p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors

The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response

Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD

Checklist of the Braconidae of Germany (Hymenoptera).

Es wird eine aktualisierte Checkliste der Braconidae Deutschlands vorgelegt. 1485 Arten werden, verbunden mit einer Quellenangabe, für Deutschland aufgeführt. Für zweifelhafte Nachweise sowie aus der Deutschlandliste zu streichende Arten und species incertae sedis erfolgte eine gesonderte Auflistung. Die Datierungen verschiedener wichtiger Arbeiten über Braconiden werden diskutiert. Weil diese Angaben und die Kommentare in der Liste in ihrer Wirkung über Deutschland hinausgehen, wurden die hauptsächlichen Kapitel auf Englisch verfasst.A revised checklist of the German braconids is presented. 1485 species are listed for Germany, accompanied by a reference. In addition doubtful records, species to be deleted from the German checklist, and species incertae sedis are listed. The dates of several important papers on braconids are discussed. Because these data and the comments in the list concern not only Germany, the main chapters were written in English

Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Ion exchange membranes derived from sulfonated polyaramides

Homo- and both random and block copolyaramides of high molecular weights, with sulfonated moieties in the backbone, were obtained by low temperature polycondensation technique in a dipolar aprotic solvent (NMP) using (a) free aromatic diamines in the presence of pyridine as acid acceptor and (b) N,N ′-bis-trimethylsilyl derivatives of the diamines without additional acid acceptor. The addition of low molecular weight electrolytes (LiCl or CaCl2) and in some cases trimesoyl chloride to the reaction mixture was found to be favorable for the synthesis of high molecular weight polyamides. The materials had a theoretical ion exchange capacity of up to 3.14 meq/g. The membranes were characterized in terms of morphology, thermal stability, water-uptake, and ion exchange capacities.Fil: Taeger, A.. Institute of Polymer Research Dresden; AlemaniaFil: Vogel, C.. Institute of Polymer Research Dresden; AlemaniaFil: Lehmann, D.. Institute of Polymer Research Dresden; AlemaniaFil: Jehnichen, D.. Institute of Polymer Research Dresden; AlemaniaFil: Komber, H.. Institute of Polymer Research Dresden; AlemaniaFil: Meier Haack, J.. Institute of Polymer Research Dresden; AlemaniaFil: Ochoa, Nelio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich"; ArgentinaFil: Nunes, S.P.. GKSS Research Center; AlemaniaFil: Peinemann, K.-V.. GKSS Research Center; Alemani

Rapid and Precise Semi-Automatic Axon Quantification in Human Peripheral Nerves

We developed a time-efficient semi-automated axon quantification method using freeware in human cranial nerve sections stained with paraphenylenediamine (PPD). It was used to analyze a total of 1238 facial and masseteric nerve biopsies. The technique was validated by comparing manual and semi-automated quantification of 129 (10.4%) randomly selected biopsies. The software-based method demonstrated a sensitivity of 94% and a specificity of 87%. Semi-automatic axon counting was significantly faster (p<0.001) than manual counting. It took 1hour and 47minutes for all 129 biopsies (averaging 50sec per biopsy, 0.04seconds per axon). The counting process is automatic and does not need to be supervised. Manual counting took 21hours and 6minutes in total (average 9minutes and 49seconds per biopsy, 0.52seconds per axon). Our method showed a linear correlation to the manual counts (R=0.944 Spearman rho). Attempts have been made by several research groups to automate axonal load quantification. These methods often require specific hard- and software and are therefore only accessible to a few specialized laboratories. Our semi-automated axon quantification is precise, reliable and time-sparing using publicly available software and should be useful for an effective axon quantification in various human peripheral nerves

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

On Scottish sawflies, with results of the 14th International Sawfly Workshop, in the southern Highlands, 2010 (Hymenoptera, Symphyta).

Die Ergebnisse der Feldarbeit aus dem 14. Internationalen Sawfly Workshop werden vorgestellt. Dies fand im südlichen schottischen Hochland, überwiegend in Perthshire, statt. Einige Nachweise von Pflanzenwespen aus anderen Teilen von Schottland sind enthalten. Erstnachweise für die Britischen Inseln werden für acht tenthredinide Arten erbracht: Amauronematus mimus, Phyllocolpa alienata, P. erythropyga, P. plicalapponum, P. plicaphylicifolia, P. prussica, Pristiphora thalictri und Tenthredo ignobilis. A. mimus ist auch aus Irland nachgewiesen. Amauronematus stenogaster ist aus der Liste der Symphyta der Britischen Inseln zu entfernen. Erstmalig sind in Schottland eine Cephiden-Art (Hartigia xanthostoma) und zehn Tenthrediniden gefunden worden (Claremontia uncta, Dolerus brevicornis, Empria basalis, Empria parvula, Parna apicalis, Pristiphora decipiens, Pristiphora leucopus, Pristiphora testacea, Tenthredo mandibularis und Tenthredopsis ornata). Merkmale für die Unterscheidung einzelner Arten werden dargestellt. Der Locus typicus von Nematus herbaceae Cameron, 1876 ist geklärt. Geranium pratense ist als Wirtspflanze von Macrophya albipuncta bestätigt. Salix reticulata ist eine Wirtspflanze von Amauronematus mcluckieae. Sedum rosea kann eine Wirtspflanze von Tenthredo ignobilis sein. Allgemeine Schlussfolgerungen: hoher Artenreichtum der Pflanzenwespenfauna von Perthshire im Vergleich zu anderen Regionen in Schottland, darunter mehrere Arten, die auf den Britischen Inseln nur von dort bekannt sind; die Wichtigkeit der Erhaltung der Lebensräume von Felssimsen; große Defizite in unseren Kenntnissen bei vielen Arten, insbesondere zu Wirtspflanzen, Phänologie und Verbreitung; hoher Wert der Malaise-Falle in faunistischen Untersuchungen von Symphyta, weil das Spektrum von erfassten Taxa sich unterscheidet von dem was mit Streifnetz erfasst wird; Zusammensetzung des 'fall-out’ auf Schneeresten deutet darauf hin, dass Pflanzenwespen in einem größeren Ausmaß als bisher angenommen, aktiver Dispersion innerhalb von Landmassen unterliegen.StichwörterBritish Isles, Cephidae, Pamphiliidae, Tenthredinoidea, hosts, phenology, distribution.Results of fieldwork are presented from the 14th International Sawfly Workshop, held in the southern Highlands of Scotland, mostly in Perthshire. Some records of Symphyta from other parts of Scotland are included. First records in the British Isles are given for eight tenthredinid species: Amauronematus mimus, Phyllocolpa alienata, P. erythropyga, P. plicalapponum, P. plicaphylicifolia, P. prussica, Pristiphora thalictri and Tenthredo ignobilis. A. mimus is also recorded from Ireland. Amauronematus stenogaster is removed from the list of British Isles Symphyta. Recorded for the first time in Scotland are one cephid (Hartigia xanthostoma) and ten tenthredinids (Claremontia uncta, Dolerus brevicornis, Empria basalis, Empria parvula, Parna apicalis, Pristiphora decipiens, Pristiphora leucopus, Pristiphora testacea, Tenthredo mandibularis and Tenthredopsis ornata). Characters useful for the distinction of some species are illustrated. The type locality of Nematus herbaceae Cameron, 1876 is clarified. Geranium pratense is confirmed as a host of Macrophya albipuncta. Salix reticulata is a host of Amauronematus mcluckieae [mandatory correction of spelling of species name]. Sedum rosea may be a host of Tenthredo ignobilis. General conclusions: high species richness of Perthshire sawfly fauna compared to other regions of Scotland, including several species only known in British Isles from there; importance to conservation of rock-ledge habitats; large data deficits for many species, particularly on hosts, phenology and distribution; high value of Malaise traps in faunal survey of Symphyta, because spectrum of taxa captured differs from that recorded by hand-netting; as indicated by species and sex composition of ‘fall-out’ on snow patches, adult sawflies undertake active dispersal, within landmasses, to a greater extent than is often assumed.KeywordsBritish Isles, Cephidae, Pamphiliidae, Tenthredinoidea, hosts, phenology, distribution

Morphological and Physiological Responses to Drought Stress of European Provenances of Scots Pine

Increased frequency and intensity of drought episodes as a consequence of current and predicted climatic changes require an understanding of the intra-specific variability in structural and physiological characteristics of forest trees. Adaptive plasticity and genotypic variability are considered two of the main processes by which trees can either be selected or can acclimate to changing conditions. We tested for the relative importance of genotypic variability, phenotypic plasticity and their interaction by comparing the growth and physiological performance of 15 provenances of Scots pine (Pinus sylvestris L.), under two contrasting irrigation regimes. Selected provenances representing the distribution range of the species in Anatolia, Turkey, were contrasted with seed sources spanning the range from Spain to the UK, in Europe. We found a strong latitudinal differentiation among the 15 provenances for survival after drought, largely the result of the higher mortality of some western and central European provenances. Differentiation in diameter and height growth was also clear with the worst provenance coming from Western Europe (UK). Among the Turkish provenances, the more extreme southern high-elevation populations showed greater survival and lower growth rates overall. Differences in growth and survival were related to differences in photosynthetic pigment and nutrient contents and in the photosynthetic efficiency of photosystem II. Plasticity was strongest for growth characters and pigment contents.WoSScopu