378 research outputs found
Socketed Ball-Bar Set SRM 2083
No full textSocketed Ball-Bar Set, Standard Reference Material 2083. This set was designed for measuring the performance of coordinate measuring machines in accordance with ASME Standard B89.1.12. This device was designed by Robert J. Hocken, T. Charlton, and William C. Haight of the National Bureau of Standards (NBS) Automated Production Technology Division and S. Gerner, S. Wiser, and M. Osti of the NBS Fabrication Technology Division.7 x 81 x 22 c
The determinants of apprenticeship training with particular reference tobusiness expectations
No full text"Whilst in applied empirical research, training in general human capital is mainly explained by structural characteristics of firms, this paper introduces business expectations as an additional explanatory factor. Business expectations are strictly time-variate and firm-specific and reflect both a firm's development in competitive markets and in the business cycle. We assume that a firm's business expectations strongly modify the cost-utility concept for firms' decisions as regards providing apprenticeship places. When controlling for firms' structural characteristics, static econometric models support our assumption that a change in business expectations leads to an asymmetric adjustment process of firms' qualitative decisions regarding apprenticeship training. Concerning the quantitative decision as to how many apprenticeship places a firm provides we found a significant but not asymmetric response to a change in business expectations. A dynamic approach confirms the results obtained in the static models of a symmetric quantitative adjustment process in a short-term perspective. In a longer perspective the dynamic model supports the assumption of an asymmetric quantitative adjustment process. Further on an application shows that an increasing uncertainty regarding business expectations tends to reduce the apprenticeship training at firm level." (Author's abstract, IAB-Doku) ((en)) Additional Information Kurzfassung (deutsch) Executive summary (English)Ausbildungsverhalten - Determinanten, Betrieb, Ausbildungsbetrieb, Unternehmensentwicklung, Personalpolitik, Kosten-Nutzen-Analyse, Ausbildungskosten, betriebliche Berufsausbildung - Nutzen, betriebliche Berufsausbildung, Bildungsökonomie, Bildungsinvestitionen, wirtschaftliche Situation
Abstract PL01-04: ODC genotype as prognostic and predictive factors in colorectal carcinogenesis and prevention
No full textAbstract
Polyamines are increased in many intraepithelial neoplasia, which are risk factors for cancer in humans (1). Ornithine decarboxylase (ODC1), the first enzyme in polyamine synthesis, is regulated in part by Ebox transcription factors including MYC and MAD family members. The ODC1 gene contains several single nucleotide polymorphisms (SNPs) which are associated with risk of colorectal neoplasia. A SNP located 316 nucleotides from the start of transcription (rs2302615) has functional consequences for Ebox transcription factor binding and promoter activity. Both the transcription activator MYC and transcriptional repressors in the MAD family preferentially bind the ODC promoter element containing the minor A allele, which is flanked by two canonical E-boxes, resulting in allele-specific expression (2, 3). This SNP is associated with both risk of metachronous colorectal adenoma (CRA), in several independent studies (2, 4), and survival of patients with stages I-III colon cancer (3). The ODC1 SNP was also found to be predictive of reduced risk of CRA in association with aspirin use by three independent groups (2, 4, 5). The mechanism underlying the relationship between the ODC1 SNP and aspirin appears to involve the action of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on polyamine catabolism and export. NSAIDs, including aspirin and sulindac, and celecoxib transcriptionally activate SAT1, a spermidine/spermine acetyltransferase, by unique mechanisms (6-8). Acetylation targets these polyamines for export by an SLC3A2-dependent arginine antiporter (9). Thus, NSAIDs and celecoxib, by activating polyamine export, complement ODC1 inhibitors, which suppress polyamine synthesis, to reduce tissue polyamine contents. In a prospective, randomized, placebo-controlled clinical trial of difluoromethylornithine (DFMO), a selective ODC1 inhibitor, and the NSAID sulindac for three years, combination treatment was associated with a 70% reduction of all, and over a 90% reduction of advanced and/or multiple CRAs, in patients with prior colon polyps (10). The 30% rate of non-advanced CRA development in the treatment arm was strongly associated with both the ODC1 SNP and dietary polyamines (11). Consideration of homeostatic regulatory processes, supported by measurements of tissue polyamine contents in participants in this trial, support the interpretation that decreased ODC transcription, resulting from the ODC1 SNP, is associated with altered polyamine transport. Treatment-associated toxicities were rare and associated with pretreatment clinical and genetic risk factors. The ODC1 SNP was predictive of ototoxicity in this trial (11). These studies identify genetic variability in ODC1, a MYC target gene, as a prognostic factor for colorectal carcinogenesis and as a predictive factor for treatments targeting this pathway. The role(s) of other ODC1 SNPs in colorectal or other cancers remains to be established.
References:
1. Gerner EW, Meyskens FL, Jr. Polyamines and cancer: old molecules, new understanding. Nature Reviews Cancer 2004;4(10):781-92.
2. Martinez ME, O'Brien TG, Fultz KE, et al. Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. Proc Natl Acad Sci U S A 2003;100(13):7859-64.
3. Zell JA, Ziogas A, Ignatenko N, et al. Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival. Clin Cancer Res 2009;15(19):6208-16.
4. Hubner RA, Muir KR, Liu JF, Logan RF, Grainge MJ, Houlston RS. Ornithine decarboxylase G316A genotype is prognostic for colorectal adenoma recurrence and predicts efficacy of aspirin chemoprevention. Clin Cancer Res 2008;14(8):2303-9.
5. Barry EL, Baron JA, Bhat S, et al. Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma prevention. Journal of the National Cancer Institute 2006;98(20):1494-500.
6. Babbar N, Ignatenko NA, Casero RA, Jr., Gerner EW. Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. J Biol Chem 2003;278(48):47762-75.
7. Babbar N, Gerner EW, Casero RA, Jr. Induction of spermidine/spermine N1-acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells. Biochemical Journal 2006;394(Pt 1):317-24.
8. Ignatenko NA, Besselsen DG, Stringer DE, Blohm-Mangone KA, Cui H, Gerner EW. Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis. Nutr Cancer 2008;60 Suppl 1:30-5.
9. Uemura T, Yerushalmi HF, Tsaprailis G, et al. Identification and characterization of a diamine exporter in colon epithelial cells. J Biol Chem 2008;283(39):26428-35.
10. Meyskens FL, Jr., McLaren CE, Pelot D, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila Pa) 2008;1(1):32-8.
11. Zell JA, McLaren CE, Chen WP, Thompson PA, Gerner EW, Meyskens FL. Ornithine Decarboxylase-1 Polymorphism, Chemoprevention With Eflornithine and Sulindac, and Outcomes Among Colorectal Adenoma Patients. J Natl Cancer Inst 2010; epub ahead of print.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL01-04.</jats:p
Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction
No full textThe current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia
Comparison of edoxaban and enoxaparin in a rat model of AlCl3-induced thrombosis of the superior sagittal sinus
No full textCerebral sinus venous thrombosis (CSVT) is an uncommon disease that is usually treated with anticoagulation (heparin, low-molecular heparin, or vitamin K-antagonists). We compared treatment with edoxaban, an oral factor Xa-antagonist, that has not been approved in patients with CSVT, with enoxaparin, a well-established therapy, in a rat model of CSVT. Fifty male Wistar rats were randomized into 5 groups (10 animals each) and subjected to aluminum chloride (AlCl3)-induced thrombosis of the superior sagittal sinus (SSS) or sham procedure. Animals with thrombosis of the SSS were treated with edoxaban, enoxaparin, or placebo. Diagnostic workup included neurological examination, MRI imaging, MR-flow measurements of the SSS, and immunohistochemical staining. Neurological examination revealed no differences between treatment groups. Seven days after initial thrombosis, flow in the SSS was lower in the active treatment group as compared to sham-operated animals (p 0.05). Immunohistochemical staining showed no differences in the actively treated animals. Edoxaban proved to be similar to enoxaparin in a model of experimental AlCl3-induced CSVT
OPTIMAL CONVEX DOMAINS FOR THE FIRST CURL EIGENVALUE IN DIMENSION THREE
No full textWe prove that there exists a bounded convex domain Ω ⊂ R3 of fixed volume that minimizes the first positive curl eigenvalue among all other bounded convex domains of the same volume. We show that this optimal domain cannot be analytic, and that it cannot be stably convex if it is sufficiently smooth (e.g., of class C1,1). Existence results for uniformly Hölder optimal domains in a box (that is, contained in a fixed bounded domain D ⊂ R3) are also presented. ©2024 American Mathematical Society.The authors are grateful to Rainer Picard for providing them with a copy of
Ref. [26]. Wadim Gerner would like to thank Kristin L¨uke for a concise introduction into the convex optimization of the Dirichlet Laplacian and for pointing
out Ref. [9]. This work has received funding from the European Research Counc
OPTIMAL CONVEX DOMAINS FOR CURL 19
(ERC) under the European Union’s Horizon 2020 research and innovation programme through the grant agreement 862342 (A.E.). It is partially supported by
the grants CEX2019-000904-S, RED2018-102650-T, and PID2019-106715GB GBC21 (D.P.-S.) funded by MCIN/AEI/10.13039/501100011033.Peer reviewe
Clinical efficacy of a novel therapeutic principle, anakoinosis
No full textClassic tumor therapy, consisting of cytotoxic agents and/or targeted therapy, has not overcome therapeutic limitations like poor risk genetic parameters, genetic heterogeneity at different metastatic sites or the problem of undruggable targets. Here we summarize data and trials principally following a completely different treatment concept tackling systems biologic processes: the principle of communicative reprogramming of tumor tissues, i.e., anakoinosis (ancient greek for communication), aims at establishing novel communicative behavior of tumor tissue, the hosting organ and organism via re-modeling gene expression, thus recovering differentiation, and apoptosis competence leading to cancer control - in contrast to an immediate, "poisoning" with maximal tolerable doses of targeted or cytotoxic therapies. Therefore, we introduce the term "Master modulators" for drugs or drug combinations promoting evolutionary processes or regulating homeostatic pathways. These "master modulators" comprise a broad diversity of drugs, characterized by the capacity for reprogramming tumor tissues, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs etc., or for example differentiation inducing therapies. Data on 97 anakoinosis inducing schedules indicate a favorable toxicity profile: The combined administration of master modulators, frequently (with poor or no monoactivity) may even induce continuous complete remission in refractory metastatic neoplasia, irrespectively of the tumor type. That means recessive components of the tumor, successively developing during tumor ontogenesis, are accessible by regulatory active drug combinations in a therapeutically meaningful way. Drug selection is now dependent on situative systems characteristics, to less extent histology dependent. To sum up, anakoinosis represents a new substantive therapy principle besides novel targeted therapies
Immune response to in piglets: local and systemic changes in ‐cell subsets and selected m transcripts in the small intestine
No full textGabner S, Worliczek HL, Witter K, Meyer FRL, Gerner W, Joachim A. Immune response to in piglets: local and systemic changes in ‐cell subsets and selected m transcripts in the small intestine. Parasite Immunology. 2014;36(7):277-291.**Summary**
Infections of neonatal piglets with
C
ystoisospora suis
are responsible for substantial economic losses in pig production. To investigate kinetics of
T
‐cell populations, which are possibly involved in this infection, lymphocytes from blood, spleen, mesenteric lymph nodes and the jejunal mucosa of infected and noninfected piglets were investigated by flow cytometry and immunohistochemistry at five time points during the acute phase of primary infection. Additionally, m
RNA
expression levels of pattern recognition receptors and immunomodulatory cytokines in the jejunum were investigated.
T
‐cell receptor‐γδ
+
T
cells were found to be increased in the gut mucosa 4 days after infection and were most likely involved in the primary local immune response. Five to eleven days later, cytotoxic
T
cells peaked in this location, which was preceded by an expansion of this lymphocyte population in the mesenteric lymph nodes. In intestines of infected piglets, m
RNA
expressions of
TLR
‐2,
NOD
2 and
TNF
‐α were significantly upregulated, suggesting an involvement in parasite recognition, immune response and possibly also in immunopathology. Taken together, this study identifies cellular and molecular players involved in the early immune responses against
C
. suis,
but their precise role in the pathogenesis and control of this neonatal disease requires further investigation.
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Physical properties, transmission and emission spectra of the WASP-19 planetary system from multi-colour photometry
No full textpeer reviewedWe present new ground-based, multi-colour, broad-band photometric measurements of the physical parameters, transmission and emission spectra of the transiting extrasolar planet WASP-19b. The measurements are based on observations of eight transits and four occultations through a Gunn i filter using the 1.54-m Danish Telescope, 14 transits through an R[SUB]c[/SUB] filter at the Perth Exoplanet Survey Telescope (PEST) observatory and one transit observed simultaneously through four optical (Sloan g[SUP]'[/SUP], r[SUP]'[/SUP], i[SUP]'[/SUP], z[SUP]'[/SUP]) and three near-infrared (J, H, K) filters, using the Gamma Ray Burst Optical and Near-Infrared Detector (GROND) instrument on the MPG/ESO 2.2-m telescope. The GROND optical light curves have a point-to-point scatter around the best-fitting model between 0.52 and 0.65 mmag rms. We use these new data to measure refined physical parameters for the system. We find the planet to be more bloated (R[SUB]b[/SUB] = 1.410 ± 0.017R[SUB]Jup[/SUB]; M[SUB]b[/SUB] = 1.139 ± 0.030M[SUB]Jup[/SUB]) and the system to be twice as old as initially thought. We also used published and archived data sets to study the transit timings, which do not depart from a linear ephemeris. We detected an anomaly in the GROND transit light curve which is compatible with a spot on the photosphere of the parent star. The starspot position, size, spot contrast and temperature were established. Using our new and published measurements, we assembled the planet's transmission spectrum over the 370-2350 nm wavelength range and its emission spectrum over the 750-8000 nm range. By comparing these data to theoretical models we investigated the theoretically predicted variation of the apparent radius of WASP-19b as a function of wavelength and studied the composition and thermal structure of its atmosphere. We conclude that: (i) there is no evidence for strong optical absorbers at low pressure, supporting the common idea that the planet's atmosphere lacks a dayside inversion; (ii) the temperature of the planet is not homogenized, because the high warming of its dayside causes the planet to be more efficient in re-radiating than redistributing energy to the night side; (iii) the planet seems to be outside of any current classification scheme
Advancing biological hazards risk assessment
No full textThis paper focusses on biological hazards at the global level and considers the challenges to risk assessment (RA) from a One Health perspective. Two topics – vector-borne diseases (VBD) and antimicrobial resistance (AMR) – are used to illustrate the challenges ahead and to explore the opportunities that new methodologies such as next-generation sequencing can offer. Globalisation brings complexity and introduces drivers for infectious diseases. Cooperation and the application of an integrated RA approach – one that takes into consideration food farming and production systems including social and environmental factors – are recommended. Also needed are methodologies to identify emerging risks at a global level and propose prevention strategies. AMR is one of the biggest threats to human health in the infectious disease environment. Whereas new genomic typing techniques such as whole genome sequencing (WGS) provide further insights into the mechanisms of spread of resistance, the role of the environment is not fully elucidated, nor is the role of plants as potential vehicles for spread of resistance. Historical trends and recent experience indicate that (re)-emergence and/or further spread of VBD within the EU is a matter of when rather than if. Standardised and validated vector monitoring programs are required to be implemented at an international level for continuous surveillance and assessment of potential threats. There are benefits to using WGS – such as a quicker and better response to outbreaks and additional evidence for source attribution. However, significant challenges need to be addressed, including method standardisation and validation to fully realise these benefits; barriers to data sharing; and establishing epidemiological capacity for cluster triage and response
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