Approaches for improving cutting processes and machine too in re-contouring

Re-contouring in the repair process of aircraft engine blades and vanes is a crucial task. Highest demands are made on the geometrical accuracy as well as on the machined surface of the part. Complexity rises even more due to the unique part characteristic originating from the operation and repair history. This requires well-designed processes and machine tool technologies. In this paper, approaches for coping with these challenges and improving the re-contouring process are described and discussed. This includes an advanced process simulation with its capabilities to accurately depict different material areas and predict process forces. Beyond, experimental investigations on workpiece-tooldeflection are presented. Finally, a machine tool prototype with a novel electromagnetic guiding system is introduced and the benefits of this technology in the field of repair are outlined.DFG/CRC/87

Teaching undergraduate students gynecological and obstetrical examination skills: the patient's opinion

Introduction Our study assesses the patients’ opinion about gynecological examination performed by undergraduate students (UgSts). This assessment will be used in improving our undergraduate training program. A positive opinion would mean a lower chance of a patient refusing to be examined by a tutor or student, taking into account vaginal examination (VE). Materials and methods We performed a prospective cross-sectional survey on 1194 patients, consisting of outpatient and inpatient at the departments of obstetrics and gynecology from November 2015 to May 2016. The questionnaire consisted of 46 questions. Besides demographic data, we assessed the mindset of patients regarding the involvement of undergradu ate student (UgSt) in gynecological and obstetrical examinations. We used SPSS version 23 for the statistical analysis. For reporting the data, we followed the STROBE statement of reporting observational studies. Results The median age was 38 years having a median of one child. 34% presented due to obstetrical problems, 38% due to gynecological complaints, and 19% due to known gynecological malignancies. Generally, we retrieved a positive opinion of patients towards the involvement of students in gynecological and obstetrical examination under supervision in 2/3 of the cases. Conclusions There is no reason to exclude medical UgSts from gynecological and obstetrical examinations after obtaining a written or oral consent

The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis

Tofisopam is a member of the 2,3-benzodiazepine compound family which is marketed for the treatment of anxiety in some European countries. In contrast to classical 1,4-benzodiazepines, the compound does not bind to the benzodiazepine binding site of the γ-aminobutyric acid receptor and its psychopharmacological profile differs from such compounds. In addition to anxiolytic properties, antipsychotic effects are reported. We now show that tofisopam, 50 mg/kg intraperitoneally (i.p.), administered in parallel to repeated doses of dizocilpine 0.2 mg/kg i.p. can ameliorate dizocilpine-induced prolongation of immobility, which is considered to be a model of negative symptoms of psychosis. We further show that tofisopam acts as an isoenzyme-selective inhibitor of phosphodiesterases (PDEs) with highest affinity to PDE-4A1 (0.42 μM) followed by PDE-10A1 (0.92 μM), PDE-3 (1.98 μM) and PDE-2A3 (2.11 μM). The data indicate that tofisopam is an interesting candidate for the adjuvant treatment of psychosis with focus on negative symptoms. Combined partial inhibition of PDE-4 and PDE-10 as well as PDE-2 may be the underlying mechanism to this activity. Due to the good safety profile of tofisopam as evident from long-term use of this agent in patients, it may be concluded that dual or triple inhibition of PDE isoenzymes with additive or synergistic effects may be an interesting approach to pharmacological activity, resulting in active compounds with beneficial safety profile. Dose-limiting side effects such as emesis induced by selective inhibition of PDE-4 may be prevented by such strategies

Comparison of transcriptional responses in liver tissue and primary hepatocyte cell cultures after exposure to hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine

BACKGROUND: Cell culture systems are useful in studying toxicological effects of chemicals such as Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), however little is known as to how accurately isolated cells reflect responses of intact organs. In this work, we compare transcriptional responses in livers of Sprague-Dawley rats and primary hepatocyte cells after exposure to RDX to determine how faithfully the in vitro model system reflects in vivo responses. RESULTS: Expression patterns were found to be markedly different between liver tissue and primary cell cultures before exposure to RDX. Liver gene expression was enriched in processes important in toxicology such as metabolism of amino acids, lipids, aromatic compounds, and drugs when compared to cells. Transcriptional responses in cells exposed to 7.5, 15, or 30 mg/L RDX for 24 and 48 hours were different from those of livers isolated from rats 24 hours after exposure to 12, 24, or 48 mg/Kg RDX. Most of the differentially expressed genes identified across conditions and treatments could be attributed to differences between cells and tissue. Some similarity was observed in RDX effects on gene expression between tissue and cells, but also significant differences that appear to reflect the state of the cell or tissue examined. CONCLUSION: Liver tissue and primary cells express different suites of genes that suggest they have fundamental differences in their cell physiology. Expression effects related to RDX exposure in cells reflected a fraction of liver responses indicating that care must be taken in extrapolating from primary cells to whole animal organ toxicity effects

Zebrafish Whole-Adult-Organism Chemogenomics for Large-Scale Predictive and Discovery Chemical Biology

The ability to perform large-scale, expression-based chemogenomics on whole adult organisms, as in invertebrate models (worm and fly), is highly desirable for a vertebrate model but its feasibility and potential has not been demonstrated. We performed expression-based chemogenomics on the whole adult organism of a vertebrate model, the zebrafish, and demonstrated its potential for large-scale predictive and discovery chemical biology. Focusing on two classes of compounds with wide implications to human health, polycyclic (halogenated) aromatic hydrocarbons [P(H)AHs] and estrogenic compounds (ECs), we generated robust prediction models that can discriminate compounds of the same class from those of different classes in two large independent experiments. The robust expression signatures led to the identification of biomarkers for potent aryl hydrocarbon receptor (AHR) and estrogen receptor (ER) agonists, respectively, and were validated in multiple targeted tissues. Knowledge-based data mining of human homologs of zebrafish genes revealed highly conserved chemical-induced biological responses/effects, health risks, and novel biological insights associated with AHR and ER that could be inferred to humans. Thus, our study presents an effective, high-throughput strategy of capturing molecular snapshots of chemical-induced biological states of a whole adult vertebrate that provides information on biomarkers of effects, deregulated signaling pathways, and possible affected biological functions, perturbed physiological systems, and increased health risks. These findings place zebrafish in a strategic position to bridge the wide gap between cell-based and rodent models in chemogenomics research and applications, especially in preclinical drug discovery and toxicology

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038

Selective phosphodiesterase inhibitors: a promising target for cognition enhancement

# The Author(s) 2008. This article is published with open access at Springerlink.com Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer’s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. Objective The aim of this review was to provide an overvie