The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models.

Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNß) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNß production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4+ T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin's ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies.

Asymmetric conjugate addition of alkylzirconium reagents to α,ß-unsaturated lactones.

The asymmetric synthesis of ß-substituted lactones by catalytic asymmetric conjugate addition of alkyl groups to α,ß-unsaturated lactones is reported. The method uses alkylzirconium nucleophiles prepared in situ from alkenes and the Schwartz reagent. Enantioselective additions to 6- and 7-membered lactones proceed at rt, tolerate a wide variety of functional groups, and are readily scalable. The method was used in a formal asymmetric synthesis of mitsugashiwalactone.

Relationship of mild fatty liver, β-carotene, vitamins a and e status of periparturient Holstein cows / Relación del hígado graso leve y el estatus de β-caroteno, vitaminas A y E en vacas Holstein durante el periparto

The objectives of this study were to determine the association between mild fatty liver and β-carotene (BC), retinol (ROL), and a-tocopherol (AT) status. Multiparous Holstein cows were defined as having mild fatty liver using a threshold of 2% liver triacylglycerol (TAG, wet basis) at day (d) 2 after calving. Cows with mild fatty liver decreased dry matter intake (DMI) as a % of body weight (BW) from calving to 5th week (wk) of lactation (3.47 vs. 3.99, P = 0.02) and increased plasma nonesterified fatty acids (NEFA) concentration (345.0 vs. 266.0 µeq/dL, P = 0.10) as compared to normal cows. Fatty liver tended to lower plasma ROL (0.20 vs. 0.23 µg/mL, P = 0.10), but had no effect on plasma BC, plasma AT, liver BC, and liver ROL (P > 0.12) concentrations. However, depression in liver BC at calving was very small (8.0 vs. 68.0%) for fatty liver than for normal cows. Liver AT concentrations were greater (5.5 vs. 4.0 µg/g, P = 0.06) for cows with more than 2% liver TAG concentration. Concentration of plasma NEFA was positively correlated with plasma BC concentrations (r = 0.18, P < 0.05) and negatively correlated with concentrations of plasma ROL (r = -0.36, P < 0.0001) or AT (r = -0.35, P < 0.0001). A positive direct relationship between DMI and plasma vitamins status was found to exist only for ROL and AT, which suggests that stores of ROL or AT are less labile than stores for BC. At different times from calving, liver BC concentrations were positively correlated with liver TAG concentrations in a consistent manner but, correlations among liver ROL or liver AT concentrations and liver TAG concentrations were nonsignificants. The results suggest that the regulatory role of the liver in maintaining retinol concentrations in plasma may be compromise in cows with fatty liver.

Este estudio fue realizado con los objetivos de determinar la asociación entre hígado graso leve (HGL) y estatus de β-caroteno (BC), retinol (ROL) y a-tocoferol (AT). Para definir HGL en vacas Holstein multíparas se empleó como valor crítico el 2% de triacilgliceroles (TAG, base fresca) en el hígado al segundo día después del parto. El consumo de materia seca (CMS), como porcentaje del peso vivo, disminuyó (3,47 vs. 3,99; P = 0,02) mientras que la concentración de ácidos grasos no-esterificados (AGNE) incrementó (345,0 vs. 266,0 µeq/dL; P = 0,10), desde el parto hasta la 5ta semana de lactancia en las vacas con HGL en comparación con las vacas control. El hígado graso tuvo la tendencia a disminuir el ROL plasmático (0,20 vs. 0,23 µg/mL, P = 0,10), pero no afectó las concentraciones de BC y AT en plasma, ni las de BC y ROL hepático (P > 0,12). Sin embargo, en el parto, la caída del BC hepático fue muy pequeña (8,0 vs. 68,0%) en las vacas con HGL. Las concentraciones de AT hepático fueron mayores (5,5 vs. 4,0 µg/g, P = 0,06) en las vacas con más de 2% de TAG hepático. La concentración plasmática de AGNE tuvo una correlación positiva con las concentraciones plasmáticas de BC (r = 0,18; P < 0,05) pero negativa con las concentraciones de ROL (r = -0,36: P < 0,0001) o AT (r = -0,35; P < 0,0001) plasmático. Solo el estatus plasmático de ROL y AT evidenciaron una relación directa positiva con el CMS, lo que sugiere que los depósitos de ROL o AT son menos lábiles que los de BC. En días diferentes del postparto, las concentraciones hepáticas de BC fueron correlacionadas positivamente con las concentraciones hepáticas de TAG de una manera consistente, pero las correlaciones entre las concentraciones de ROL o AT hepático vs. las de TAG hepático no fueron significativas. Los resultados sugieren que la función reguladora del hígado para mantener las concentraciones plasmáticas de retinol puede estar comprometida en las vacas que sufren hígado graso.

c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells.

During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-kappaB transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel(-/-) mice, thymic T reg cell numbers are markedly reduced as a result of a T cell-intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-beta conversion of peripheral CD4(+)CD25(-) T cells into CD4(+)Foxp3(+) cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel(-/-) mice, the residual peripheral c-rel(-/-) T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.