Description: BACKGROUND Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO-7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia. METHODS This double-blind clinical trial (ONO-7643-04) enrolled 174 patients with unresectable stage III/IV non–small cell lung cancer (NSCLC) and cachexia in Japan. Patients were randomized to daily oral anamorelin (100 mg) or a placebo for 12 weeks. The primary endpoint was the change from the baseline LBM (measured with dual-energy x-ray absorptiometry) over 12 weeks. The secondary endpoints were changes in appetite, body weight, quality of life, handgrip strength (HGS), and 6-minute walk test (6MWT) results. RESULTS The least squares mean change (plus or minus the standard error) in LBM from the baseline over 12 weeks was 1.38 ± 0.18 and −0.17 ± 0.17 kg in the anamorelin and placebo groups, respectively ( P  〈 .0001). Changes from the baseline in LBM, body weight, and anorexia symptoms showed significant differences between the 2 treatment groups at all time points. Anamorelin increased prealbumin at weeks 3 and 9. No changes in HGS or 6MWT were detected between the groups. Twelve weeks' treatment with anamorelin was safe and well tolerated in NSCLC patients. CONCLUSIONS Anamorelin significantly increased LBM and improved anorexia symptoms and the nutritional state, but not motor function, in Japanese patients with advanced NSCLC. Because no effective treatment for cancer cachexia is currently available, anamorelin can be a beneficial treatment option. Cancer 2017. © 2017 American Cancer Society .

Description: Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well-differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5-deficient ( Snx5 -/- ) mice. In comparison to wild-type ( Snx5 +/+ ) mice, Snx5 -/- mice exhibited enlarged thyroid glands that consisted of thyrocytes with large irregular-shaped vacuoles. Snx5 -/- thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid-stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5 -/- thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5 -/- thyrocytes were also confirmed by results showing that Snx5 -/- mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti-thyroidal agent revealed that Snx5 -/- mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma.

Description: REV1, REV3 and REV7 are pivotal proteins in translesion DNA synthesis that allows DNA synthesis to continue even in the presence of DNA damage. REV1 and REV3 are error-prone DNA polymerases, while REV7 acts as an adaptor protein that links them together. A ternary complex of the C-terminal domain of human REV1 in complex with REV7 bound to a REV3 fragment has been crystallized. The crystals belonged to space group P 3 1 21, with unit-cell parameters a = b = 74.7, c = 124.5 Å.

Description: How herbivores respond to resource heterogeneity is important for predicting plant resistance to herbivores. Experimental studies thus far have revealed that herbivore responses differ depending on whether herbivores are offered single or multiple plant types, but the reports have rarely been combined. Here, we conducted a meta-analysis of 47 publications on choice and no-choice experiments to reveal how the presence/absence of multiple plants (i.e., choice/no-choice conditions) alters the extent of behavioral avoidance by herbivores. The herbivore diet breadth and response traits (feeding, growth, or oviposition) explained a significantly large amount of heterogeneity in the herbivore response under choice and no-choice conditions. In contrast, a small amount of heterogeneity was explained by the herbivore types (vertebrates, exophagous, or endophagous invertebrates), plant resistance traits (chemical or nonchemical), plant life form, and relatedness of plant pairs (intraspecific or interspecific) as well as interactions between the herbivore and plant characteristics. Compared with the no-choice conditions, specialist herbivores further avoided suboptimal plants under choice conditions. Generalist herbivores more evenly utilized optimal and suboptimal plants under choice conditions. The avoidance of suboptimal plants under choice conditions was the most prominent in oviposition response. Thus, our meta-analysis found that herbivore characteristics rather than plant traits were more responsible for driving behavioral avoidance by herbivores to a particular plant. The contrasting response between specialist and generalist herbivores to plant heterogeneity may be more ubiquitous than previously thought.

Description: Geographic variation is commonly observed in plant resistance traits, where plant species might experience different selection pressure across a heterogeneous landscape. Arabidopsis halleri subsp. gemmifera is dimorphic for trichome production, generating two morphs, trichome-producing (hairy) and trichomeless (glabrous) plants. Trichomes of A. halleri are known to confer resistance against the white butterfly, cabbage sawfly, and brassica leaf beetle, but not against flea beetles. We combined leaf damage, microclimate, and microsatellite loci data of 26 A. halleri populations in central Japan, to explore factors responsible for fine-scale geographic variation in the morph frequency. We found that hairy plants were less damaged than glabrous plants within populations, but the among-site variation was the most significant source of variation in the individual-level damage. Fixation index ( ) of a putative trichome locus exhibited a significant divergence along population-level damage with an exception of an outlier population, inferring the local adaptation to herbivory. Notably, this outlier was a population wherein our previous study reported a balancing role of the brassica leaf beetle Phaedon brassicae on the morph frequency. This differentiation of the trichome locus was unrelated to neutral genetic differentiation (evaluated by of microsatellite loci) and meteorological factors (including temperature and solar radiation). The present findings, combined with those of our previous work, provide suggestive evidence that herbivore-driven divergence and occasional outbreak of a specific herbivore have jointly contributed to the ecogeographic pattern in the frequency of two morphs. Many studies have shown that plant trichomes act as a physical defense against herbivory, but clear evidence remains limited about geographic association between herbivory and the trichome production. By combining field surveys with meteorological and genetic data, our study revealed that herbivory was a crucial driver of population differentiation in the frequency of hairy and glabrous morphs in Arabidopsis halleri subsp. gemmifera . To our knowledge, this is one of few examples to clearly show the relevance of herbivory with ecogeographic patterns in the trichome production.

Description: [1]  Lower Aptian carbonates in the Bab Basin at the southern Neo-Tethys margin record significant environmental changes across Oceanic Anoxic Event 1a (OAE1a). A long-lasting negative shift of carbon-isotope ratios (δ 13 C) associated with a distinct decrease in oxygen-isotope ratios (δ 18 O) in orbitolinid-rich carbonates characterizes the onset of OAE1a (Livello Selli), supporting a hypothesis that a long-lasting volcanic CO 2 emission is a main cause of OAE1a, inducing global warming. A bloom of microencrusters ( Lithocodium and Bacinella ) across the proto-Bab Basin occurred synchronously at the beginning of the subsequent positive δ 13 C excursion, responding to the global carbon-cycle perturbations. The carbonates, formed during the OAE1a, show higher strontium-isotope ratios ( 87 Sr/ 86 Sr) compared with those of global seawater; this was likely caused by a local influx of isotopically heavier strontium, along with nutrients, into the proto-Bab Basin. These biotic proliferations were triggered by an increased nutrient supply induced by intensified continental weathering due to the global warming suggested by the increase in δ 18 O values. Spatial variations in the δ 13 C values among sites in the Bab Basin and its surrounding platform are related to local environmental factors, such as the degree of mixing of basin water with ocean water and local removal of 12 C by metabolic activity at the platform-top. The δ 13 C profile of the studied core indicates global removal of organic carbon of OAE1a began during the early stage of the second-order transgression and lasted until the early stage of the highstand after the OAE1a. The Livello Selli corresponds to the early stage of this transgression.