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Ground ice distribution and abundance have wide-ranging effects on periglacial environments and possible impacts on climate change scenarios. In contrast, very few studies measure ground ice in the High Arctic, especially in polar deserts and where coarse surficial material complicates coring operations. Ground ice volumes and cryostructures were determined for eight sites in a polar desert, near Resolute Bay, Nunavut, chosen for their hydrogeomorphic classification. Dry, unvegetated polar desert sites exhibited ice content close to soil porosity, with a

In formerly glaciated permafrost regions, extensive areas are still underlain by a considerable amount of glacier ice buried by glacigenic sediments. It is expected that large parts of glacier ice buried in the permafrost will melt in the near future, although the intensity and timing will depend on local terrain conditions and the magnitude and rate of future climate trends in different Arctic regions. The impact of these ice bodies on landscape evolution remains uncertain since the extent and volume of undisturbed relict glacier ice are unknown. These remnants of glacier ice buried and preserved in the permafrost contribute to the high spatial variability in ground ice condition of these landscapes, leading to the formation of lakes with diverse origins and morphometric and limnological properties. This study focuses on thermokarst lake initiation and development in response to varying ground ice conditions in a glacial valley on Bylot Island (Nunavut). We studied a lake-rich area using lake sediment cores, detailed bathymetric data, remotely sensed data and observations of buried glacier ice exposures. Our results suggest that initiation of thermokarst lakes in the valley was triggered from the melting of either buried glacier ice or intrasedimental ice and ice wedges. Over time, all lakes enlarged through thermal and mechanical shoreline erosion, as well as vertically through thaw consolidation and subsidence. Some of them coalesced with neighbouring water bodies to develop larger lakes. These glacial thermokarst lakes formed in buried glacier ice now evolve as “classic” thermokarst lakes that expand in area and volume as a result of the melting of intrasedimental ground ice in the surrounding material and the underlying glaciofluvial and till material. It is expected that the deepening of thaw bulbs (taliks) and the enlargement of Arctic lakes in response to global warming will reach undisturbed buried glacier ice where it is still present, which in turn will substantially alter lake bathymetry, geochemistry and greenhouse gas emissions from Arctic lowlands.

Arctic permafrost is degrading and is thus releasing nutrients, solutes, sediment and water into soils and freshwater ecosystems. The impacts of this degradation depends on the geochemical characteristics and in large part on the spatial distribution of ground ice and solutes, which is not well-known in the High Arctic polar desert ecosystems. This research links ground ice and solute concentrations, to establish a framework for identifying locations vulnerable to permafrost degradation. It builds on landscape classifications and cryostratigraphic interpretations of permafrost history. Well-vegetated wetland sites with syngenetic permafrost aggradation show a different geochemical signature from polar desert and epigenetic sites. In wetlands, where ground ice contents were high (+ and Cl− ions, reflecting a post-glacial marine inundation during permafrost formation. Dissolved organic carbon and total dissolved nitrogen concentrations usually increased at the top of permafrost and could not be as clearly associated with permafrost history. The research shows that the geochemistry of polar desert permafrost is highly dependent on permafrost history, and it can be estimated using hydrogeomorphological terrain classifications. The lower ice content of polar desert sites indicates that these areas are more vulnerable to thaw relative to the ice-rich wetland sites, and the elevated solute concentrations indicate that these areas could mobilise substantial solutes to downstream environments, should they become hydrologically connected with future warming.

A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) and its comparison with 16α-[18F]-fluoroestradiol (FES) in mice, rats, and humans with a focus on the brain uptake. Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semi-quantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field of view, brain uptake of discernable foci was measured and reported as SUVMax. Regardless of the species studied, 4FMFES and FES uptake were relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates that the signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial preoptic area. Dissection data further confirmed those findings and revealed additional signals corresponding to the arcuate and ventromedial nuclei, along with the medial and cortical amygdala. 4FMFES allowed visualization of ER expression in the pituitary in humans and two different rodent species with better contrast than FES. Improvement in clinical spatial resolution might allow visualization and analysis of other ER-rich brain areas in humans. Further work is now possible to link 4FMFES pituitary uptake to cognitive functions.

BackgroundNuclear medicine is on the constant search of precision radiopharmaceutical approaches to improve patient management. Although discordant expression of the estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2) in breast cancer is a known dilemma for appropriate patient management, traditional tumor sampling is often difficult or impractical. While 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG)-positron emission tomography (PET) is an option to detect subclinical metastases, it does not provide phenotype information. Radiolabeled antibodies are able to specifically target expressed cell surface receptors. However, their long circulating half-lives (days) require labeling with long-lived isotopes, such as89Zr, in order to allow sufficient time for tracer clearance from the blood compartment and to accumulate adequately in target tumors and, thus, generate high-quality PET images. The aim of this study was to develop a dual-tracer PET imaging approach consisting of a fast-clearing small molecule and a slow-clearing antibody. This approach was evaluated in a model consisting of mice harboring separate breast cancer xenografts with either an ER+/HER2− or ER−/HER2+ phenotype, comparable to human metastatic disease with intertumor heterogeneity. Lastly, the aim of our study was to determine the feasibility of specifically identifying these two important phenotypes in an acceptable time window.MethodsFemale nude mice were subcutaneously implanted on opposite shoulders with the ER+/HER2− and ER−/HER2+ MCF-7 and JIMT-1 tumor cell lines, respectively. A second model was developed consisting of mice implanted orthotopically with either MCF-7 or JIMT-1 cells. Pharmacokinetic analysis, serial PET imaging, and biodistribution were first performed for [89Zr]Zr-DFO-trastuzumab (89Zr-T) up to 8 days post-injection (p.i.) in JIMT-1 bearing mice. Region-of-interest (ROI) and biodistribution-derived uptake (% injected-activity/gram of tissue [%IA/g]) values and tumor-to-background ratios were obtained. Results were compared in order to validate ROI and identify early time points that provided high contrast tumor images. For the dual-tracer approach, cohorts of tumor-bearing mice were then subjected to sequential tracer PET imaging. On day 1, mice were administered 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) which targets ER and imaged 45 min p.i. This was immediately followed by the injection of89Zr-T. Mice were then imaged on day 3 or day 7. ROI analysis was performed, and uptake was calculated in tumors and selected healthy organs for all radiotracers. Quality of tumor targeting for all tracers was evaluated by tumor contrast visualization, tumor and normal tissue uptake, and tumor-to-background ratios.Results89Zr-T provided sufficiently high tumor and low background uptake values that furnished high contrast tumor images by 48 h p.i. For the dual-tracer approach, 4FMFES provided tumor uptake values that were significantly increased in MCF-7 tumors. When89Zr-T-PET was combined with18F-4FMFES-PET, the entire dual-tracer sequential-imaging procedure provided specific high-quality contrast images of ER+/HER2− MCF-7 and ER−/HER2+ JIMT-1 tumors for 4FMFES and89Zr-T, respectively, as short as 72 h from start to finish.ConclusionsThis protocol can provide high contrast images of tumors expressing ER or HER2 within 3 days from injection of 4FMFES to final scan of89Zr-T and, hence, provides a basis for future dual-tracer combinations that include antibodies.

In formerly glaciated permafrost regions, extensive areas are still underlain by a considerable amount of glacier ice buried by glacigenic sediments. Although the extent and volume of undisturbed relict glacier ice are unknown, these ice bodies are predicted to melt with climate warming but their impact on landscape evolution remains poorly studied. The spatial distribution of buried glacier ice can play a significant role in reshaping periglacial landscapes, in particular thermokarst aquatic systems. This study focuses on lake initiation and development in response to the melting of buried glacier ice on Bylot Island, Nunavut. We studied a lake-rich area using lake-sediment cores, detailed bathymetric data, remotely sensed data and observations of buried glacier ice exposures. Our results suggest that initiation of deeper thermokarst lakes was triggered by the melting of buried glacier ice. They have subsequently enlarged through thermal and mechanical shoreline erosion, as well as vertically through thaw consolidation and subsidence, and they later coalesced with neighbouring water bodies to form larger lakes. Thus, these lakes now evolve as “classic” thermokarst lakes that expand in area and volume as a result of the melting of intrasedimental ground ice in the surrounding material and the underlying glaciofluvial and till material. It is expected that the deepening of thaw bulbs (taliks) and the enlargement of Arctic lakes in response to global warming will reach undisturbed buried glacier ice, if any, which in turn will substantially alter lake bathymetry, geochemistry and greenhouse gas emissions from Arctic lowlands.

Haptic technologies are widely used in multimedia entertainment to psychophysiologically enhance user experience. Psychometric-based research regarding vibrokinetic stimulation during multimedia viewing supports this notion. However, scant neurophysiological evidence exists to verify this effect. Using a between groups design with source-localized electroencephalography, the present study analyzed the effect of high fidelity vibrokinetic (HFVK) stimulation during passive multimedia interaction (i.e. watching a haptically enhanced movie) on self-reported emotional state and intercortical theta coherence. Results indicate that HFVK increases emotional reactivity in association with increased interhemispheric coherence between the right inferiortemporal gyrus and the left insular cortex, thereby conferring neurophysiological support for the efficaciousness of HFVK to enhance emotional response during movie watching.

PURPOSE: A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11β-methoxy-16α-[(18)F]-fluoroestradiol (4FMFES) and its comparison with 16α-[(18)F]-fluoroestradiol (FES) in mice, rats and humans with a focus on the brain uptake. PROCEDURES: Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semi-quantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field-of-view, brain uptake of discernable foci was measured and reported as SUV(Max). RESULTS: Regardless of the species studied, 4FMFES and FES uptake was relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates that the signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial preoptic area. Dissection data further confirmed those findings and revealed additional signals corresponding to the arcuate and ventromedial nuclei, along with the medial and cortical amygdala. CONCLUSION: 4FMFES allowed visualization of ER expression in the pituitary in humans and two different rodent species with better contrast than FES. Improvement in clinical spatial resolution might allow visualization and analysis of other ER-rich brain areas in humans. Further work is now possible to link 4FMFES pituitary uptake to cognitive functions.

International audience; An increased interest in Arctic environments, mainly due to climate change, has changed the conditions for permafrost research in recent years. This change has been accompanied by a global increase in scientific publications, as well as a trend towards open access publications. We have analyzed abstracts, titles and keywords for publications on permafrost from 1998 to 2017 to identify developments (topics, impact and collaboration) in the field of permafrost research in light of these changes. Furthermore, to understand how scientists build on and are inspired by each other's work, we have (a) developed citation networks from scientific publications on permafrost and (b) conducted an online survey on inspiration in permafrost science. Our results show an almost 400% increase in publications containing the word permafrost in the title, keywords or abstract over the study period, and a strong increase in climate-change-related research in terms of publications and citations. Survey respondents (n = 122) find inspiration not only in scientific journal publications, but to a large extent in books and public outreach materials. We argue that this increase in global-scope issues (i.e., climate change) complementing core permafrost research has provided new incentives for international collaborations and wider communication efforts.

Introduction Gastrin releasing peptide receptors (GRPRs) are significantly over-expressed on a large proportion of prostate cancers making them prime candidates for receptor-mediated nuclear imaging by PET. Recently, we synthesized a novel bifunctional chelator (BFC) bearing hydroxamic acid arms (DOTHA 2 ). Here we investigated the potential of a novel DOTHA 2 -conjugated, 64 Cu-radiolabeled GRPR peptide antagonist, [D-Phe 6 -Sta 13 -Leu 14 -NH 2 ]bombesin(6-14) (DOTHA 2 -PEG-RM26) to visualize prostate tumors by PET imaging. Methods DOTHA 2 -PEG-RM26 was conveniently and efficiently assembled on solid support. The compound was radiolabeled with 64 Cu and its affinity, stability, cellular uptake on PC3 prostate cancer cells were evaluated. The in vitro and in vivo behavior of [ 64 Cu]DOTHA 2 -PEG-RM26 was examined by PET imaging using human PC3 prostate cancer xenografts and its behavior was compared to that of the analogous [ 64 Cu]NOTA-PEG-RM26. Results The inhibition constant of nat Cu-DOTHA 2 -PEG-RM26 was in the low nanomolar range (0.68 ± 0.19 nM). The [ 64 Cu]DOTHA 2 -PEG-RM26 conjugate was prepared with a labeling yield > 95% and molar activity of 56 ± 3 GBq/μmol after a 5-min room temperature labeling. [ 64 Cu]-DOTHA 2 -PEG-RM26 demonstrated rapid blood and renal clearance as well as a high tumor uptake. Small animal PET images confirmed high and specific uptake in PC3 tumor. Both [ 64 Cu]-DOTHA 2 -PEG-RM26 and [ 64 Cu]-NOTA-PEG-RM26 displayed similar tumor and normal tissue uptakes at early time point post injection. Conclusions [ 64 Cu]-DOTHA 2 -PEG-RM26 allows visualization of prostate tumors by PET imaging. DOTHA 2 enables fast 64 Cu chelation under mild condition, and as such could be used advantageously for the development of other 64 Cu-labeled peptide-derived PET tracers.

In this study, the preliminary results of a phase II clinical trial investigating the use of the Estrogen Receptor (ER) targeting PET tracer 4-fluoro-11β-methoxy-16α-[18F]fluoroestradiol (18F-4FMFES) and [18F]-fluorodeoxyglucose (18F-FDG)-PET in endometrial cancers will be accounted. In parallel, non-invasive interventions will be attempted to slow down progression of 18F-4FMFES metabolites in the intestines to reduce abdominal background. Methods: In an ongoing study, 25 patients that received prior pathological confirmation of an ER+ endometrial cancer or endometrial intraepithelial neoplasia agreed to participate to the ongoing clinical trial. Patients were scheduled for 18F-FDG and 18F-4FMFES PET/CT imaging in random order and within 2 weeks. Patients were administered either 4 mg loperamide per os before 18F-4FMFES tracer injection or repeated intravenous injection of 20 mg hyoscine N-butylbromide during 18F-4FMFES-PET/CT. Regions-of-interest (ROIs) covering the whole abdomen and excluding the liver, bladder and uterus were drawn for the 18F-4FMFES-PET images, and a threshold of SUV > 4 was applied. The volume of the resulting region was compared between the different interventions to estimate the extent of the intestinal background. Results: Repeated injection of hyoscine N-butylbromide substantially reduced the intestinal background volume, whereas loperamide had a significant but moderate effect. 18F-4FMFES tumor uptake ranged between SUVmax 3.0 and 14.4 (9.4 ± 3.2), whereas 18F-FDG uptake spreaded between SUVmax 0 and 22.0 (7.5 ± 5.1). Tumor-to-background ratio were significantly higher for 18F-4FMFES (16.4 ± 5.4) than for 18F-FDG (7.4 ± 4.6). Significant differences were observed between grade 1 and higher-grade tumors concerning 18F-4FMFES uptake and contrast. 18F-FDG uptake, and the 18F-FDG/18F-4FMFES uptake ratio. Conclusion: It is possible to improve 18F-4FMFES abdominal background using hyoscine N-butylbromide. Both 18F-FDG and 18F-4FMFES-PET are suitable for detection of ER+ endometrial cancers, although 18F-4FMFES yielded a better tumor contrast than 18F-FDG.

After encouraging preclinical and human dosimetry results for the novel estrogen receptor (ER) PET radiotracer 4-fluoro-11β-methoxy-16α-18F-fluoroestradiol (18F-4FMFES), a phase II clinical trial was initiated to compare the PET imaging diagnostic potential of 18F-4FMFES with that of 16α-18F-fluoroestradiol (18F-FES) in ER-positive (ER+) breast cancer patients. Methods: Patients diagnosed with ER+ breast cancer (n = 31) were recruited for this study, including 6 who underwent mastectomy or axillary node dissection. For each patient, 18F-FES and 18F-4FMFES PET/CT scans were done sequentially (within a week) and in random order. One hour after injection of either radiotracer, a head-to-thigh static scan with a 2-min acquisition per bed position was obtained. Blood samples were taken at different times after injection to assess each tracer metabolism by reverse-phase thin-layer chromatography. The SUVmean of nonspecific tissues and the SUVmax of the tumor were evaluated for each detected lesion, and tumor-to-nonspecific organ ratios were calculated. Results: Blood metabolite analysis 60 min after injection of the tracer showed a 2.5-fold increase in metabolic stability of 18F-4FMFES over 18F-FES. Although for most foci 18F-4FMFES PET had an SUVmax similar to that of 18F-FES PET, tumor contrast improved substantially in all cases. Lower uptake was consistently observed in nonspecific tissues for 18F-4FMFES, notably a 4-fold decrease in blood-pool activity as compared with 18F-FES. Consequently, image quality was considerably improved using 18F-4FMFES, with lower overall background activity. As a result, 18F-4FMFES successfully identified 9 more lesions than 18F-FES. Conclusion: This phase II study with ER+ breast cancer patients showed that 18F-4FMFES PET achieves a lower nonspecific signal and better tumor contrast than 18F-FES PET, resulting in improved diagnostic confidence and lower false-negative diagnoses.

Repeated freeze–thaw cycles on slopes trigger sorting and solifluction mass movements, while subsequent displacement of material modifies the geomorphology of slopes as well as permafrost dynamics. This study focuses on the geomorphology and the cryostratigraphy of a polar desert stone-banked solifluction lobe with the objective to clarify the impact of slow mass movements on ground ice aggradation. The morphology of the solifluction lobe was characterized by peripheral ridges of coarse gravel, partially surrounding a depression filled with finer sediments saturated with water and covered by organics. Cryostratigraphic analysis demonstrated that the solifluction lobe’s formation led to the development of a syngenetic layer of permafrost with an ice content that varied according to the location in the lobe. The ice-rich cryofacies formed in the central depression of the lobe should act as a buffer to potential active layer deepening, slowing down its thawing, whereas the ice-poor cryofacies formed under the ridges is expected to thaw faster than the central depression under climate warming scenarios. Thawing of the ice-rich zone in the future will result in differential thaw subsidence between the ridges and the central depression of solifluction lobes, along with increased drainage through the ridges and subsequent changes in hydrology.

Water tracks play a major role in the headwater basin hydrology of permafrost landscapes in Alaska and Antarctica, but less is known about these features in the High Arctic. We examined the physical and hydrological properties of water tracks on Ward Hunt Island, a polar desert site in the Canadian High Arctic, to evaluate their formation process and to compare with water tracks reported elsewhere. These High Arctic water tracks flowed through soils that possessed higher near-surface organic carbon concentrations, higher water content, and coarser material than the surrounding soils. The water track morphology suggested they were initiated by a combination of sorting, differential frost heaving, and eluviation. The resultant network of soil conduits, comparable to soil pipes, dominated the hydrology of the slope. The flow of cold water through these conduits slowed down the progression of the thawing front during summer, making the active layer consistently shallower relative to adjacent soils. Water tracks on Ward Hunt Island, and in polar desert catchments with these features elsewhere in the High Arctic, strongly influence slope hydrology and active-layer properties while also affecting vegetation distribution and the quality of runoff to the downstream lake.

In this study, we investigated for the first time the influence of 2-aminoethyl-piperazine-1-carboxylic acid (APCA) and amino-hexanedioic-1-acid (AHDA) on tumor uptake and elimination kinetics of [64Cu]-radiolabeled gastrin releasing peptide receptors (GRPR) antagonists. Three GRPR antagonists containing the RM26 sequence were synthesized and conjugated with NOTA via different linkers (LK): polyethylene glycol (PEG–neutral), APCA (dicationic) or AHDA (dianionic). The NOTA-LK-RM26 peptides were radiolabeled with 64Cu to assess their pharmacokinetic and positron emission tomography (PET) imaging properties using PC3 tumor-bearing athymic nude mice. The inhibition constants (Ki) of the 3 natCu/NOTA-LK-RM26 peptides bearing PEG, dicationic and dianionic linkers were 0.98 ± 0.48 nM, 0.95 ± 0.21 nM, and 17.97 ± 2.79 nM, respectively. The [64Cu] NOTA-LK-RM26 conjugates were prepared with labeling yields superior to 95% and specific activities of 67 to 77 TBq/mmol. The 3 radiopeptides were stable in vivo and showed GRPR-specific uptake in pancreas with a very fast washout of this tissue observed for [64Cu]-NOTA-AHDA-RM26 peptide. Results from imaging studies displayed specific PC3 tumor uptake for both [64Cu]-NOTA-APCA- and AHDA-RM26, similar kidney elimination and fast liver washout. Considering their adequate imaging characteristics, [64Cu]-NOTA-LK-RM26 bearing APCA- and AHDA-linkers are promising candidates for GRPR-targeted PET imaging prostate cancer.

In vivo imaging of estrogen receptor (ER) densities in human breast cancer is a potential tool to stage disease, guide treatment protocols and follow-up on treatment outcome. Both positron emission tomography (PET) and fluorescence imaging have received ample attention to detect ligand-ER interaction. In this study we prepared BODIPY-estradiol conjugates using 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) as fluorescent probe and estradiol derivatives as ligand and established their relative binding affinity (RBA) for the ERα. The synthesis of the conjugates involves attachment of a BODIPY moiety to the C17α-position of estradiol using Sonogashira or click reactions of iodo-BODIPY or aza-BODIPY with various 17α-ethynylestradiol (EE2) derivatives. The highest RBA for the ERα was observed with the EE2-BODIPY conjugate (7) featuring a linear eight carbon spacer chain. Cell uptake studies and in vivo imaging experiments in an ER-positive mouse tumor model are in progress.

Thermokarst lakes are widespread and diverse across permafrost regions and they are considered significant contributors to global greenhouse gas emissions. Paleoenvironmental reconstructions documenting the inception and development of these ecologically important water bodies are generally limited to Pleistocene-age permafrost deposits (Yedoma) of Siberia, Alaska, and the western Canadian Arctic. Here we present the gradual transition from syngenetic ice-wedge polygon terrains to a thermokarst lake in the Eastern Canadian Arctic. We combine geomorphological surveys with paleolimnological reconstructions from sediment cores in an effort to characterize local landscape evolution from terrestrial to freshwater environment. Located on an ice-rich and organic-rich polygonal terrace, the studied lake is now evolving through active thermokarst, as revealed by subsiding and eroding shores, and was likely created by water pooling within a pre-existing topographic depression. Organic sedimentation in the valley started during the mid-Holocene, as documented by the oldest organic debris found at the base of one sediment core and dated at 4.8 kyr BP. Local sedimentation dynamics were initially controlled by fluctuations in wind activity, local moisture and vegetation growth/accumulation, as shown by alternating loess (silt) and peat layers. Fossil diatom assemblages were likewise influenced by local hydro-climatic conditions and reflect a broad range of substrates available in the past (both terrestrial and aquatic). Such conditions likely prevailed until ~ 2000 BP, when peat accumulation stopped as water ponded the surface of degrading ice-wedge polygons, and the basin progressively developed into a thermokarst lake. Interestingly, this happened in the middle of the Neoglacial cooling period, likely under wetter-than-average conditions. Thereafter, the lake continued to develop as evidenced by the dominance of aquatic (both benthic and planktonic) diatom taxa in organic-rich lacustrine muds. Based on these interpretations, we present a four-stage conceptual model of thermokarst lake development during the late Holocene, including some potential future trajectories. Such a model could be applied to other formerly glaciated syngenetic permafrost landscapes.

In the last decade, entertainment industries have been creating multi-sensory experiences using haptic stimulation delivered via vibro-kinetic (VK) seats that produce vibration and motion coincidental with audiovisual content. However, the effects of VK stimulation during purely auditory experiences remains unclarified. We addressed this scientific shortcoming by investigating the effects of high fidelity VK (HFVK) stimulation, on psychophysiological indices of emotional valence and arousal. The HFVK stimulation was delivered to 24 healthy participants through an HFVK enhanced seat during active music listening. Participants listened to six popular songs randomly chosen from a pool of 15 songs, with the songs presented randomly with or without HFVK stimulation. Psychological emotional valence and arousal were indexed based on two items of the Self-Assessment Manikin (SAM) scale. Physiological emotional valence and arousal were respectively indexed based on micro facial expressions and electrodermal activity. Our results revealed that psychological and physiological valence, and psychological arousal were higher with HFVK stimulation compared to a control condition where the chair was static. A post-experiment questionnaire further revealed greater subjective appreciation for the HFVK stimulation condition compared to the control condition. Overall, our results highlight the potential for HFVK technologies to enhance auditory listening experiences.

Investigations into the susceptibility of permafrost landscapes response to thermokarst can be performed using various approaches, depending on the scale of investigation. In many cases, point-based field measurements are extrapolated to larger scales and vice versa. The integration of scales often requires some form of ground control in addition to remote sensing surveys, which are at times exclusively conducted. As upscaling from discrete field measurements can provide spatial coverage and landscape-scale significance, downscaling from remote sensing can offer insight into processes and serve as calibration or verification. Here we present a multiple-scale evaluation of an area initially interpreted as a relict active layer detachment slide (before 1950) on Melville Island in the High Arctic, where differential interferometric synthetic aperture radar (DInSAR) showed subsidence between 2013 and 2015. Ground-based, cryostratigraphy measurements were combined with ground-penetrating radar (GPR) to investigate permafrost ice-content. The results indicate greater subsidence within the relict active layer detachment as detected by DInSAR. GPR surveys and permafrost coring indicated the presence of an ice-rich or massive ice layer near the base of the active layer in this area. In addition, cryostratigraphic evidences of thaw unconformity and of massive ice depth helped validate the interpretations of the geomorphology in the active layer detachment. This combination of methods indicated a localized and inherited landform-subsidence association, which brought further insight into the interpretation of DInSAR subsidence data. The framework presented in this study demonstrates the importance of site-specific investigations of thermokarst signal in order to understand the processes behind the remote sensing results.

Antibody-conjugates (ACs) modified with virus-derived peptides are a potentially powerful class of tumor cell delivery agents for molecular payloads used in cancer treatment and imaging due to increased cellular accumulation over current ACs. During early AC in vitro development, fluorescence techniques and radioimmunoassays are sufficient for determining intracellular localization, accumulation efficiency, and target cell specificity. Currently, there is no consensus on standardized methods for preparing cells for evaluating AC intracellular accumulation and localization. The initial testing of ACs modified with virus-derived peptides is critical especially if several candidates have been constructed. Determining intracellular accumulation by fluorescence can be affected by background signal from ACs at the cell surface and complicate the interpretation of accumulation. For radioimmunoassays, typically treated cells are fractionated and the radioactivity in different cell compartments measured. However, cell lysis varies from cell to cell and often nuclear and cytoplasmic compartments are not adequately isolated. This can produce misleading data on payload delivery properties. The intravenous injection of radiolabeled virus-derived peptide-modified ACs in tumor bearing mice followed by radionuclide imaging is a powerful method for determining tumor targeting and payload delivery properties at the in vivo phase of development. However, this is a relatively recent advancement and few groups have evaluated virus-derived peptide-modified ACs in this manner. We describe the processing of treated cells to more accurately evaluate virus-derived peptide-modified AC accumulation when using confocal microscopy and radioimmunoassays. Specifically, a method for trypsinizing cells to remove cell surface bound ACs. We also provide a method for improving cellular fractionation. Lastly, this protocol provides an in vivo method using positron emission tomography (PET) for evaluating initial tumor targeting properties in tumor-bearing mice. We use the radioisotope (64)Cu (t(1/2) = 12.7 h) as an example payload in this protocol.

Receptor-mediated internalization followed by trafficking and degradation of antibody-conjugates (ACs) via the endosomal-lysosomal pathway is the major mechanism for delivering molecular payloads inside target tumor cells. Although a mainstay for delivering payloads with clinically approved ACs in cancer treatment and imaging, tumor cells are often able to decrease intracellular payload concentrations and thereby reduce the effectiveness of the desired application. Thus, increasing payload intracellular accumulation has become a focus of attention for designing next-generation ACs. We developed a composite compound (ChAcNLS) that enables ACs to escape endosome entrapment and route to the nucleus resulting in the increased intracellular accumulation as an interleukin-5 receptor α-subunit (IL-5Rα)-targeted agent for muscle invasive bladder cancer (MIBC). We constructed ⁶⁴Cu-A14-ChAcNLS, ⁶⁴Cu-A14-NLS, and ⁶⁴Cu-A14 and evaluated their performance by employing mechanistic studies for endosome escape coupled to nuclear routing and determining whether this delivery system results in improved ⁶⁴Cu cellular accumulation. ACs consisting of ∼20 ChAcNLS or NLS moieties per ⁶⁴Cu-A14 were prepared in good yield, high monomer content, and maintaining high affinity for IL-5Rα. Confocal microscopy analysis demonstrated ChAcNLS mediated efficient endosome escape and nuclear localization. ⁶⁴Cu-A14-ChAcNLS increased ⁶⁴Cu cellular accumulation in HT-1376 and HT-B9 cells relative to ⁶⁴Cu-A14 and ⁶⁴Cu-A14-NLS. In addition, we tested ⁶⁴Cu-A14-ChAcNLS in vivo to evaluate its tissue distribution properties and, ultimately, tumor uptake and targeting. A model of human IL-5Rα MIBC was developed by implanting NOD/SCID mice with subcutaneous HT-1376 or HT-B9MIBC tumors, which grow containing high and low IL-5Rα-positive tumor cell densities, respectively. ACs were intravenously injected, and daily blood sampling, biodistribution at 48 and 96 h, and positron emission tomography (PET) at 24 and 48 h were performed. Region of interest (ROI) analysis was also performed on reconstructed PET images. Pharmacokinetic analysis and biodistribution studies showed that ⁶⁴Cu-A14-ChAcNLS had faster clearance rates from the blood and healthy organs relative to ⁶⁴Cu-A14. However, ⁶⁴Cu-A14-ChAcNLS maintained comparable tumor accumulation relative to ⁶⁴Cu-A14. This resulted in ⁶⁴Cu-A14-ChAcNLS having superior tumor/normal tissue ratios at both 48 and 96 h biodistribution time points. Visualization of AC distribution by PET and ROI analysis confirmed that ⁶⁴Cu-A14-ChAcNLS had improved targeting of MIBC tumor relative to ⁶⁴Cu-A14. In addition, ⁶⁴Cu-A14 modified with only NLS had poor tumor targeting. This was a result of poor tumor uptake due to extremely rapid clearance. Thus, the overall findings in this model of human IL-5Rα-positive MIBC describe an endosome escape-nuclear localization cholic-acid-linked peptide that substantially enhances AC cellular accumulation and tumor targeting. Refereed/Peer-reviewed

Permafrost occupies 20 million square kilometres of Earth's high-latitude and high-altitudelandscapes. These regions are sensitive to climate change and human activities; hence,permafrost research is of considerable scientific and societal importance. However, the resultsof this research are generally not known by the general public. Communicating scientificconcepts is an increasingly important task in the research world. Different ways to engagelearners and incorporate narratives in teaching materials exist, yet they are generallyunderused. Here we report on an international scientific outreach project called “FrozenGround Cartoons”, which aims at making permafrost science accessible and fun for students,teachers, and parents through the creation of comic strips. We present the context in whichthe project was initiated, and recent education and outreach activities. The future phases ofthe project primarily involve a series of augmented reality materials, such as maps, photos,videos, and 3D drawings. With this project we aim to foster understanding of permafrostresearch among broader audiences, inspire future permafrost researchers, and raise publicand science community awareness of polar science, education, outreach, and engagement.

Field records, aerial photographs, and satellite imagery show that the perennial ice cover on Ward Hunt Lake at Canada's northern coast experienced rapid contraction and thinning after at least 50 years of relative stability. On all dates of sampling from 1953 to 2007, 3.5 to 4.3 m of perennial ice covered 65–85% of the lake surface in summer. The ice cover thinned from 2008 onward, and the lake became ice free in 2011, an event followed by 26 days of open water conditions in 2012. This rapid ice loss corresponded to a significant increase in melting degree days (MDD), from a mean (±SD) of 80.4 (±36.5) MDD (1996–2007) to 136.2 (±16.4) MDD (2008–2012). The shallow bathymetry combined with heat advection by warm inflows caused feedback effects that accelerated the ice decay. These observations show how changes across a critical threshold can result in the rapid disappearance of thick perennial ice.

In intestinal epithelial cells (IEC), it was reported that the activation of the P2X7 receptor leads to the internalization of the glucose transporter GLUT2, which is accompanied by a reduction of IEC capacity to transport glucose. In this study, we used P2rx7−/− mice to decipher P2X7 functions in intestinal glucose transport and to evaluate the impacts on metabolism. Immunohistochemistry analyses revealed the presence of GLUT2 at the apical domain of P2rx7−/− jejunum enterocytes. Positron emission tomography and biodistribution studies demonstrated that glucose was more efficiently delivered to the circulation of knockout animals. These findings correlated with increase blood glucose, insulin, triglycerides and cholesterol levels. In fact, P2rx7−/− mice had increased serum triglyceride and cholesterol levels and displayed glucose intolerance and resistance to insulin. Finally, P2rx7−/− mice developed a hepatic steatosis characterized by a reduction of Acaca, Acacb, Fasn and Acox1 mRNA expression, as well as for ACC and FAS protein expression. Our study suggests that P2X7 could play a central role in metabolic diseases.

Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Rα immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Rα and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 ( 64 Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64 Cu-A14 treatments. Our findings suggest that although IL-5Rα protein expression is preferentially increased in MIBC, it is rapid IL-5Rα-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64 Cu-A14 to detect MIBC tumors in vivo. This is the first report to elucidate the potential of IL-5Rα as an attractive MIBC target for antibody-conjugate applications. Refereed/Peer-reviewed

Gastrin releasing peptide receptors (GRPRs) are significantly over-expressed on a large proportion of prostate cancers making them prime candidates for receptor-mediated nuclear imaging by PET. Recently, we synthesized a novel bifunctional chelator (BFC) bearing hydroxamic acid arms (DOTHADOTHAThe inhibition constant of[

Purpose Trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) is a new drug intended to be used for the management of visceral pain in patients undergoing sedation-free, full colonoscopy. The objectives of this Phase I, single-center, randomized, double-blinded, placebo-controlled, integrated study were to evaluate the safety and pharmacokinetics of GIC-1001 after single ascending doses (SAD) and multiple ascending doses (MAD) and to evaluate the influence of food on the pharmacokinetics in healthy volunteers. Methods GIC-1001 or placebo was orally administered to 80 healthy male and female subjects (non- or ex-smokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m 2 . The SAD portion of the study consisted of 5 cohorts with dose levels of 125 to 1000 mg. The MAD portion included 4 cohorts in which subjects received TID doses of 125 to 500 mg over 7 days (19 consecutive doses). Subjects were randomized (6:2) to receive GIC-1001 or placebo. The third portion of the study included a single 375-mg dose of GIC-1001 in a randomized, 2-period, crossover design to assess the influence of food (n = 8 subjects). Safety was evaluated by using adverse events (AEs), vital signs, ECGs, physical examination, cardiac monitoring, and laboratory test results. The analytes were assayed by using validated HPLC-MS/MS methods. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity. To evaluate the effect of food, 90% CIs of the ratio of geometric least squares means from ln-transformed pharmacokinetic parameters were calculated. Findings The most frequently reported drug-related AEs were of nervous system and gastrointestinal origin. The most common AEs included headache, somnolence, and nausea. After single-dose administration, T max of trimebutine ranged from 1.0 to 1.5 hours. C max and AUC T were linear (nonlinearity P ≥ 0.05) and proportional ( P max and AUC of trimebutine; the ratio of geometric least squares means (90% CI) were 140% (84–234) and 174% (138–221), respectively. In the MAD study portion, the T max of trimebutine ranged from 0.5 to 2 hours and AUC τ increased from 38 to 170 ng · h/mL. AUC τ and C max were linear and proportional over the studied dose range. Implications GIC-1001 was well tolerated, and its safety profile was similar to that of placebo. Pharmacokinetics of GIC-1001 and its metabolites were mainly linear and proportional over the studied dose ranges. Steady state was generally considered to be reached after 3 days. Food consumption affected the pharmacokinetic profile of the analytes differently. (ClinicalTrials.gov identifier: NCT01738425.)

218 Objectives: Several studies have shown that liver tumor burden (LTB), estimated by morphological modalities, such as CT and MR, is a significant factor for management and prognosis in patients with neuroendocrine tumors (NETs). PET/CT using 68Ga-DOTATOC or 18F-FDG, as a functional imaging tool, has been widely used in NETs, which might provide additional information for predicting prognosis. The aim of this study was to investigate the prognostic performance of DOTATOC-PET/CT and FDG-PET/CT in comparison to the morphological imaging modalities. Methods: We retrospectively analyzed 31 patients (male:female=17:14, 22-84 y.o.) with pancreatic NETs who had undergone DOTATOC-PET/CT and had been diagnosed to have liver metastasis by some imaging modalities. All patients had enhanced CT and/or MRI within a month of DOTATOC-PET/CT, and 26 patients FDG-PET/CT. We assessed LTB by a visual scale (0-10%, 10-25%, 25-50%, 50%-) on CT or MRI images. Then, we measured maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion uptake (TLU) on DOTATOC-PET/CT or total lesion glycolysis (TLG) on FDG-PET/CT for all metastatic liver tumors or all lesions in a whole body. In addition, the SUVmax ratio, MTV ratio, and TLU ratio, defined as a value in FDG-PET/CT divided by a value in DOTATOC-PET/CT, were calculated. The progression-free survival (PFS) and the overall survival (OS) were evaluated during their follow-up periods (8-83mo). The Kaplan-Meier analysis with the log-rank test was used to estimate and compare the correlation between each imaging parameter and PFS or OS. Results: On CT and/or MRI (n=31), LTB was significantly negatively correlated with PFS (p=0.003) and OS (p=0.007) [Fig. 1, 2]. On DOTATOC-PET/CT (n=31), 27 patients had DOTATOC-avid liver metastases and 30 patients had DOTATOC-avid lesions. The absence of DOTATOC-avid lesions was significantly negatively correlated with OS (p=0.041), although the number of the non-avid group was only one. Among the DOTATOC-PET/CT parameters, SUVmax, MTV, TLU for liver metastases and MTV for all lesions were significantly negatively correlated with PFS (p=0.003, p=0.005, p=0.006, p

The aim of this study was to compare the in vivo stability, uptake, and positron emission tomography (PET) imaging performance of a novel estrogen receptor PET tracer, 4-fluoro-11β-methoxy-16α-[(18)F]fluoroestradiol (4FMFES), with 16α-[(18)F]fluoroestradiol (FES).MC7-L1 and MC4-L2 (ER+) cell lines and their ERα-knockdown variants (ERαKD) were implanted subcutaneously in Balb/c mice. After 21 days, mice were imaged using either FES or 4FMFES. One hour post-injection, static images were acquired for 30 min and the tumor %ID/g uptake values were derived. Biodistribution data were also obtained 1 h following the injection of either FES or 4FMFES. Blood samples were taken at different times and analyzed on thin-layer chromatography to quantify the presence of radiometabolites for each radiotracer. To assess specific targeting to the estrogen receptors, mice bearing only ER+ tumors were treated with the competitive ER inhibitor fulvestrant 48 h prior to imaging with 4FMFES.Metabolic stability was found to be similar for both tracers in mice. Both FES and 4FMFES differentiated ER+ tumors from ERαKD tumors in biodistribution and PET imaging studies. 4FMFES achieved a significantly higher %ID/g uptake in ER+ tumors and MC4-L2 ERαKD tumors than FES in the PET imaging studies. Also, tumor-to-background ratio was higher in ER+ tumors using 4FMFES compared to FES. Dissection data showed a significantly higher %ID/g in all tested cell lines and ER-rich tissues using 4FMFES versus FES. Fulvestrant-treated mice had either low or undetectable tumor uptake.In a tumor-bearing mouse model, 4FMFES achieves better specific tumor uptake and better contrast than FES, making it a promising candidate for ER imaging.