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Hafnium oxide films were deposited on Si (100) substrates using metal-organic chemical vapor deposition (MOCVD) and evaluated for gate dielectric applications. For this study, two types of precursors were tested: an oxygenated one, Hf butoxide-mmp, and an oxygen-free one, Hf diethyl-amide. Depositions were carried out in the temperature range of 350–650°C. However, the discussion is focused on amorphous films. The films were compared on the basis of growth rate, phase development, density, interface characteristics, and electrical properties. A similar amorphous to polycrystalline phase transition temperature was found for both precursors. For low deposition temperatures the growth rate for the amide precursor was significantly higher than for the butoxide-mmp precursor and films prepared with the amide precursor contained a lower carbon impurity content than with the butoxide-mmp one. The dielectric constant was slightly higher for amorphous HfO2 deposited from the amide precursor than for the butoxide-m...

IFNs are a family of cytokines with pleiotropic biological effects mediated by scores of responsive genes. IFNs were the first human proteins to be effective in cancer therapy and were among the first recombinant DNA products to be used clinically. Both quality and quantity of life has been improved in response to IFNs in various malignancies. Despite its beneficial effects, unraveling the mechanisms of the anti-tumor effects of IFN has proven to be a complex task. IFNs may mediate anti-tumor effects either indirectly by modulating immunomodulatory and anti-angiogenic responses or by directly affecting proliferation or cellular differentiation of tumor cells. Both direct or indirect effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). In addition to the ISGs implicated in anti-viral, anti-angiogenic, immunomodulatory and cell cycle inhibitory effects, oligonucleotide microarray studies have identified ISGs with apoptotic functions. These include TNF-alpha related apoptosis inducing ligand (TRAIL/Apo2L), Fas/FasL, XIAP associated factor-1 (XAF-1), caspase-4, caspase-8, dsRNA activated protein kinase (PKR), 2'5'A oligoadenylate synthetase (OAS), death activating protein kinases (DAP kinase), phospholipid scramblase, galectin 9, IFN regulatory factors (IRFs), promyelocytic leukemia gene (PML) and regulators of IFN induced death (RIDs). In vitro IFN-alpha, IFN-beta and IFN-gamma induced apoptosis in multiple cell lines of varied histologies. This review will emphasize possible mechanisms and the role of ISGs involved in mediating apoptotic function of IFNs.

High degree of ordering was observed in the SrTiO 3 , Ba 0.1 Sr 0.9 TiO 3 and BaTiO 3 thin films grown by injection metal-organic chemical vapour deposition on sapphire substrates. Orientation of the Al 2 O 3 substrates was (0 0 1) perpendicular to the surface; orientation of the films was (1 1 1). Atomic ordering at the interface between the substrates and the films approached locally heteroepitaxial growth. Two distinct in-plane orientations of the films were observed. The projection of the [1 0 0] direction in the cubic or cubic-like films was rotated either +30 or −30° with respect to the [1 0 0] crystallographic direction of the substrate. Still, a slight disorientation of the films from the dominant directions was observed. The in-plane disorientation of the films increased with increasing barium contents. In SrTiO 3 , the in-plane disorientation of crystallites was 1.5°, in BaTiO 3 3.2°. The residual stress analysis has shown that the films grew without residual stress at the deposition temperature (800 °C). Consequently, the interface layer between films and substrates was very strained but able to pass the in-plane orientation of the substrate to the film.

Interferons (IFNs), pleiotropic cytokines that regulate antiviral, antitumor, apoptotic, and cellular immune responses, were the first endogenous antiangiogenic regulators identified. In a species-specific manner, IFNs inhibit secretion of such angiogenic factors as basic fibroblast growth factor from tumor cells. The antiangiogenic activity of IFNs is enhanced when they are combined with other antiangiogenic agents, such as tamoxifen and thalidomide.

Cancer cell resistance limits the efficacy of IFNs. In this study, we show that sodium stibogluconate (SSG) and IFN-α synergized to overcome IFN-α resistance in various human cancer cell lines in culture and eradicated IFN-α-refractory WM9 human melanoma tumors in nude mice with no obvious toxicity. SSG enhanced IFN-α-induced Stat1 tyrosine phosphorylation, inactivated intracellular SHP-1 and SHP-2 that negatively regulate IFN signaling, and induced cellular protein tyrosine phosphorylation in cancer cell lines. These effects are consistent with inactivation of phosphatases as the basis of SSG anticancer activity. Characterization of SSG by chromatography revealed that only selective compounds in SSG were effective protein tyrosine phosphatase inhibitors. These observations suggest the potential of SSG as a clinically usable protein tyrosine phosphatase inhibitor in cancer treatment and provide insights for developing phosphatase-targeted therapeutics.

Background The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin (Cbl; vitamin B12), an essential micronutrient. Tumors often require more Cbl than normal tissue, and increased Cbl uptake may result from increased TC II-R expression. To examine whether Cbl could therefore be used as a carrier molecule to target a chemotherapy drug, we tested an analogue of Cbl with nitric oxide as a ligand, nitrosylcobalamin (NO-Cbl). Because interferon beta (IFN-beta) has antitumor effects and increases expression of some membrane receptors, we examined whether it may enhance the effects of NO-Cbl. Methods Antiproliferative effects of NO-Cbl were assessed in 24 normal and cancer cell lines. Xenograft tumors of human ovarian cancer NIH-OVCAR-3 cells were established in athymic nude mice, and tumor growth was monitored after treatment with NO-Cbl and IFN-beta, both individually and concomitantly. TC II-R expression and apoptosis was monitored in vitro and in vivo. RNA protection assays and mitochondrial membrane potential assays were used to distinguish the extrinsic and intrinsic apoptotic pathways, respectively. Results Cancer cell lines were more sensitive to NO-Cbl (with ID(50)s [the dose that inhibits growth by 50%] as low as 2 microM) than normal cell lines (with ID(50)s of 85-135 microM). Single-agent NO-Cbl and IFN-beta treatment of NIH-OVCAR-3 xenografts induced tumor regression, whereas combination treatment induced tumor eradication. IFN-beta treatment increased TC II-R expression in vitro and uptake of [(57)Co]cobalamin in vivo. Compared with NIH-OVCAR-3 cells treated with NO-Cbl, cells treated with NO-Cbl and IFN-beta were more apoptotic and expressed higher mRNA levels of various apoptosis-associated genes. No changes in mitochondrial membrane potential were observed in cells treated with NO-Cbl. Conclusion NO-Cbl inhibited tumor growth in vivo by activating the extrinsic apoptotic pathway. The increased expression of TC II-R induced by IFN-beta resulted in enhanced antitumor effects with NO-Cbl both in vitro and in vivo.

Objectives : To compare triathletes with exercise dependence and/or eating disorders on their metamotivational characteristics using the framework of Reversal Theory. Design : Participants were classified according to their scores on an eating disorder and an exercise dependence questionnaire into a primary, a secondary, an eating disorder, and a no dependence or disorder group. These groups were contrasted on measures derived from the Motivational Style Profile [(1998) Personal. Indiv. Diff. , 24 , 7]. Method : Triathletes ( n =171) completed instruments at competitive events in either Hong Kong or Switzerland. MANOVA and follow-up ANOVA were applied to measures of dominances and saliences. Results : There were significant differences in dominances and saliences between the exercise dependent and other groups, while the secondary group was significantly more telic dominant than the primary group. The eating disordered groups were significantly more mastery dominant than the no dependence group. There was a significant group by status interaction effect. Conclusions : The four groups were associated with different psychological profiles, but this association was moderated by the triathletes' status as professional or amateur. The appropriateness of the commonly used terms ‘primary’ and ‘secondary’ with regard to exercise dependence is questioned.

The interferon (IFN)-β and all-trans-retinoic acid combination suppresses tumor growth by inducing apoptosis in several tumor cell lines. A genetic technique permitted the isolation of human thioredoxin reductase (TR) as a critical regulator of IFN/all-trans-retinoic acid-induced cell death. Our recent studies have shown that TR1:thioredoxin 1-regulated cell death is effected in part through the activation of p53-dependent responses. To understand its death regulatory function, we have performed a mutational analysis of TR. Human TR1 has three major structural domains, the FAD binding domain, the NADPH binding domain, and an interface domain (ID). Here, we show that the deletion of the C-terminal interface domain results in a constitutive activation of TR-dependent death responses and promotes p53-dependent gene expression. TR mutant without the ID still retains its dependence on thioredoxin for promoting these responses. Thus, our data suggest that TR-ID acts as a regulatory domain.

This study examined the relationship between academic performance and physical activity participation using objective measures of scholastic achievement, and the effect of banding (academic tracking). The sample comprised 1,447 students (aged 13–17 years) in secondary grades 2, 4, and 6 (736 boys; 711 girls). Academic records were collected from the schools, and a participation questionnaire was administered to the students. School banding was found to be a significant predictor of participation time, and students from higher-banded schools had generally greater participation time than lower-band students. Conversely, perceived academic performance and potential tended to be higher for students with more participation time in physical activity, particularly so for the males. However, for actual academic grades this positive association was not found when banding was taken into consideration. No relationship was found for the middle- and high-band students, while a slight negative relationship was observed for the low-band students.

In the silicon industry new materials and particularly, their deposition methods have become a fundamental integral part to enable next generations of highly integrated devices. Especially in the field of volatile and non-volatile memory applications as well as in integrated capacitor devices for high-frequency applications existing technologies generate an increasing demand for new advanced innovative solutions to further follow “Moore's law” in the near future. Amongst available film growth technologies, metal organic chemical vapor deposition (MOCVD) basically offers unique combination of composition controllability, high uniformity over large areas, high throughput, and last but not least a high degree of conformality over 3D structures. However, MOCVD of complex materials was in the past often confronted with an absence of appropriate metal organic precursors and MOCVD-tools. This work provides an overview of some of the latest achievements in the field of MOCVD of complex oxides and electrode materials using novel MOCVD deposition methods and tools. It proves that there now exist mature deposition methods with the high degree of reliability and reproducibility mandatory for production.

Triathletes ( N = 203) completed both the Exercise Dependence Questionnaire (EDQ) and the Eating Attitudes Test (EAT). Cluster and discriminant analysis showed that there were four distinct groups. Two out of the four groups showed high EDQ scores with one of these groups displaying an additional eating disorder. The members of the third group only had a high EAT score and the last group showed low scores on both inventories. These four dependence groups differed significantly in a number of descriptive variables, but there were few differences between the primary and secondary exercise dependent groups. It was concluded that the existence of primary exercise dependence was demonstrated, but that there was little distinction between it and secondary dependence for the variables examined.

The nonamethylene bridge of the title compound shows high conformational mobility and an asymmetric structure in the crystal. Molecular mechanics (MM+) calculations reproduced well the crystal structure, which has the lowest energy conformation.

To investigate the function of mGBP-2, a member of the interferon (IFN)-induced guanylate-binding protein family of GTPases, NIH 3T3 fibroblasts were generated that constitutively expressed mGBP-2. mGBP-2 induced a faster growth rate, with the highest expressing clones showing approximately a 50% reduction in doubling time. mGBP-2-expressing cells also grew to higher density and exhibited partial loss of contact growth inhibition, as evidenced by the formation of foci in post-confluent cultures. In addition, mGBP-2-expressing cells showed decreased dependence on serum-derived growth factors. However, they did not lose the requirement for anchorage-dependent growth. Finally, NIH 3T3 cells expressing mGBP-2 formed tumors in athymic mice. An mGBP-2 protein carrying a point mutation (S52N) that reduced GTP binding failed to produce these phenotypes when expressed at the same levels as wild type. The additional finding that IFN-γ treatment of NIH 3T3 cells resulted in an increase in proliferation similar to that observed for mGBP-2 in the absence of other IFN-induced proteins suggests that mGBP-2 may indeed be important for these growth changes.

Platinum (Pt), ruthenium (Ru), and ruthenium dioxide (RuO 2 ) have been considered as possible candidates as electrodes for high permittivity and ferroelectric oxides. The films were grown by metal organic chemical vapor deposition (MOCVD). High purity Pt films with near bulk resistivities (11 w z cm) were deposited. The Pt, Ru and RuO 2 films were found to be continuous and smooth and exhibited excellent adhesion properties on the underlying substrates. The temperature dependent electrical conductivity of the Ru and RuO 2 films was metallic type. Room temperature resistivities as low as 18 and 30 w z cm were determined for Ru and RuO 2 , respectively.

Intratumoral Prostate cancer (PCa) heterogeneity is characterized by multiple intrinsic mechanisms including Androgen signaling, aerobic glycolysis, aberrant transcriptional activation of c-Myc and dysregulation of miRNAs. The ability of prostate cancer cells to alter growth and metabolism in a manner distinct from benign cells is a major concern in the treatment of castration-resistant prostate cancer. Therefore, targeting the diverse oncogenesis promoting pathways involved in PCa progression and resistance at the posttranscriptional level using micro RNAs (miRNAs) offers a novel therapeutic option. Using a miRNA mimic screen, we identified a human-specific miRNA miR-644a, which modulates expression of a diverse set of oncogenic pathways in PCa including androgen signaling, AKT/IGF-1R signaling, c-myc mediated signaling and EMT pathways. We have also demonstrated a potent tumor suppressive function of miR-644a in mouse prostate cancer xenograft model. miR-644a also sensitizes the PCa tumors to current therapeutic options including AR antagonist Enzalutamide by regulating the key modulators in development of drug resistance. In conclusion, our study demonstrates that miR-644a is a novel tumor suppressor miRNA regulating key prostate carcinogenesis promoting pathways. Citation Format: Jey Sabith Ebron, Jagjit Singh, Eswar Shankar, Crystal Weyman, Sanjay Gupta, Daniel J. Lindner, Girish C. Shukla. Fine-tuning the expression of heterogeneous network of genes involved in androgen signaling, aerobic glycolysis, apoptosis and epithelial-mesenchymal transition by microRNA-644a in prostate cancer potentiation of AR signaling therapy by miR-644a: Selective manipulation of the prostate cancer transcriptome by miR-644a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1470. doi:10.1158/1538-7445.AM2017-1470

Clear cell renal cell cancers (RCC) universally inactivate PBRM1 (single allele deletion 100%, bi-allelic deletion/mutation ~40%), however, the mechanisms by which PBRM1 loss contributes to RCC-genesis are unknown. Of ~4000 genes consistently less expressed in RCC than normal renal cortex, >30% were kidney differentiation genes by gene ontology analysis, e.g., 394 (~10%) suppressed genes had specialized renal epithelial functions of cation transport, cell adhesion and excretion (TCGA). Suppression of hundreds of epithelial-differentiation genes suggested disruption to the core transcription factor circuit (protein network hub) activating this program. This master transcription factor hub contains PAX2, PAX8, GATA3 and LHX1, shown by murine knock-outs and human pedigrees with renal defects, and confirmed by our protein interactome studies. Of these master transcription factors, PAX2 and PAX8 expression was preserved in RCC compared to normal kidney, but downstream GATA3 and LHX1 expression was markedly decreased (2 to 4-fold) even though PAX8 localized at these target genes by chromatin immunoprecipitation - this suggested compromised PAX8 transcription activating function. PAX8 protein interactome in RCC cells indicated that PBRM1 is a PAX8 coactivator, and introduction of PBRM1 into PBRM1-haploinsufficient RCC cells (ACHN) by transfection increased activation of GATA3, WT1 and HNF4A, decreased MYC protein, increased p27/CDKN1B protein that mediates cell cycle exits by terminal differentiation, produced morphological changes of epithelial differentiation, and decreased proliferation. Coactivator versus corepressor recruitment by master transcription factors is a dynamic interchange, and the protein interactome studies indicated PBRM1 loss unbalanced stoichiometry of the PAX8-associated protein hub towards corepressors including DNMT1. Depletion of DNMT1 by non-cytotoxic concentrations of decitabine (0.5 µM) produced a remarkable shift from corepressors to coactivators in the PAX8 protein interactome, accompanied by terminal epithelial-differentiation as observed with PBRM1 reintroduction. Cell cycle exits by differentiation do not require p53/p16, and this effect was also produced in vivo in a subcutaneous xenograft model of TP53-mutated refractory/relapsed RCC, especially when decitabine in vivo pharmacology was optimized for non-cytotoxic DNMT1-depletion by avoiding a high Cmax and increasing its half-life and distribution into solid tissue, by administration of low dose in combination with an inhibitor of the enzyme cytidine deaminase that degrades decitabine. PBRM1 loss in RCC thus alters composition of a master transcription factor hub to repress instead of activate terminal epithelial-differentiation, an effect that can be reversed pharmacologically for novel, p53/p16-independent differentiation-restoring therapy. Citation Format: Xiaorong Gu, Francis Enane, Reda Mahfouz, Tomas Radivoyevitch, Bartlomiej Przychodzen, Yvonne Parker, Daniel Lindner, Brian Rini, Yogen Saunthararajah. PBRM1 inactivation in renal cell cancer alters master transcription factor hub composition to repress instead of activate epithelial-differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3520. doi:10.1158/1538-7445.AM2017-3520

Prostate cancer growth and proliferation depends on androgen signaling mediated by transactivation of Androgen Receptor (AR). Androgen ablation remains the mainstay therapy for treatment of the disease. However, despite androgen ablation, the disease relapses to more aggressive form known as castration-resistant prostate cancer (CRPC). Androgen Signaling Inhibitor such as Abiraterone Acetate and Enzalutamide are the most effective treatment methods currently being used to treat CRPC. However, more than one-third of CRPC patients develop resistance to these treatments, mostly due to the gain of function in the AR protein and increase in intratumoral dihydrotestosterone (DHT) synthesis. Intratumoral DHT synthesis from steroid precursors in tumors is augmented by up-regulation of enzymes of cholestrogenesis and steroidogenesis, such as HMG-CoA reductase, SCARB1, and 17βHSD respectively. Tumor-specific downregulation of microRNAs which regulate the AR and steroid biosynthesis has been implicated in tumor growth and resistance to therapeutics in CRPC. We are focusing on tumor suppressive role of miR-149-5p in PCa. We discovered that miR-149-5p expression was significantly lower in prostate cancer tissues compared to normal tissues. The mechanistic investigation revealed that miR-149-5p downregulates wild type and alternatively spliced variant of AR. It also down regulates the expression of SCARB1, HMGCS and HMG-CoA reductase, the proteins known to facilitate intratumoral DHT synthesis. Ectopic expression of miR-149-5p negatively regulated the expression of prostate-specific antigen, a downstream target of androgen signaling and it also inhibited invasion and proliferation of CRPC cells. Our findings indicate a significant role of miR-149-5p in regulating androgen signaling and possibly DHT synthesis in CRPC. This provides a strong rationale for further investigating the significance of miR-149-5p for generation of new therapeutic for CRPC. Citation Format: Savita Singh, Jey Sabith Ebron, Eswar Shankar, Sanjay Gupta, Daniel Lindner, Girish Shukla. Regulation of androgen signaling axis and tumor suppressive function of miR-149-5p in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2531. doi:10.1158/1538-7445.AM2017-2531

We describe the results of a survey of claim forms that are used when starting rehabilitation following inpatient treatment and of an evaluation of a claim form developed on the basis of the results. The survey of different existing forms shows a high overlapping in content, suggesting the possibility of unification to one claim form that can be accepted by all insurers. In analogy to the Delphi method criteria for evaluation were consented and applied by the author group to assess the relevance of the claim forms content items for the process of initiating rehabilitation. A group of further experts added their evaluations. We prioritised the results and extracted the essential contents to conceive a unified claim form eligible for all types of rehabilitation. The claim form was discussed in 3 focus groups, revised accordingly and tested in the Hannover Medical School. Test results show that all relevant information is asked for and that the form is well manageable. The users' request for an IT-based solution and further ideas for improvement were integrated into the revised and validated version of the claim form. It is now available for all stake holders, in particular for insurers, as a means to improve quality of care and efficiency by standardisation of rehabilitation claim forms.

Physicians routinely prescribe short-acting inhalers for asthmatic patients and also strive to help patients understand the necessity of carrying their inhalers at all times as a measure against asthmatic episodes. However, the actual rate of compliance among patients remains unclear. In order to gain a better understanding of adult inhaler compliance, this study utilized a questionnaire in which asthmatic patients in an allergy practice answered questions pertaining to their inhaler usage. For instance, while some queries addressed the patient's age and gender, others asked about the inhaler carrying rate, and severity of asthma. As a result of the study and subsequent statistical analysis, a few interesting findings were concluded: women were much more likely to carry an inhaler with them than men (61% vs 30%, P0.0001), the severity of asthma directly correlated to an increase in patient inhaler compliance, and a large percentage of patients indicated that they did not feel the need to carry their inhalers even though their physician had specified otherwise. The results of this study bear implications for patient education regarding inhaler usage and can serve to guide manufacturers in the development of better delivery systems for short-acting bronchodilators.

The contributions of murine models to elucidation of processes central to tumor growth are reviewed. Localized acidosis, increased interstitial pressure, perturbations in structure and function of the extracellular matrix, hypoxia, angiogenesis, and co-optation of the immune response are all phenomena that promote tumor survival and metastasis. The use of animal models is critical to understanding the pathophysiology of these processes and the development of more effective cancer therapies.

PSA � 25%, PSMA � 18%, and hK2 � 33%. In the sipuleucel-T arm of IMPACT, IgG response against PSA was positively correlated with improved OS (HR¼0.41; 95% CI, 0.22e0.78; p 33 months) in pts with IgG response to PSA (n¼35), compared to 22 months in pts with no IgG response to PSA (n¼105), and 21.4 months for the control group. IgG responses to PSMA and hK2 were not correlated with OS. CONCLUSIONS: The immune response to sipuleucel-T adapts over time through antigen spreading to target multiple prostate antigens. Sipuleucel-T-induced IgG responses against PSA were predictive of OS and may be a potential biomarker of treatment benefit. These data may identify pharmacodynamic biomarkers of clinical outcome after treatment with sipuleucel-T. Source of Funding: Dendreon Corporation

The FERM domain containing protein Kindlin-3 has been recognized as a major regulator of integrin function in hematopoietic cells, but its role in neoplasia is totally unknown. We have examined the relationship between Kindlin-3 and breast cancer in mouse models and human tissues. Human breast tumors showed a ∼7-fold elevation in Kindlin-3 mRNA compared with nonneoplastic tissue by quantitative polymerase chain reaction. Kindlin-3 overexpression in a breast cancer cell line increased primary tumor growth and lung metastasis by 2.5- and 3-fold, respectively, when implanted into mice compared with cells expressing vector alone. Mechanistically, the Kindlin-3-overexpressing cells displayed a 2.2-fold increase in vascular endothelial growth factor (VEGF) secretion and enhanced β1 integrin activation. Increased VEGF secretion resulted from enhanced production of Twist, a transcription factor that promotes tumor angiogenesis. Knockdown of Twist diminished VEGF production, and knockdown of β1 integrins diminished Twist and VEGF production by Kindlin-3-overexpressing cells, while nontargeting small interfering RNA had no effect on expression of these gene products. Thus, Kindlin-3 influences breast cancer progression by influencing the crosstalk between β1 integrins and Twist to increase VEGF production. This signaling cascade enhances breast cancer cell invasion and tumor angiogenesis and metastasis.—Sossey-Alaoui, K., Pluskota, E., Davuluri, G., Bialkowska, K., Das, M., Szpak, D., Lindner, D. J., Downs-Kelly, E., Thompson, C. L., Plow, E. F. Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis.

Magnetic Resonance in the frequency domain provides a tool to investigate and quantitatively measure many important magnetic key parameters, such like the effective magnetization, magnetic anisotropies, magnetic damping parameters or coupling field strengths. Although it has been widely employed for studying magnetic bulk and thin film samples, the sensitivity of this classical method often suffers from being too low when single nanostructures are of interest. This review discusses Magnetic Resonance as technique, providing an introduction also to non-experts in the field. The theoretical background is discussed on an ‘easy to read’ basis, followed by a brief summary of methods that are capable of investigation spin dynamics within single nanostructures (nearfield microscopy, Brillouin Light Scattering, time-resolved Magneto-optical Kerr-effect). Focusing on frequency-domain approaches we then give a detailed explanation of what we call conventional way of experimentally detecting Magnetic Resonance which is based on the use of microwave cavities. This serves a basis to discuss different approaches to enhance sensitivity within a frequency-domain Magnetic Resonance experiment. As shown this includes either improving the conventional setup itself (microresonators) or using alternative detection routes, such as optical or electrical detection.

Das aus dem pentafulvenoiden Allen 1 leicht zugängliche, kinetisch stabilisierte 1,1′-Diethinylferrocen lässt sich durch oxidative Kupplung in das [4.4]Ferrocenophan 2 überführen. Diese Verbindung hat eine bemerkenswert symmetrische Struktur, die Elektronen sind über die Butadiinbrücken hinweg delokalisiert, und im Kristall liegt 2 in einer helical-chiralen Konformation vor.

Building butadiyne bridges: The kinetically stabilized 1,1′-diethynylferrocene, readily prepared from the pentafulvenoid allene 1, can be transformed into the [4.4]ferrocenophane 2 by oxidative coupling. This compound exhibits a remarkably symmetrical structure in which the electrons are delocalized through the butadiyne bridges; in the crystalline state 2 exists in a helical-chiral conformation.

We have prepared RuO 2 layers by metal organic chemical vapour deposition using liquid delivery source and by thermal evaporation of powder precursors. The films were prepared on silicon and r-plane cut sapphire substrates. We discuss thermodynamics of both types of MOCVD techniques. Liquid delivery source technique using diglyme solvent results in deposition of metallic Ru film with some traces of RuO 2 , while films prepared by thermal evaporation of powder precursors consist of pure RuO 2 phase. Thermal evaporation MOCVD grown RuO 2 films exhibit excellent electrical properties; room temperature resistivity of 30 μΩcm and residual resistivity ratio between 8 and 30.

Interferons (IFNs) and retinoids are potent tumor growth suppressors. We have shown earlier that the IFN-beta and all-trans retinoic acid combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic approach we have recently identified several Genes associated with Retinoid-IFN induced Mortality (GRIM) that mediate the cell death effect of IFN/RA combination. One of the GRIMs, GRIM-12, was identical to human thioredoxin reductase (TR), an enzyme that controls intracellular redox state. To define the participants of TR mediated death pathway we have examined the role of thioredoxin (Trx), its downstream substrate, and its influence on IFN/RA-induced death regulation. Inhibition of the thioredoxin expression by antisense RNA suppressed cell death. Similarly, a mutant Trx1 lacking the critical cysteine residues blocked cell death. In contrast, overexpression of wildtype thioredoxin augmented cell death. This effect of Trx1 was in part due to its ability to augment cell death via caspase-8. The redox inactive Trx1 mutant inhibits the cell death induced by caspase-8 but not caspase-3. These studies identify a novel mechanism of cell death regulation by IFN/RA combination involving redox enzymes.

The hypothesis of a relationship among metamotivational dominances as assessed by dominance scales, life metamotivational orientations (LifeMOs) and more specific metamotivational orientations towards sport and physical activity participation (SportMOs), derived from questionnaire responses, was tested using the framework of Reversal Theory. Regression analyses showed that participation motivation was weakly but reliably predictable from metamotivational dominances in a large sample of Hong Kong school children and youth (N=2346), and that SportMOs were similarly predictable from LifeMOs and dominances in a sample of Hong Kong university entrants (N=3162). These findings are interpreted as supportive of Reversal Theory, which would anticipate low, but statistically significant relationships on the basis that motivation for behavior, in this case sport participation, is believed to be influenced by a complex interaction of situational variables, metamotivational states, metamotivational dominances and metamotivational orientations. The findings provide a better understanding of the relationships between the motivational factors that influence sport participation.

We treated 58 patients with osteoid osteoma by CT-guided radiofrequency ablation (RF). In 16 it followed one or two unsuccessful open procedures. It was performed under general anaesthesia in 48, and spinal anaesthesia in ten. The nidus was first located by thin-cut CT (2 to 3 mm) sections. In hard bony areas a 2 mm coaxial drill system was applied. In softer areas an 11-gauge Jamshidi needle was inserted to allow the passage of a 1 mm RF probe into the centre of the nidus. RF ablation was administered at 90°C for a period of four to five minutes. Three patients had recurrence of pain three, five and seven months after treatment, respectively, and a second percutaneous procedure was successful. Thus, the primary rate of success for all patients was 95% and the secondary rate was 100%. One minor complication was encountered. CT-guided RF ablation is a safe, simple and effective method of treatment for osteoid osteoma.

Autophagy is a degradation process for the turnover of damaged organelles and long-lived proteins that also plays an important role during erythropoiesis. Accordingly, knockout of the essential autophagy gene Atg7 in mice leads to clinico-morphologic features of MDS. To date, no study has determined the prevalence and impact of defects (mutations, aberrant expression) in the autophagy machinery in MDS. We interrogated the occurrence of alterations in 180 autophagy genes by analyzing WES of patients with MDS (N=120). For comparison, we analyzed results from other hematologic neoplasms (N=103) and TCGA (N=202). We detected somatic mutations in autophagy genes in 40/425 patients (9%). Mutations were enriched in MDS (12%;14/120) and prevalent in higher risk MDS patients (30%;12/40). Mutations were found in: ATG2A, ATG4C, ATG14, ATG16L1, BCL2, CDKN2AIPNL, COG8, DNM1L, DNM2, GYS1, HIF1A, KIF1B, LAMP2, MLST8, MTOR, NOD2, PIK3CB, PIK3C2A/B, PIK3C2G, PPP2R2A/B, PPP2R3A, PRKAA1/2, PRKACB, PRKAG1/G2, PTPN2, RICTOR, RPTOR, SEC22B, SMURF1, SQSTM1, STAT3, SUPT20H, TAB2, TNFSF10/13B, ULK4, USP10, VPS11/33B, VTI1A, WDFY3/4, WAC. Twenty-five mutations had a cut-off >20% VAF. Most patients (31/40;78%) had a sole mutation, 4 patients carried 2 mutations each (ULK4, WDFY3), (KIF1B, SEC22B), (VIT1A, TAB2), (DNM2, WAC). PRKACB mutations were found in 3 patients. NOD2, PTPN2, PRKAG1, SEC22B, ULK4, VPS11 and WAC mutations were found in 2 patients. inces autophagy genes has been Loss of function mutations were observed in ULK4, NOD2 and WAC. Four genes mapped to commonly deleted regions e.g., 5q (CDKN2AIPNL, SQSTM1) or 7q (SMURF1, PRKAG2) and coincided with haploinsufficient expression, while 3 genes had hemizygous configuration (SMURF1, PPP2R3A, PIK3C2G). Reactome analysis clustered the mutations in effectors/inhibitors and early stage. The analysis of 263,973 germline variants detected that PIK3C2G, NOD2 and HIF1A were also associated with exonic germline variants predicted to be significantly deleterious. Mutations or aberrant expression of core components of the autophagy network have been associated with poor outcomes in multiple diseases. In our cohort, 21 patients died. Most (57%;21/37) of patients had abnormal karyotype with 4 patients having complex karyotype including -17 and -7. Among the cases with abnormal karyotype, 4 cases had del(5q). Mutant patients had worse survival trending toward significance compared to WT patients (MUTvs. WT=20 vs. 90; median 14 vs. 20 months; LogR=.09). Among disease groups, autophagy mutations were associated with significantly inferior survival in MDS (MUT vs. WT=13 vs. 61; 17 vs. 35 months; LogR=.018) and MDS/MPN (MUT vs. WT=4 vs. 31; 12 vs. 30 months; LogR=.037). Seven mutant patients who received hypomethylating agents had no response. Comparative analyses (Sanger, TruSeq, WES, TCGA) identified that autophagy gene mutations were significantly associated with TET2 (28%;11/40; P=.02) among other mutations [RUNX1, STAG2 (20%;8/40), SRSF2 (18%;7/40), DNMT3A, ASXL1 (15%;6/40)]. Clonal hierarchy showed that autophagy gene mutations were mainly secondary events, were ancestral events in 7 (ATG2A, DNML1, PRKACB, PRKAG1, PTPN2, SEC22B, STAT3) and co-dominant in 2 patients (NOD2, MLST8). When autophagy genes mutations were secondary, the most represented ancestral mutationswere in splicing factors (N=9; SRSF2, PRPF8, U2AF1) and DNA methylation (N=4; TET2, DNMT3A). RNA sequencing determined that changes in autophagy gene expression are overrepresented in specific MDS subtypes with distinct mutational profiles. The expression levels of 2 ULK family members commonly elevated during erythroid maturation were found in SF3B1K700E compared to SF3B1WT MDS patients (N=6; ULK1, FC=2; ULK3, FC=4; P=.05). Erythroid cells of these SF3B1K700E patients showed increased autophagosomes compared to SF3B1WT cells. In vivo administration of the mTOR inhibitor, temsirolimus (10 mg/kg i.p. 5d/week for 2 wk) improved the erythropoiesis of a transgenic Sf3b1 mouse model by increasing CD71+ cells (10-20% vs. 5%) and ameliorating anemia (Hgb: 7.9 vs. 6.6 g/dL; P=.07; MCV: 43.5 vs. 42.4 fL; P=.08). In sum, defects in autophagy genes are present in MDS, co-occur with other mutations and impact survival. Changes in expression levels of autophagy genes may be associated with MDS phenotypes and modulated by autophagy inducing drugs as evidenced in models of SF3B1 mutations. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Speakers Bureau. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau.

Autophagy is a conserved mechanism of protein degradation that plays a physiologic role in iron homeostasis. The RARS subtype of MDS is characterized by inefficient erythropoiesis and the presence of erythroblasts with iron-laden mitochondria (ring sideroblasts, RS). Patients with RARS exhibit an accumulation of iron due to the inability of their erythroid precursors to properly process iron intended for hemoglobin synthesis. RARS erythroid cells display increased autophagy compared to cells from healthy subjects and mice lacking the essential autophagy genes Atg1 and Atg7 develop progressive anemia due to the inefficient removal of defective mitochondria. We previously showed that the presence of SF3B1 mutations, which are frequent in RARS patients, are associated with the presence of increased mitochondrial iron content and low levels of apoptosis. This finding suggests that cell death-independent mechanisms may temper excess iron by triggering the clearance of mitochondria during erythroid maturation. RNA sequencing analyses have shown that the autophagy pathway is upregulated in SF3B1MUT cells. We investigated the role of mitochondrial autophagy in the alleviation of iron-related damage in RARS erythroid cells and the potential therapeutic benefit of autophagy-stimulating agents for the selective improvement of erythropoiesis and iron homeostasis in SF3B1MUT RARS cells. Transmission electron microscopy (TEM) demonstrated an accumulation of iron in the mitochondria of SF3B1MUT (K700E, n=4) compared to SF3B1WT RARS erythroblasts. Flow cytometry confirmed increased mitochondrial iron in SF3B1MUT (n=10) compared to SF3B1WT (n=10) RARS cells (82% ± 10 vs. 24% ± 5; P = 0.004). Autophagic vacuolization of the cytoplasm and an increased number of autophagosomes were found in SF3B1MUT (K700E) compared to SF3B1WT erythroblasts (n=2). The mRNA expression levels of numerous autophagy genes were elevated in SF3B1MUT vs. SF3B1WT RARS cells: ATG complexes (ATG2A/B, FC=2; ATG4A, FC=2; ATG9A, FC=5; ATG4C, P=0.05; ATG18 (FC=4.8; P= 0.02), autophagy-initiating kinases (ULK1, FC=2; ULK3, FC=3.9; P=0.05), and cathepsins involved in late stage autophagy (CTSL1, FC=20; CTSD, FC=5.8; P=0.05; CTSB, FC=2.1; CTSE, FC=5.9; CTSD, FC=2; P=0.01). qRT-PCR confirmed that SF3B1MUT cells expressed elevated mRNA levels of selected genes. We next administered 3 FDA-approved drugs with established autophagy-stimulating properties [temsirolimus, metformin, arsenic trioxide (ATO)] to a transgenic SF3B1 mouse model (SF3B1+/-) that exhibits anemia, dysplasia, and RS (Visconte, J Hematol Oncol 2014) to evaluate drug-mediated improvement of erythropoiesis and autophagic clearance of excess iron. Eight-month-old SF3B1+/- mice (n = 10 per group) were treated with vehicle control and the following: temsirolimus (10 mg/kg i.p. 5d/week for 2 wk), metformin (250 mg/kg/d, gavage for 2 wk), and ATO (10 mg/kg i.p. 5 d/wk for 2 wk). All agents were well tolerated and triggered morphologic features of autophagy including increased autophagosome-like structures by TEM. No effects on BM cellularity and/or dysplasia were noted, although changes in the morphology of myeloid cells (numerous swollen nuclei) were detected by Wright stain. Mitochondria that were engulfed in autophagosomes were frequently seen. After 2 weeks, temsirolimus-treated SF3B1+/- mice showed an incremental increase in hemoglobin by 1.2 g/dL (7.9 vs. 6.6 g/dL; P=0.07) and in mean corpuscular volume (43.5 vs. 42.4 fL; P=0.08). Erythropoiesis was improved as shown by increased levels of CD71-positive cells by immunohistochemistry in cells post-temsirolimus treatment compared to pre-treatment (10-20% vs. 5%). Increased dividing erythroid cells with binucleation and budding were also observed in cells following temsirolimus treatment. These hematologic changes were not detected with ATO or metformin. In sum, our data support a role for activated autophagy in the pathogenesis of RARS and indicate that stimulating autophagy with approved existing drugs or novel investigational drugs may yield therapeutic benefit in SF3B1MUT RARS patients. Disclosures Kelly: Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Speakers Bureau. Advani:Pfizer: Consultancy, Research Funding. Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding, Speakers Bureau.

Interferons (IFNs) regulate the expression of genes that mediate their antiviral, antitumor, and immunomodulatory actions. We have previously shown that IFN-beta suppresses growth of human ovarian carcinoma xenografts in vivo and induces apoptosis of ovarian carcinoma cells in vitro. To investigate mechanisms of IFN-beta-induced apoptosis we employed an antisense technical knockout approach to identify gene products that mediate cell death and have isolated several regulators of interferon-induced death (RIDs). In this investigation, we have characterized one of the RIDs, RID-2. Sequence analysis revealed that RID-2 was identical to human inositol hexakisphosphate kinase 2 (IP6K2). IP6K2 is post-transcriptionally induced by IFN-beta in ovarian carcinoma cells. A mutant IP6K2 with substitutions in the putative inositol phosphate binding domain abrogates IFN-beta-induced apoptosis. These studies identify a novel function for IP6K2 in cell growth regulation and apoptosis.

It was demonstrated by X-ray diffraction analysis that the reaction of 3,3-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyrone with hydroxylamine afforded 5-hydroxyamino-3-(2-hydroxy-1,1-dimethylethyl)-5-trifluoromethyl-Δ2-isoxaline.

MOCVD is a suitable technique for the synthesis of functional metal oxide thin films. In the present paper, injection-MOCVD was proved to be an efficient method, not only to grow single layers, but also heterostructures and superlattices of functional oxide materials. We report on the deposition of BaxSr1−xTiO3 (BST) films and BaTiO3/SrTiO3 superlattices [(BTO/STO)n] obtained by injection MOCVD. In a first step, BST films were deposited on various substrates such as LaAlO3(LAO)(012), SrTiO3:Nb(STO:Nb)(001) and Al2O3(0001), resulting in epitaxial films in the case of STO or LAO substrates and highly textured films in the case of Al2O3 substrates. The good crystallinity of the films obtained was evidenced using X-ray analysis. Concerning the dielectric properties of BST films on STO:Nb, the Tc values were found to be the same as those for bulk materials. In a next step the feasibility of (BTO/STO)n superlattices was studied. The multilayers obtained were epitaxially grown on LAO and STO:Nb substrates. XPS was used to check in detail the pattern repetition of the superlattice and proved the low interface roughness of 1 nm as well as the absence of carbon contamination in the film. The measured periodicity of these superlattices were found to be in good agreement with simulation experiments. Further superlattices have been obtained by combining ferroelectric, magnetic (CMR) and superconducting (HTS) oxides. Typical results of these superlattices will be reported.

BaTiO3 (BTO) and SrTiO3 (STO) and BaxSr1-xTiO3 (x=0–1) (BST) thin films have been epitaxially grown on LaAlO3 and SrTiO3:Nb at a substrate temperature of 800°C using a new liquid source delivery technique called injection MOCVD. A X-ray study evidenced FWHMs of 0.16° and 0.45° for SrTiO3 and BaTiO3 respectively. In a next step the feasibility of BaTiO3/SrTiO3 superlattices was studied. The multilayers obtained were epitaxially grown on LaAlO3 as well as on SrTiO3:Nb. The structural properties were studied using X-ray diffraction as well as XPS, proving the low interface roughness of 1nm. The XPS study also confirmed the absence of carbon contamination in the film.

YBa2Cu3O7-x /BaxSr1-xTiO3 /LaAlO3 heterostructures can be used as a basis for devices with voltage control in microwave circuits. BaxSr1-xTiO3 (x=0–0.1) (BST) thin films have been epitaxially grown on LaAlO3 substrates using injection MOCVD. The excellent crystalline quality of the obtained BST films can be proven by a FWHM of

Objectives: The primary objective of this study was to extend the application of reversal theory for understanding motives for participation or non-participation in sport and physical activity. A secondary objective was to add to previous findings by investigating data from an Asian population. Design: Distributions of different groups of participants and non-participants, including male and female groups, were examined using Chi Square and two-way ANOVA procedures. Methods: New university entrants ( N =3151) responded to a survey questionnaire in which motives for participation or non-participation were phrased in terms of reversal theory's eight metamotivational categories. For group comparison purposes, questionnaire responses were then used to classify respondents according to their primary sport participation or non-participation metamotivational orientation (MO). Frequency of intended future participation, perceived physical ability (PPA) and perceived physical fitness (PPF) among MO groups was also examined. Results: Generally, the telic and alloic MOs were rated most frequently by participants, although some significant gender differences were found. For non-participants, the paratelic , telic, mastery and autic MOs were rated most frequently and significant differences between participants and non-participants were found. Also, both male and female participant MO groups differed significantly in their frequency of intended future participation, PPA and PPF. Conclusions: Reversal theory metamotivational categories were found to provide a useful means of examining motives for sport participation and non-participation.

New BaTiO 3 -SrTiO 3 (BTO-STO)-superlattices which may be interesting for future electronic applications have been investigated by X-ray photoelectron spectroscopy (XPS) depth profiling. At first XPS measuring conditions were optimized for that non-conducting and thin layer systems (21 nm double layer thickness) considering the practical instrumental limitations. Second a simulation of the sputtering process for the concrete experimental conditions were done by a dynamic T-DYN code. By comparison of experimental and simulated depth profiles the maximum sample roughness could be estimated to be in the range of 2 nm.

IFNs were the first new therapeutic products resulting from recombinant DNA technology. IFNs were also the first human proteins effective in cancer treatment. There is however much to be discovered which will lead to new clinical applications. Areas which represent major research challenges for full understanding and application of the IFN system are: (i) the diversity of the IFN family; (ii) the role of induction; (iii) molecular mechanism of action; (iv) cellular modulatory effects; (v) advantages of combinations, and (vi) identification of new therapeutic indications. This review will emphasize the diversity of the IFN family and chemical modifications which will result in second-generation IFNs. Pre-clinical and clinical findings form the basis for new therapeutic directions in chronic myelogenous leukemia, lymphomas, myelomas, melanoma, urologic malignancies, primary brain tumors, and ovarian carcinoma.

MOCVD (metal–organic chemical vapor deposition) of new materials, such as perovskite-type ceramic thin films, will be a major key technology in the field of ULSI non-volatile and volatile memory applications. This article outlines the latest trends in the field of MOCVD equipment and process development, in particular in the field of high k-dielectric and ferroelectrics. Using liquid precursor delivery systems reproducible evaporation can be achieved. Furthermore, perfect temperature control, as well as a precise gas and vapor flow control through the gas inlet to the substrate, ensure high quality BST, PZT and SBT thin films, bearing superior electrical and microstructural properties and near 100% step coverage at low process temperatures. Copyright © 2000 John Wiley & Sons, Ltd.

In three patients with carcinoid liver and/or lymph node metastases, we studied the process of tumor tracer uptake and decarboxylation by means of positron emission tomography (PET) using 5-hydroxy-L-tryptophan (5-HTP) 11C-labeled in the beta-position (HTP) and later the same day with 5-HTP 11C-labeled in the carboxyl group (HTC). With HTP, in which the 11C-label follows the molecule through decarboxylation to form 11C-serotonin, a high tumor accumulation of the tracer was found. With HTC, in which the label is rapidly eliminated from the tissues as 11CO2 if decarboxylation takes place, there was virtually no uptake by the tumors. By utilizing data from PET scanning with both tracers, we could quantify the decarboxylation rate and tissue accumulation of [11C]-serotonin and hence the enzymatic action of aromatic amino acid decarboxylase.