Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma

Background: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. Methods: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. Results: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg$h/mL or CPT-11 AUC values below 10 mcg$h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC 28 mcg$h/mL [HR ¼ 0.251, 95and CPT-11 AUC <10 mcg$h/mL [HR ¼ 0.189, 95% CI 0.073e0.486, p ¼ 0.001]. Conclusions: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation.

TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and Aβ and inducing an innate immune response. Missense mutations (e.g., R47H) of TREM2 increase risk of Alzheimer's disease (AD). The soluble ectodomain of wild-type TREM2 (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to Aβ oligomers (measured by single-molecule imaging, dot blots, and Bio-Layer Interferometry) inhibited Aβ oligomerization and disaggregated preformed Aβ oligomers and protofibrils (measured by transmission electron microscopy, dot blots, and size-exclusion chromatography). Wild-type sTREM2 also inhibited Aβ fibrillization (measured by imaging and thioflavin T fluorescence) and blocked Aβ-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial cocultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the Aβ-induced release of sTREM2, which blocks Aβ aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes Aβ aggregation into protofibril that may be toxic to neurons. These findings may explain how wild-type sTREM2 apparently protects against AD in vivo and why a single copy of the R47H variant gene is associated with increased AD risk.European Unio

Detecting forest response to droughts with global observations of vegetation water content

Droughts in a warming climate have become more common and more extreme, making understanding forest responses to water stress increasingly pressing. Analysis of water stress in trees has long focused on water potential in xylem and leaves, which influences stomatal closure and water flow through the soil-plant-atmosphere continuum. At the same time, changes of vegetation water content (VWC) are linked to a range of tree responses, including fluxes of water and carbon, mortality, flammability, and more. Unlike water potential, which requires demanding in situ measurements, VWC can be retrieved from remote sensing measurements, particularly at microwave frequencies using radar and radiometry. Here, we highlight key frontiers through which VWC has the potential to significantly increase our understanding of forest responses to water stress. To validate remote sensing observations of VWC at landscape scale and to better relate them to data assimilation model parameters, we introduce an ecosystem-scale analog of the pressure-volume curve, the non-linear relationship between average leaf or branch water potential and water content commonly used in plant hydraulics. The sources of variability in these ecosystem-scale pressure-volume curves and their relationship to forest response to water stress are discussed. We further show to what extent diel, seasonal, and decadal dynamics of VWC reflect variations in different processes relating the tree response to water stress. VWC can also be used for inferring belowground conditions-which are difficult to impossible to observe directly. Lastly, we discuss how a dedicated geostationary spaceborne observational system for VWC, when combined with existing datasets, can capture diel and seasonal water dynamics to advance the science and applications of global forest vulnerability to future droughts

Weak tradeoff between xylem safety and xylem-specific hydraulic efficiency across the world\u27s woody plant species.

The evolution of lignified xylem allowed for the efficient transport of water under tension, but also exposed the vascular network to the risk of gas emboli and the spread of gas between xylem conduits, thus impeding sap transport to the leaves. A well-known hypothesis proposes that the safety of xylem (its ability to resist embolism formation and spread) should trade off against xylem efficiency (its capacity to transport water). We tested this safety-efficiency hypothesis in branch xylem across 335 angiosperm and 89 gymnosperm species. Safety was considered at three levels: the xylem water potentials where 12%, 50% and 88% of maximal conductivity are lost. Although correlations between safety and efficiency were weak (r(2) \u3c 0.086), no species had high efficiency and high safety, supporting the idea for a safety-efficiency tradeoff. However, many species had low efficiency and low safety. Species with low efficiency and low safety were weakly associated (r(2) \u3c 0.02 in most cases) with higher wood density, lower leaf- to sapwood-area and shorter stature. There appears to be no persuasive explanation for the considerable number of species with both low efficiency and low safety. These species represent a real challenge for understanding the evolution of xylem

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Non-structural carbohydrates in woody plants compared among laboratories

Non-structural carbohydrates (NSC) in plant tissue are frequently quantified to make inferences about plant responses to environmental conditions. Laboratories publishing estimates of NSC of woody plants use many different methods to evaluate NSC. We asked whether NSC estimates in the recent literature could be quantitatively compared among studies. We also asked whether any differences among laboratories were related to the extraction and quantification methods used to determine starch and sugar concentrations. These questions were addressed by sending sub-samples collected from five woody plant tissues, which varied in NSC content and chemical composition, to 29 laboratories. Each laboratory analyzed the samples with their laboratory-specific protocols, based on recent publications, to determine concentrations of soluble sugars, starch and their sum, total NSC. Laboratory estimates differed substantially for all samples. For example, estimates for Eucalyptus globulus leaves (EGL) varied from 23 to 116 (mean = 56) mg g⁻¹ for soluble sugars, 6–533 (mean = 94) mg g⁻¹ for starch and 53–649 (mean = 153) mg g⁻¹ for total NSC. Mixed model analysis of variance showed that much of the variability among laboratories was unrelated to the categories we used for extraction and quantification methods (method category R² = 0.05–0.12 for soluble sugars, 0.10–0.33 for starch and 0.01–0.09 for total NSC). For EGL, the difference between the highest and lowest least squares means for categories in the mixed model analysis was 33 mg g⁻¹ for total NSC, compared with the range of laboratory estimates of 596 mg g⁻¹. Laboratories were reasonably consistent in their ranks of estimates among tissues for starch (r = 0.41–0.91), but less so for total NSC (r = 0.45–0.84) and soluble sugars (r = 0.11–0.83). Our results show that NSC estimates for woody plant tissues cannot be compared among laboratories. The relative changes in NSC between treatments measured within a laboratory may be comparable within and between laboratories, especially for starch. To obtain comparable NSC estimates, we suggest that users can either adopt the reference method given in this publication, or report estimates for a portion of samples using the reference method, and report estimates for a standard reference material. Researchers interested in NSC estimates should work to identify and adopt standard methods.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press. The published article can be found at: http://treephys.oxfordjournals.org/Keywords: soluble sugars, starch, particle size, reference method, standardization, non-structural carbohydrate chemical analysis, extraction and quantification consistenc

Association of depression phenotypes and antidepressant treatment with mortality due to cancer and other causes: a community-based cohort study

ObjectiveThis study aimed to assess the association of somatic depressive symptoms (SDS), cognitive/emotional depressive symptoms (C-EDS), and antidepressant treatment on mortality due to cancer and other causes in a community cohort.MethodsA community-based sample recruited in 1995, 2000, and 2005 aged between 35 and 75 years was examined in two waves and followed for a median of 6.7 years. SDS and C-EDS phenotypes were assessed using the Patient Health Questionnaire-9. Medication used by participants was collected. Deaths and their causes were registered during follow-up. Cox proportional hazard models stratified by sex were performed to determine the association between depressive phenotypes and mortality.ResultsThe cohort consisted of 5,646 individuals (53.9% women) with a mean age of 64 years (SD = 11.89). During the follow-up, 392 deaths were recorded, of which 27.8% were due to cancer. C-EDS phenotype was associated with an increased risk of cancer mortality in both men (HR = 2.23; 95% CI = 1.11-4.44) and women (HR = 3.69; 95% CI = 1.69-8.09), and SDS was significantly associated with non-cancer mortality in men (HR = 2.16; 95 CI % = 1.46-3.18). Selective serotonin reuptake inhibitors (SSRIs) were significantly associated with both cancer (HR = 2.78; 95% CI = 1.10-6.98) and non-cancer mortality (HR = 2.94; 95% CI = 1.76-4.90) only in the male population.ConclusionC-EDS phenotype was related to an increased risk of cancer mortality at 6 years. In addition, the use of SSRIs in the male population was associated with cancer and all-cause mortality

Quantification of roughness and spatial distribution of dislocations in MBE and MOVPE grown LED heterostructures

A combination of nanoscale imaging techniques such as atomic force microscopy and scanning electron microscopy are used to investigate the relationship between surface morphology and height statistics of GaN cap layers in InGaN/GaN light emitting diode heterostructures. The investigated samples were grown in two very different growth regimes which lead to distinct characteristic superficial landscapes. We also report here on the introduction of a new methodological approach that adapt the concept of height-height correlation function, a well known statistical tool in the field of studies on rough surfaces. We evaluate to which extent the geometrical properties of the constitutive 'bricks' (hillocks for ammonia assisted molecular beam epitaxial film) and structural defects (dislocation pits for metal organic vapor phase epitaxial film) affects the statistical properties of heights of these GaN surfaces. Finally, we have studied the spatial distribution of dislocation pits in both the samples to assess the quantitative differences between these heterostructures of very distinct surface morphology. (C) 2016 Elsevier Ltd. All rights reserved

Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma

Background: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. Methods: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. Results: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg$h/mL or CPT-11 AUC values below 10 mcg$h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC 28 mcg$h/mL [HR ¼ 0.251, 95and CPT-11 AUC <10 mcg$h/mL [HR ¼ 0.189, 95% CI 0.073e0.486, p ¼ 0.001]. Conclusions: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma

Weak tradeoff between xylem safety and xylem-specific hydraulic efficiency across the world's woody plant species

* The evolution of lignified xylem allowed for the efficient transport of water under tension, but also exposed the vascular network to the risk of gas emboli and the spread of gas between xylem conduits, thus impeding sap transport to the leaves. A well-known hypothesis proposes that the safety of xylem (its ability to resist embolism formation and spread) should trade off against xylem efficiency (its capacity to transport water). * We tested this safety–efficiency hypothesis in branch xylem across 335 angiosperm and 89 gymnosperm species. Safety was considered at three levels: the xylem water potentials where 12%, 50% and 88% of maximal conductivity are lost. * Although correlations between safety and efficiency were weak (r2 < 0.086), no species had high efficiency and high safety, supporting the idea for a safety–efficiency tradeoff. However, many species had low efficiency and low safety. Species with low efficiency and low safety were weakly associated (r2 < 0.02 in most cases) with higher wood density, lower leaf- to sapwood-area and shorter stature. * There appears to be no persuasive explanation for the considerable number of species with both low efficiency and low safety. These species represent a real challenge for understanding the evolution of xylem.Fil: Gleason, Sean M.. Macquarie University. Department of Biological Sciences ; Australia. USDA-ARS. Water Management Research; Estados UnidosFil: Westoby, Mark. Macquarie University. Department of Biological Sciences; AustraliaFil: Jansen, Steven. Ulm University. Institute of Systematic Botany and Ecology; AlemaniaFil: Choat, Brendan. Western Sydney University. Hawkesbury Institute for the Environment; AustraliaFil: Hacke, Uwe G.. University of Alberta. Department of Renewable Resources; CanadáFil: Pratt, Robert B.. California State University. Department of Biology; Estados UnidosFil: Bhaskar, Radika. Haverford College. Department of Biology; Estados UnidosFil: Brodibb, Tim J.. University of Tasmania. School of Biological Sciences; AustraliaFil: Bucci, Sandra Janet. Universidad Nacional de la Patagonia Austral. Centro de Investigaciones y Transferencia Golfo San Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia Golfo San Jorge. Universidad Nacional de la Patagonia "san Juan Bosco". Centro de Investigaciones y Transferencia Golfo San Jorge; ArgentinaFil: Cao, Kun-Fang. Guangxi University. College of Forestry. Utilization of Subtropical Agro-Bioresources ; ChinaFil: Cochard, Hervé. Clermont Université. Université Blaise Pascal. UMR547 PIAF; Francia. Institut National de la Recherche Agronomique; FranciaFil: Delzon, Sylvain. Institut National de la Recherche Agronomique; FranciaFil: Domec, Jean-Christophe. Duke University, Durham. Nicholas School of the Environment; Estados Unidos. Institut National de la Recherche Agronomique; FranciaFil: Fan, Ze-Xin. Chinese Academy of Sciences. Xishuangbanna Tropical Botanical Garden. Key Laboratory of Tropical Forest Ecology; ChinaFil: Feild, Taylor S.. James Cook University. School of Marine and Tropical Biology; AustraliaFil: Jacobsen, Anna L.. California State University. Department of Biology; Estados UnidosFil: Johnson, Daniel M.. University of Idaho. Rangeland and Fire Sciences. Department of Forest; Estados UnidosFil: Lens, Frederic. Leiden University. Naturalis Biodiversity Center; Países BajosFil: Maherali, Hafiz. University of Guelph. Department of Integrative Biology; CanadáFil: Martínez-Viralta, Jordi. CREAF; España. Institució Catalana de Recerca i Estudis Avancats; EspañaFil: Mayr, Stefan. University of Innsbruck. Department of Botany; AustriaFil: McCulloh, Katherine A.. University of Wisconsin-Madison. Department of Botany; Estados UnidosFil: Mencuccini, Maurizio. University of Edinburgh. School of GeoSciences; Reino Unido. Institució Catalana de Recerca i Estudis Avancats; EspañaFil: Mitchell, Patrick J.. CSIRO Land and Water Flagship; AustraliaFil: Morris, Hugh. Ulm University. Institute of Systematic Botany and Ecology ; AlemaniaFil: Nardini, Andrea. Università Trieste. Dipartimento Scienze della Vita ; ItaliaFil: Pittermann, Jarmila. University of California. Department of Ecology and Evolutionary Biology; Estados UnidosFil: Plavcová, Lenka. Ulm University. Institute of Systematic Botany and Ecology; Alemania. University of Alberta. Department of Renewable Resources; CanadáFil: Schreiber, Stefan G.. University of Alberta. Department of Renewable Resources; CanadáFil: Sperry, John S.. University of Utah. Department of Biology; Estados UnidosFil: Wright, Ian J.. Macquarie University. Department of Biological Sciences; AustraliaFil: Zanne, Ami E.. George Washington University. Department of Biological Sciences; Estados Unido