Accurate positioning of long, flexible ARM's (Articulated Robotic Manipulator)

An articulated robotic manipulator (ARM) system is being designed for space applications. Work being done on a concept utilizing an infinitely stiff laser beam for position reference is summarized. The laser beam is projected along the segments of the ARM, and the position is sensed by the beam rider modules (BRM) mounted on the distal ends of the segments. The BRM concept is the heart of the system. It utilizes a combination of lateral displacements and rotational and distance measurement sensors. These determine the relative position of the two ends of the segments with respect to each other in six degrees of freedom. The BRM measurement devices contain microprocessor controlled data acquisition and active positioning components. An indirect adaptive controller is used to accurately control the position of the ARM

The Enantioselective Construction of Tetracyclic Diterpene Skeletons with Friedel-Crafts Alkylation and Palladium-catalyzed Cycloalkenylation Reactions

Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8 + T effector cells and natural killer cells and induces CD4 + T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial, and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance “immunogenic” chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation, and metastasis beyond effects on adaptive immune tolerance. Discovery and development of two small molecule enzyme inhibitors of IDO1 have advanced furthest to date in Phase II/III human trials (epacadostat and navoximod, respectively). Indoximod, a tryptophan mimetic compound with a different mechanism of action in the IDO pathway has also advanced in multiple Phase II trials. Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8 + T effector cells and natural killer cells and induces CD4 + T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial, and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance “immunogenic” chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation, and metastasis beyond effects on adaptive immune tolerance. Discovery and development of two small molecule enzyme inhibitors of IDO1 have advanced furthest to date in Phase II/III human trials (epacadostat and navoximod, respectively). Indoximod, a tryptophan mimetic compound with a different mechanism of action in the IDO pathway has also advanced in multiple Phase II trials. Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer

Can cyberloafing and Internet addiction affect organizational information security?

Researchers have noted potential links between Internet addiction, the use of work computers for non-work purposes and an increased risk of threat to the organisation from breaches in cybersecurity. However, much of this research appears conjectural in nature and lacks clear empirical evidence to support such claims. In order to fill this knowledge gap, a questionnaire-based study explored the link between cyberloafing, Internet addiction, and information security awareness (ISA). A total of 338 participants completed an online questionnaire, which comprised of the Online Cognition Scale (OCS), Cyberloafing scale, and the Human Aspects of Information Security Questionnaire (HAIS-Q). Participants who reported higher Internet addiction and cyberloafing tendencies had lower ISA, and Internet addiction and cyberloafing predicted a significant 45% of the variance in ISA. Serious cyberloafing, such as the propensity to visit adult websites and online gambling, was shown to be the significant predictor for poorer ISA. Implications for organisations and recommendations to reduce or manage inappropriate Internet use are discussed

Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase

Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2

Monitoring a simple hydrolysis process in an organic solid by observing methyl group rotation

We report a variety of experiments and calculations and their interpretations regarding methyl group (CH3) rotation in samples of pure 3-methylglutaric anhydride (1), pure 3-methylglutaric acid (2), and samples where the anhydride is slowly absorbing water from the air and converting to the acid [C6H8O3(1) + H2O → C6H10O4(2)]. The techniques are solid state 1H nuclear magnetic resonance (NMR) spin-lattice relaxation, single-crystal X-ray diffraction, electronic structure calculations in both isolated molecules and in clusters of molecules that mimic the crystal structure, field emission scanning electron microscopy, differential scanning calorimetry, and high resolution 1H NMR spectroscopy. The solid state 1H spin-lattice relaxation experiments allow us to observe the temperature dependence of the parameters that characterize methyl group rotation in both compounds and in mixtures of the two compounds. In the mixtures, both types of methyl groups (that is, molecules of 1 and 2) can be observed independently and simultaneously at low temperatures because the solid state 1H spin-lattice relaxation is appropriately described by a double exponential. We have followed the conversion 1 → 2 over periods of two years. The solid state 1H spin-lattice relaxation experiments in pure samples of 1 and 2 indicate that there is a distribution of NMR activation energies for methyl group rotation in 1 but not in 2 and we are able to explain this in terms of the particle sizes seen in the field emission scanning electron microscopy images

36. A prospective, randomized study to compare the value of two fractionation schemes of palliative radiotherapy for inoperable non-small cell lung cancer

A prospective, randomized study was conducted in eight Polish institutions to compare the value of two fractionation schemes of palliative radiotherapy for inoperable non-small cell lung cancer. Assessed was the impact of either treatment on the degree and duration of relief of tumor-related symptoms and on patient's performance status. Secondary endpoints included treatment side-effects, objective response and overall survival. One hundred patients were randomly assigned to the dose of 20 Gy/5×/5 days (Arm A) or 16 Gy/2×/8 days (Arm B). There were 90 men and 10 women aged between 47 and 79 (mean 66). Eighty four patients had locally advanced tumor and 16 patients had metastatic disease. Squamous cell carcinoma was diagnosed in 65 patients, adenocarcinoma – in 9 patients, large cell carcinoma – in 1 patient and unspecified non-small cell carcinoma – in 25 patients. Fifty five patients were assigned to Arm A and 45 – to Arm B. Ninety eight patients received assigned treatment whereas two patients died before the end of treatment. The final results of the study will be presented at the conference

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

<p>Abstract</p> <p>Background</p> <p>Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.</p> <p>Methods</p> <p>In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.</p> <p>Results</p> <p>Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.</p> <p>Conclusions</p> <p>Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.</p