) Laboratory for Global Marine and Atmospheric Chemistry, School of Environmental Sciences, University of East Anglia, Norwich NR4 7TJ, UK (b) Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK (c) Baltic Sea Research Institute, Seestrasse 15, D-18119 Warnemunde, Germany (d) Leibniz-Institut fur Meereswissenschaften, Dusternbrooker Weg 20, D-24105 Kiel, Germany (e) Centre for Ecology and Hydrology, Bush Estate, Penicuik, Midlothian EH26 0QB, UK Article History: Received 23 March 2007; Revised 21 June 2007; Accepted 10 July 2007

The concentration of particulate organic nitrogen in the North Atlantic waters decreases by 7% from winter to spring and increases during winter. This is due to fractionation while nitrate uptake occurs, or to settling down of the phytodetritus. The increase in stable nitrogen isotopes delta(super 15)N after spring is due to degradation of the particles by microorganisms. The seasonal cycles are detailed by month.

Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1a and 2a. In a phase Ib/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC. Patients and methods: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101+bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. Results: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101+bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101+bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P=0.831). The objective response rate by IRR was 5% with CRLX101+bevacizumab versus 14% with SOC (Mantel-Haenszel test, P=0.836). Consistent with previous studies, the CRLX101+bevacizumab combination was generally well tolerated, and no new safety signal was identified. Conclusions: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. Clinical trial identification: NCT02187302 (NIH). [ABSTRACT FROM AUTHOR]

In this analysis of 85 patients with metastatic renal cell carcinoma (RCC) and nonclear or sarcomatoid histologies, treatment benefit from mTOR inhibitors was limited for most patients. While a few patients achieved prolonged responses, no histologic variant was found to be predictive. These findings argue in favor of investigating predictive biomarkers to identify patients most likely to respond.Background The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC. Patients and methods Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS). Results Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC. Conclusions A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers. [ABSTRACT FROM PUBLISHER]

Abstract: We studied an amputee patient who experiences a conscious sense of movement (SoM) in her phantom hand, without significant activity in remaining muscles, when transcranial magnetic stimulation (TMS) is applied at appropriate intensity over the corresponding sector of contralateral motor cortex. We used the novel methodological combination of TMS during fMRI to reveal the neural correlates of her phantom SoM. A critical contrast concerned trials at intermediate TMS intensities: low enough not to produce overt activity in remaining muscles; but high enough to produce a phantom SoM on approximately half such trials. Comparing trials with versus without a phantom SoM reported phenomenally, for the same intermediate TMS intensities, factored out any non-specific TMS effects on brain activity to reveal neural correlates of the phantom SoM itself. Areas activated included primary motor cortex, dorsal premotor cortex, anterior intraparietal sulcus, and caudal supplementary motor area, regions that are also involved in some hand movement illusions and motor imagery in normals. This adds support to proposals that a conscious sense of movement for the hand can be conveyed by activity within corresponding motor-related cortical structures. [Copyright &y& Elsevier]

Selection to reduce susceptibility to Enterococcus faecalis infection in laying hens may contribute to the prevention of amyloid arthropathy since it is mainly induced by this bacterium. Therefore, the aim of the present study was to investigate the possibility to select more laying hens that are resistant against E. faecalis infection through the embryo lethality assay (ELA), which is proposed as an alternative model to replace the adult avian challenge assay. Ten-day-old embryos of 500 Lohmann Brown layers were inoculated into the allantoic cavity with an infectious dose of 2.5 colony-forming units (cfu)/mL of the avian E. faecalis strain K923/96 in 3 ELAs. The embryonic mortality rate (EMR) was determined by candling the eggs daily over a period of 4 d. The average EMR estimated during the 3 ELAs was 50% and the highest EMR occurred 3 to 4 d post inoculation. The estimated heritability for embryonic survivability to the infection was h2 = 0.12–0.14, calculated with the logistic and probit link function, respectively, indicating that the selection of more laying hens that are resistant to E. faecalis infection is feasible. A highly negative genetic correlation was estimated between embryonic survivability and laying performance at the peak of lay (rg = –0.22) and at the end of the production (rg = –0.65), as well as with breaking strength (rg = –0.30 to –0.37). A positive correlation was found between egg weight and the embryonic survivability (rg = +0.16), and no genetic correlation was found with body weight and dynamic stiffness. Therefore, although it was demonstrated that it is possible to breed for E. faecalis resistance, special care should be taken to monitor and to take all traits and their genetic correlations into account in order to achieve a balanced genetic progress. Besides, the ELA does not require that the hens are exposed to pathogens thereby saving labor and cost. Therefore, it could be feasible that ELA be implemented in selection programs. [ABSTRACT FROM AUTHOR]

Background: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. Patients and methods: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. Results: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. Conclusions: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine whether, and under which conditions, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) can activate similar neuronal structures of the human motor cortex, as indicated by electromyographic recordings. Methods: Focal TMS was performed on three subjects inducing a postero-anterior directed current (p-a), TES with postero-anteriorly (p-a) and latero-medially (l-m) oriented electrodes. We analyzed the onset latencies and amplitudes (single-pulse) and intracortical inhibition and excitation (paired-pulse). Results: TMS p-a and TES p-a produced muscle responses with the same onset latency, while TES l-m led to 1.4–1.9ms shorter latencies. Paired-pulse TMS p-a and TES p-a induced inhibition at short inter-stimulus intervals (ISI) (maximum: 2–3ms) and facilitation at longer ISIs (maximum: 10ms). No inhibition but a strong facilitation was obtained from paired-pulse TES l-m (ISIs 1–5ms). Conclusions: Our findings support the hypothesis, that current direction is the most relevant factor in determining the mode of activation for both TMS and TES: TMS p-a and TES p-a are likely to activate the corticospinal neurons indirectly. In contrast, TES l-m may preferentially activate the corticospinal fibres directly, distant of the neuronal body. Significance: TES is a suitable tool to induce intracortical inhibition and excitation. [Copyright &y& Elsevier]

• Resistive heating is a simple technique to speed-up the curing of glued-in rods. • The technique enables bonding of glued-in rods under low temperatures. • Glued in rods with epoxies exhibited no loss of strength under low temperatures. Adhesive bonding is a joining technique that enjoys increasing popularity in industry, including timber engineering. However, two major shortcomings still delay their widespread use, in particular on-site: long process times, and temperature requirements for curing. Accelerated curing is seen as one way to overcome both. In this paper, resistive heating is investigated as a method to both substantially accelerate curing, and to make it possible even under low temperature. The technique is illustrated on glued-in rods (GiR), a typical adhesively bonded structural joint widely used in timber engineering. Resistive heating was achieved by wrapping a thin Constantan wire within the threads of a rod, which was then subjected to an electrical current. In a series of tests, the performance of three two-component epoxies (2 K-EPX) and one two-component polyurethane (2 K-PUR), all commercially available, were investigated in terms of load capacity after resistive heating under room temperature (RT), +5 °C, and –10 °C. The results indicate that GiR bonded with two of the 2 K-EPX exhibited no significant differences in terms of joint capacity, regardless of the temperature under which they were cured, but that the 2 K-PUR proved very sensitive from departures from the recommendations of the technical data sheet. The results give, in particular practitioners, valuable indications on how to implement resistive heating in real-life applications. [ABSTRACT FROM AUTHOR]