Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer

This paper investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer, HGSOC, and defines rational combination therapies. We used three different syngeneic orthotopic mouse HGSOC models that replicated the human tumor microenvironment, TME. After 4-5 weeks treatment of established tumors, cediranib had anti-tumor activity with increased tumor T cell infiltrates and alterations in myeloid cells. However, continued cediranib treatment did not change overall survival or the immune microenvironment in two of the three models. Moreover, treated mice developed additional peritoneal metastases not seen in controls. Cediranib-resistant tumors had intrinsically high levels of IL-6 and JAK/STAT signaling and treatment increased endothelial STAT3 activation. Combination of cediranib with a murine anti-IL-6 antibody was superior to monotherapy, increasing mouse survival, reducing blood vessel density and pSTAT3, with increased T cell infiltrates in both models. In a third HGSOC model, that had lower inherent IL-6 JAK/STAT3 signaling in the TME but high PD1 signaling, long-term cediranib treatment significantly increased overall survival. When the mice eventually relapsed, pSTAT3 was still reduced in the tumors but there were high levels of immune cell PD1 and PDL1. Combining cediranib with an anti-PD1 antibody was superior to monotherapy in this model, increasing T cells and decreasing blood vessel densities. Bioinformatics analysis of two human HGSOC transcriptional datasets revealed distinct clusters of tumors with IL-6 and PD-1 pathway expression patterns that replicated the mouse tumors. Combination of anti-IL-6 or anti-PD1 in these patients may increase activity of VEGFR inhibitors and prolong disease-free survival

The POLAR gamma-ray burst polarization catalog

Context. Despite over 50 years of research, many open questions remain about the origin and nature of gamma-ray bursts (GRBs). Linear polarization measurements of the prompt emission of these extreme phenomena have long been thought to be key to answering a range of these questions. The POLAR detector was designed to produce the first set of detailed and reliable linear polarization measurements in the 50 − 500 keV energy range. During late 2016 and early 2017, POLAR detected a total of 55 GRBs. The analysis results of 5 of these GRBs have been reported, and were found to be consistent with a low or unpolarized flux. However, previous reports by other collaborations found high levels of linear polarization, including some as high as 90%. Aims. We study the linear polarization for the 14 GRBs observed by POLAR for which statistically robust inferences are possible. Additionally, time-resolved polarization studies are performed on GRBs with sufficient apparent flux. Methods. A publicly available polarization analysis tool, developed within the Multi-Mission Maximum Likelihood framework (3M

STAT3 Regulates Monocyte TNF-Alpha Production in Systemic Inflammation Caused by Cardiac Surgery with Cardiopulmonary Bypass

BACKGROUND: Cardiopulmonary bypass (CPB) surgery initiates a controlled systemic inflammatory response characterized by a cytokine storm, monocytosis and transient monocyte activation. However, the responsiveness of monocytes to Toll-like receptor (TLR)-mediated activation decreases throughout the postoperative course. The purpose of this study was to identify the major signaling pathway involved in plasma-mediated inhibition of LPS-induced tumor necrosis factor (TNF)-α production by monocytes. METHODOLOGY/PRINCIPAL FINDINGS: Pediatric patients that underwent CPB-assisted surgical correction of simple congenital heart defects were enrolled (n = 38). Peripheral blood mononuclear cells (PBMC) and plasma samples were isolated at consecutive time points. Patient plasma samples were added back to monocytes obtained pre-operatively for ex vivo LPS stimulations and TNF-α and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation by patient plasma was assessed by Western blotting. A cell-permeable peptide inhibitor was used to block STAT3 signaling. We found that plasma samples obtained 4 h after surgery, regardless of pre-operative dexamethasone treatment, potently inhibited LPS-induced TNF-α but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or IκB-α degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-α production in the presence of suppressive patient plasma. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that STAT3 signaling plays a crucial role in the downregulation of TNF-α synthesis by human monocytes in the course of systemic inflammation in vivo. Thus, STAT3 might be a potential molecular target for pharmacological intervention in clinical syndromes characterized by systemic inflammation

Reference evapotranspiration in the irrigated perimeters of the state of Sergipe

O conhecimento da evapotranspiração de referência (ETo) é essencial no manejo de irrigação de culturas agrícolas em todo o mundo. Neste trabalho se utilizaram dados meteorológicos diários de evaporação do tanque "Classe A", temperaturas máximas e mínimas, insolação, velocidade do vento a 2 m de altura e umidade relativa do ar, referentes ao período de 1989 a 1993, coletados em quatro perímetros irrigados do Estado de Sergipe, para estimativa da ETo com base nos métodos do Tanque Classe "A", Radiação Solar, Hargreaves & Samani, Linacre e Penman-Monteith (FAO/56). Comparam-se os valores diários da ETo para a região estudada, através dos quais, quando comparados com o modelo de Penman-Monteith (FAO/56) se obtiveram os melhores desempenhos com os métodos que utilizam a radiação solar como dado de entrada no modelo. O método do Tanque Classe "A" não apresentou desempenho satisfatório em nenhum perímetro irrigado estudado. _________________________________________________________________________________________ ABSTRACT: The knowledge of reference evapotranspiration (ETo) is essential for the irrigation scheduling of crops throughout the world. This work used daily meteorological data of Class A pan evaporation, maximum and minimum air temperatures, insolation, wind speed at 2 m above surface and relative humidity from 1989 to 1993 for four irrigated perimeters of Sergipe. These data were used for estimating ETo based on the following methods: Class A pan evaporation, Solar Radiation, Hargreaves & Samani, Linacre and Penman-Monteith (FAO/56). The daily values of ETo were compared to those obtained by FAO Penman-Monteith method in order to choose the best method of estimating ETo for the region. The best performance was obtained for those models which used the solar radiation as the data input. The Class A pan evaporation method did not show favorable performance in any irrigated perimeter