Tumor-responsive, multifunctional CAR-NK cells cooperate with impaired autophagy to infiltrate and target glioblastoma

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking have rendered glioblastoma (GBM) highly resistant to therapy. As a result, GBM immunotherapies have failed to demonstrate sustained clinical improvements in patient overall survival (OS). To overcome these obstacles, here we describe a novel, sophisticated combinatorial platform for GBM: the first multifunctional immunotherapy based on genetically-engineered, human NK cells bearing multiple anti-tumor functions, including local tumor responsiveness, that addresses key drivers of GBM resistance to therapy: antigen escape, poor immune cell homing, and immunometabolic reprogramming of immune responses. We engineered dual-specific CAR-NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally-released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site specific activity in the tissue and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells, but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising new NK cell-based combinatorial strategy that can target multiple clinically-recognized mechanisms of GBM progression simultaneously

Animal influence on water, sanitation and hygiene measures for zoonosis control at the household level: A systematic literature review

Neglected zoonotic diseases (NZDs) have a significant impact on the livelihoods of the world’s poorest populations, which often lack access to basic services. Water, sanitation and hygiene (WASH) programmes are included among the key strategies for achieving the World Health Organization’s 2020 Roadmap for Implementation for control of Neglected Tropical Diseases (NTDs). There exists a lack of knowledge regarding the effect of animals on the effectiveness of WASH measures. This review looked to identify how animal presence in the household influences the effectiveness of water, hygiene and sanitation measures for zoonotic disease control in low and middle income countries; to identify gaps of knowledge regarding this topic based on the amount and type of studies looking at this particular interaction

Intake, performance and estimated methane production of Nellore steers fed soybean grain

The objective of this study was to evaluate nutrient intake, performance, estimated methane production and carcass characteristics of steers fed diets containing three different levels of soybean grain: 0, 120 and 230 g/kg on the dry matter (DM). The study was conducted on eighteen castrated Nellore males with an average initial body weight (BW) of 370 +/- 12 kg in a completely randomized design, with three treatments and six repetitions. Intake of dry matter (DMI, kg/day) and crude protein tended to decrease linearly, and the intake of ether extract increased linearly in response to the soybean grain levels in the diet. Levels of soybean grain in the diet did not affect DMI (g/kg of BW), final average weight, average daily weight gain, feed efficiency and estimated methane production. Animals fed diets with different levels of soybean grain were not different with respect to carcass yield, loin eye area, subcutaneous fat thickness, or bone, muscle and fat ratios. Carcass characteristics and meat quality were also not significantly different. Replacement of soybean meal by soybean grain in the diet alters the intake of crude protein and ether extract but does not affect performance, estimates of methane production, or carcass characteristics of feedlot Nellore.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Bellman Nutricao AnimalUniv Estadual Paulista, Dept Zootecnia, Jaboticabal, SP, BrazilUniv Fed Vicosa, Inst Nacl Ciencia &Tecnol Ciencia Anim, Vicosa, MG, BrazilCtr Nacl Pesquisa Gado Leite, Empresa Brasileira Pesquisa Agr, Juiz De Fora, MG, BrazilUniv Estadual Paulista, Dept Zootecnia, Jaboticabal, SP, Brazi

Challenges in enriching milk fat with polyunsaturated fatty acids

Milk fatty acid composition is determined by several factors including diet. The milk fatty acid profile of dairy cows is low in polyunsaturated fatty acids, especially those of the n-3 series. Efforts to change and influence fatty acid profile with longer chain polyunsaturated fatty acids have proven challenging. Several barriers prevent easy transfer of dietary polyunsaturated fatty acids to milk fat including rumen biohydrogenation and fatty acid esterification. The potential for cellular uptake and differences in fatty acid incorporation into milk fat might also have an effect, though this has received less research effort. Given physiological impediments to enriching milk fat with polyunsaturated fatty acids, manipulating the genome of the cow might provide a greater increase than diet alone, but this too may be challenged by the physiology of the cow

Concentrated Loads on a Floating Ice Sheet

Abstract The safe bearing capacity of a floating ice sheet is usually determined by limiting the maximum tensile stress which occurs under the load at the bottom of the ice sheet. If the size of the load distribution is large compared to the ice thickness, the thin plate theory predicts these stresses correctly. However, if the size of the load distribution becomes small compared to the ice thickness, the plate theory overestimates the stresses. In this case the ice sheet should he treated as a three-dimensional elastic layer. Previous investigators have solved the elastic-layer problem for loads distributed over a circular area, and have limited the results to the stress at the bottom of the ice sheet directly under the center of the load. In the present paper the stresses are evaluated at any radial position, and it is shown how these stresses approach those for the plate theory as the radial position becomes large. The solutions for the stresses are presented in integral form, as well as graphs from the numerical integration. These new results are significant for the superposition of stresses when two concentrated loads act near each other. Similarly for loads distributed over a rectangular area, the plate theory will overestimate the stresses if the dimensions of the load becomes small compared to the ice thickness. For this case integral solutions are presented for the stresses, and are evaluated directly under the center of the load.</jats:p

Vibration of a floating ice sheet /

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