A multistate model for early decision making in oncology

The development of oncology drugs progresses through multiple phases, where after each phase a decision is made about whether to move a molecule forward. Early phase efficacy decisions are often made on the basis of single arm studies based on RECIST tumor response as endpoint. This decision rules are implicitly assuming some form of surrogacy between tumor response and long-term endpoints like progression-free survival (PFS) or overall survival (OS). The surrogacy is most often assessed as weak, but sufficient to allow a rapid decision making as early phase studies lack the survival follow up and number of patients to properly assess PFS or OS. With the emergence of therapies with new mechanisms of action, for which the link between RECIST tumor response and long-term endpoints is either not accessible yet because not enough data is available to perform a meta-regression, or the link is weaker than with classical chemotherapies, tumor response based rules may not be optimal. In this paper, we explore the use of a multistate model for decision making based on single-arm early phase trials. The multistate model allows to account for more information than the simple RECIST response status, namely, the time to get to response, the duration of response, the PFS time and time to death. We propose to base the decision on efficacy on the OS hazard ratio (HR), predicted from a multistate model based on early phase data with limited survival follow-up, combined with historical control data. Using three case studies and simulations, we illustrate the feasibility of the estimation of the OS HR using a multistate model based on limited data from early phase studies. We argue that, in the presence of limited follow up and small sample size, and on assumptions within the multistate model, the OS prediction is acceptable and may lead to better decisions for continuing the development of a drug

Spectral fundus autofluorescence peak emission wavelength in ageing and AMD

Purpose To investigate the spectral characteristics of fundus autofluorescence (FAF) in AMD patients and controls. Methods Fundus autofluorescence spectral characteristics was described by the peak emission wavelength (PEW) of the spectra. Peak emission wavelength (PEW) was derived from the ratio of FAF recordings in two spectral channels at 500-560 nm and 560-720 nm by fluorescence lifetime imaging ophthalmoscopy. The ratio of FAF intensity in both channels was related to PEW by a calibration procedure. Peak emission wavelength (PEW) measurements were done in 44 young (mean age: 24.0 ± 3.8 years) and 18 elderly (mean age: 67.5 ± 10.2 years) healthy subjects as well as 63 patients with AMD (mean age: 74.0 ± 7.3 years) in each pixel of a 30° imaging field. The values were averaged over the central area, the inner and the outer ring of the ETDRS grid. Results There was no significant difference between PEW in young and elderly controls. However, PEW was significantly shorter in AMD patients (ETDRS grid centre: 571 ± 26 nm versus 599 ± 17 nm for elderly controls, inner ring: 596 ± 17 nm versus 611 ± 11 nm, outer ring: 602 ± 16 nm versus 614 ± 11 nm). After a mean follow-up time of 50.8 ± 10.8 months, the PEW in the patients decreased significantly by 9 ± 19 nm in the inner ring of the grid. Patients, showing progression to atrophic AMD in the follow up, had significantly (p ≤ 0.018) shorter PEW at baseline than non-progressing patients. Conclusions Peak emission wavelength (PEW) is related to AMD pathology and might be a diagnostic marker in AMD. Possibly, a short PEW can predict progression to retinal and/or pigment epithelium atrophy

Radioprotective effect of lidocaine on neurotransmitter agonist-induced secretion in irradiated salivary glands.

Previously we verified the radioprotective effect of lidocaine on the function and ultrastructure of salivary glands in rabbits. However, the underlying mechanism of lidocaine's radioprotective effect is unknown. We hypothesized that lidocaine, as a membrane stabilization agent, has a protective effect on intracellular neuroreceptor-mediated signaling and hence can help preserve the secretory function of salivary glands during radiotherapy. Rabbits were irradiated with or without pretreatment with lidocaine before receiving fractionated radiation to a total dose of 35 Gy. Sialoscintigraphy and saliva total protein assay were performed before radiation and 1 week after the last radiation fraction. Isolated salivary gland acini were stimulated with either carbachol or adrenaline. Ca(2+) influx in response to the stimulation with these agonists was measured using laser scanning confocal microscopy. The uptake of activity and the excretion fraction of the parotid glands were significantly reduced after radiation, but lidocaine had a protective effect. Saliva total protein concentration was not altered after radiation. For isolated acini, Ca(2+) influx in response to stimulation with carbachol, but not adrenaline, was impaired after irradiation; lidocaine pretreatment attenuated this effect. Lidocaine has a radioprotective effect on the capacity of muscarinic agonist-induced water secretion in irradiated salivary glands

Monitoring macular pigment in geographic atrophy using FLIO

Purpose : The pathophysiology of geographic atrophy (GA) is not yet fully understood and prognostic factors are still under discussion. Little is known about how the macular pigment (MP) changes during the progress of the disease. Monitoring fundus autofluorescence (FAF) lifetimes in GA using Fluorescence-lifetime-Imaging-Ophthalmoscopy (FLIO) may lead to novel insights, especially since FLIO can detect MP. Methods : Using FLIO (Heidelberg-Engineering, Heidelberg, Germany), time-resolved FAF of 20 eyes with GA has been recorded in two spectral channels (ch1: 498-560nm; ch2: 560-720nm) and approximated by a series of three exponentials, resulting in three lifetimes: (τ1-τ3). Their amplitude-weighted mean (τm) per channel and pixel was utilized as the main parameter for statistical analysis. A FAF image was acquired with each measurement; OCT scans and fundus photography were obtained. τm was averaged over the standardized ETDRS grid and the area of the fovea (diameter 0,1mm). Of special interest were differences between the fovea and the Inner Ring (IR) of the grid. These differences (τm (IR) minus τm (fovea)) were correlated to the best corrected visual acuity (BCVA). Results : Mean FAF lifetimes in GA differ according to the individual progression of the disease. Additionally to hypo- and hyperfluorescent regions detectable with FAF, FLIO visualizes differences within these regions: The presence of MP results in shorter FAF lifetimes (250-400 ps) compared to other atrophic regions (>700 ps) (figure 1). These short FAF decays are often related to a spared fovea. The τm differences between the IR and the Fovea (τm (IR) minus τm (fovea)) correlate with the BCVA (r:0.6; p<0.01 for both channels). Conclusions : Whereas conventional FAF images only show differences in the fluorescence intensity, FLIO can additionally distinguish between different atrophic areas, better showing the presence of MP, resulting in different lifetimes and possibly detecting spared regions. FLIO is a new imaging method to monitor GA. If FLIO can provide information on the GA progression needs to be further evaluated. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016

Massive migration from the steppe is a source for Indo-European languages in Europe

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost four hundred thousand polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of western and far eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ~8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary, and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ~24,000 year old Siberian6 . By ~6,000-5,000 years ago, a resurgence of hunter-gatherer ancestry had occurred throughout much of Europe, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ~4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ~3/4 of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ~3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for the theory of a steppe origin of at least some of the Indo-European languages of Europe

4000 years of human dietary evolution in central Germany, from the first farmers to the first elites

Investigation of human diet during the Neolithic has often been limited to a few archaeological cultures or single sites. In order to provide insight into the development of human food consumption and husbandry strategies, our study explores bone collagen carbon and nitrogen isotope data from 466 human and 105 faunal individuals from 26 sites in central Germany. It is the most extensive data set to date from an enclosed geographic microregion, covering 4,000 years of agricultural history from the Early Neolithic to the Early Bronze Age. The animal data show that a variety of pastures and dietary resources were explored, but that these changed remarkably little over time. In the human δ15N however we found a significant increase with time across the different archaeological cultures. This trend could be observed in all time periods and archaeological cultures (Bell Beaker phenomenon excluded), even on continuously populated sites. Since there was no such trend in faunal isotope values, we were able largely to exclude manuring as the cause of this effect. Based on the rich interdisciplinary data from this region and archaeological period we can argue that meat consumption increased with the increasing duration of farming subsistence. In δ13C, we could not observe any clear increasing or decreasing trends during the archaeological time periods, either for humans or for animals, which would have suggested significant changes in the environment and landscape use. We discovered sex-related dietary differences, with males of all archaeological periods having higher δ15N values than females, and an age-related increasing consumption of animal protein. An initial decrease of δ15N-values at the age of 1-2 years reveals partial weaning, while complete weaning took place at the age of 3-4 years

Tropical and Boreal Forest Atmosphere Interactions: A Review

This review presents how the boreal and the tropical forests affect the atmosphere, its chemical composition, its function, and further how that affects the climate and, in return, the ecosystems through feedback processes. Observations from key tower sites standing out due to their long-term comprehensive observations: The Amazon Tall Tower Observatory in Central Amazonia, the Zotino Tall Tower Observatory in Siberia, and the Station to Measure Ecosystem-Atmosphere Relations at Hyytiala in Finland. The review is complemented by short-term observations from networks and large experiments.The review discusses atmospheric chemistry observations, aerosol formation and processing, physiochemical aerosol, and cloud condensation nuclei properties and finds surprising similarities and important differences in the two ecosystems. The aerosol concentrations and chemistry are similar, particularly concerning the main chemical components, both dominated by an organic fraction, while the boreal ecosystem has generally higher concentrations of inorganics, due to higher influence of long-range transported air pollution. The emissions of biogenic volatile organic compounds are dominated by isoprene and monoterpene in the tropical and boreal regions, respectively, being the main precursors of the organic aerosol fraction.Observations and modeling studies show that climate change and deforestation affect the ecosystems such that the carbon and hydrological cycles in Amazonia are changing to carbon neutrality and affect precipitation downwind. In Africa, the tropical forests are so far maintaining their carbon sink.It is urgent to better understand the interaction between these major ecosystems, the atmosphere, and climate, which calls for more observation sites, providing long-term data on water, carbon, and other biogeochemical cycles. This is essential in finding a sustainable balance between forest preservation and reforestation versus a potential increase in food production and biofuels, which are critical in maintaining ecosystem services and global climate stability. Reducing global warming and deforestation is vital for tropical forests