Fish oil has a preventive role in cardiovascular and inflammatory diseases, but little is known about the effect of olive oil, which is widely consumed in Mediterranean regions. We examined the ...influence of dietary olive oil, corn oil and fish oil-rich diets on the production of superoxide anion (O2−) and nitric oxide (·NO) by resident macrophages stimulated by phorbol 12-myristate 13-acetate (PMA) and their effect on arachidonic acid release, prostaglandin G/H synthase-2 (PGHS-2) expression and the subsequent prostaglandin E2 production. Resident peritoneal macrophages stimulated by PMA from rats fed with olive oil or corn oil had the same level of O2− production, but these levels were increased by the fish oil diet. Olive oil and the fish oil diets increased ·NO and decreased arachidonic acid mobilization and the production of prostaglandin E2. PGHS-2 expression, however, was not affected by diet. We conclude that although olive oil and fish oil reduce arachidonic acid mobilization and subsequent metabolism through the PGHS-2 pathway in PMA-stimulated macrophages, only olive oil offers an additional beneficial effect by increasing ·NO/O2− production.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Metabolic changes in the tumor microenvironment impair the generation of an efficient anti-tumor immune response. Reduction of specific amino acids like arginine and tryptophan limit ...anti-tumor immune responses, contributing to a tumor generated immune suppressive environment. Arginine levels are critical for lymphocyte proliferation and function, and they are regulated by arginase 1 & 2 and nitric oxide synthase. Arginase 1 activity has been associated with most of the immunosuppressive effects resulting from arginine depletion and the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant established tumor models. RNA sequencing of sorted cell populations from immunocompetent genetically engineered KRAS G12D mutant mouse lung tumors, showed that arginase 1 expression is elevated in the myeloid cell population in the tumor microenvironment. Ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSCs) from mouse tumors hindered T cell function by depleting arginine. These MDSCs expressed elevated levels of arginase 1, and inhibition of its activity by an Arg1/2 inhibitor, compound 9, restored effector T cell function. Treatment of a genetically engineered KRAS mutant mouse model with compound 9 increased arginine levels in blood and tumor and led to an increased number of tumor T cells and a significant reduction in tumor volume after 1 week of treatment. Compound 9 had no growth inhibitory activity across several murine and human KRAS mutant lung cancer cell lines in vitro. We also determined by immunohistochemistry that elevated levels of arginase 1 were expressed in granulocytic myeloid cells from KRAS mutant lung cancer patient samples. Given the data reported here and by others, an arginase inhibitor with excellent potency and in vivo target engagement could represent an important new immunotherapeutic agent. We have recently discovered and are fully characterizing molecules that demonstrate excellent potency and selectivity along with oral bioavailability in rodents that provide good arginase target coverage at modest doses.
Citation Format: Juan J. Miret, Paul Kirschmeier, Min Wu, Wei Huang, William Walker, Sangeetha Palakurti, Nick Saccomano, Peter S. Hammerman, Kwok-kin Wong, Esra Akbay. Suppression of myeloid cell arginase activity leads to therapeutic response in Kras mutant lung cancer by activating anti-tumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4065.
Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of ...action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.
Spatially accelerating beams are non-diffracting beams whose intensity is localized along curvilinear trajectories, also incomplete circular trajectories, before diffraction broadening governs their ...propagation. In this paper we report on numerical simulations showing the conversion of a high-numerical-aperture focused beam into a nonparaxial shape-preserving accelerating beam having a beam-width near the diffraction limit. Beam shaping is induced near the focal region by a diffractive optical element that consists of a non-planar subwavelength grating enabling a Bessel signature.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background:
Suicide prevention can be improved by knowing which variables
physicians take into account when considering hospitalization or discharge of patients who have
attempted suicide.
Aims:
To ...test whether suicide risk is an adequate
explanatory variable for predicting admission to a psychiatric unit after a suicide attempt.
Methods:
Analyses of 840 clinical records of patients who had attempted
suicide (66.3% women) at four public general hospitals in Madrid (Spain).
Results:
180 (21.4%) patients were admitted to psychiatric units.
Logistic regression analyses showed that explanatory variables predicting admission were: male
gender; previous psychiatric hospitalization; psychiatric disorder; not having a
substance-related disorder; use of a lethal method; delay until discovery of more than one
hour; previous attempts; suicidal ideation; high suicidal planning; and lack of verbalization
of adequate criticism of the attempt.
Conclusions:
Suicide risk appears to be
an adequate explanatory variable for predicting the decision to admit a patient to a
psychiatric ward after a suicide attempt, although the introduction of other variables improves
the model. These results provide additional information regarding factors involved in everyday
medical practice in emergency settings.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
We present an analytical formula for the fast and accurate evaluation of nonlinear absorption in materials exhibiting an admixture of different multiphoton processes. This approach is specifically ...addressed for its use in thin films when the slowly varying envelope approximation applies. The contribution of absorptions of distinct order is conveniently averaged in order to use well-known expressions for a single multiphoton process. In the latter case, therefore, our simple expression is reduced toward the exact solution.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Realistic mathematical models are of great importance for studying the optical performance of the human eye. Light propagation algorithms provide robust methods to calculate field distributions ...inside a homogeneous medium, and thus they can be applied to the study of light patterns inside the anterior and posterior chambers of the eye. Dealing with real eyes implies using very short propagation distances together with highly refractive power surfaces. Thus, the general solutions of the field equation are used instead of paraxial Fresnel solutions. Conditions of application and sampling conditions of the method are clearly stated here. Numerical evaluation of the different refractive surfaces is also analysed. The main result is that a complete algorithm to obtain light patterns at any axial distance inside the eye is proposed. The method uses real corneal measures and axial distances together with crystalline models. Statistical results and individual predictions show the validity of the model. Application of the method is illustrated with the study of a bifocal intraocular lens.
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