Objective As human blastocyst-derived extravillous trophoblasts (EVTs) invade the early decidua, they are positioned to interact with immune cells and resident decidual cells, and remodel spiral arteries into high capacity vessels that increase blood flow to the developing fetal-placental unit. Shallow EVT invasion elicits incomplete vascular transformation and reduces uteroplacental blood flow that presages adverse pregnancy outcomes. Excess macrophages in the decidua induce EVT apoptosis via tumor necrosis factor-alpha (TNF-α) secretion. Our previous observation that pro-inflammatory cytokines enhance neutrophil and macrophage activator granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in first trimester decidual cells is now extended to include: 1) the specific macrophage activator M-CSF; 2) macrophage activation and subsequent enhancement of EVT apoptosis by both GM-CSF and M-CSF. Study design Quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay assessed M-CSF expression in first trimester decidual cells incubated with interleukin-1 beta (IL-1β) or TNF-α. Peripheral monocyte-derived macrophages pre-incubated with conditioned media from decidual cell cultures were co-cultured with a first trimester EVT cell line, HTR-8/SVneo cells. Macrophage activation was examined and EVT apoptosis evaluated by DNA fragmentation, caspase activation and cell membrane asymmetry. Results IL-1β or TNF-α significantly enhanced M-CSF expression in first trimester decidual cells. The conditioned media from these cultures activates macrophages, which promote caspase 3/7-dependent EVT apoptosis with antibodies against GM-CSF or M-CSF blocking this effect. Conclusions Pro-inflammatory cytokines increases synthesis of M-CSF in first trimester decidual cells. Both GM-CSF and M-CSF activate macrophages, which initiate caspase-dependent EVT apoptosis.

Drug resistance is a major concern in the successful treatment of ovarian cancer. In the present study we report a combinational drug regime using arsenic trioxide (ATO) and cisplatin (CDDP) to increase therapeutic potentiality in ovarian cancer cells. ATO-mediated growth inhibition and apoptosis in human suspension ovarian cancer COC1 cells were evaluated by MTT assay and annexin V assay using flow cytometry, respectively. cDNA arrays were performed to screen ATO-mediated gene expression. Treatment of COC1 cells with ATO alone resulted in growth inhibition and apoptosis with a dose-and time-dependent fashion; further cDNA arrays showed that 34 genes (23 up-regulated genes and 11 downregulated genes) may strongly associate with the antiproliferative and pro-apoptotic effects induced by ATO. Furthermore, ChouTalalay analysis was used to evaluate the combinational effect of ATO and CDDP as well as dose-reduction index (DRI) in a panel of ovarian cancer cells including CDDP-sensitive and -resistant cell lines. The combination index (CI) analysis indicated that the interaction effect of ATO/CDDP exhibited a wide range of synergism in all the adherent ovarian cancer cells (A2780, IGROV-1, SKOV-3, and R182) as well as 0.93 to 0.69 for IC 50 to IC 90 in suspension COC1 cells where CI < 1, =1, and >1, define synergism, additive effect, and antagonism, respectively. More intriguingly, the combination of ATO and CDDP yielded favorable DRIs ranging from 1.23-fold to 13.51-fold dose reduction. These results suggest that ATO and its combination with CDDP present therapeutic potential for ovarian cancer, and deserve further preclinical and clinical studies. (Cancer Sci 2009; 100: 2459-2464 O varian carcinoma still ranks first as the leading cause of death among gynecological malignancies. (1) Platinum compounds are the key components of chemotherapy for the treatment of ovarian cancer patients. However, drug resistance is a significant obstacle hindering the successful treatment of ovarian cancer patients. As documented, patients with ovarian cancer had a 5-year survival rate of less than 30%. (2) Therefore, new therapeutic agents and new regimens consisting of combinations of chemotherapeutic agents are needed.Arsenic trioxide (ATO) is a natural substance that has been used medically as a traditional Chinese medicine for over a thousand years, following the ancient philosophy of ''treating an evil with a toxic''. (3) Approval by the Food and Drug Administration for the use of ATO in the treatment of relapsed/refractory acute promyelocytic leukemia (APL) in the 1990s was supported by the impressive clinical response rates in Chinese patients with APL (4) and confirmative clinical studies conducted in the USA. (3) Remarkable efficacy of ATO in the treatment of APL led to exploration of its anticancer activity and underlying mechanism in other malignancies. There has been promising laboratory and pre-or clinical effects observed in various hematologic malignancies (5,6) and in a variety of solid tumors. (7)(8)(9)(10) We, as we...

Up-regulation of CCL2 and CCL5 by first trimester decidual cells in response to proinflammatory stimuli may account for the accumulation of macrophages and dendritic cells in preeclamptic decidua. These chemokines and underlying IL-1β- or TNF-α-induced signaling molecules are potential diagnostic and therapeutic targets for preeclampsia.

No abstract

Notch signaling pathways play important roles in cell fate and many diseases, including preeclampsia, the dysregulation of which may be the main cause of maternal mortality. This study aimed to investigate the roles of Notch2 and Notch3 in proliferation and invasion in trophoblast cell lines (BeWo and JAR). Small hairpin RNAs targeting Notch2/Notch3 and Notch2/Notch3-overexpression vectors were designed, constructed and transfected into BeWo and JAR cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were then used to detect Notch2 and Notch3 mRNA and protein levels, and confirm the efficiency of silence and overexpression. Flow cytometry assays were conducted to evaluate the cell cycle of the two cell lines, and transwell assays were used to detect migration and invasion. Western blot analysis was also performed to show the alteration of the cell lines' physiological activities at protein level.When Notch2 was downregulated in BeWo cells, proliferation was dramatically promoted, while migration and invasion were significantly inhibited. When Notch2 was upregulated in JAR cells, proliferation was inhibited, but migration and invasion were promoted. After overexpression of Notch3 in BeWo cells, proliferation was downregulated, but migration and invasion were both upregulated. By contrast, the silencing of Notch3 expression in JAR cells significantly enhanced proliferation, but suppressed migration and invasion. These data indicated that Notch2 and Notch3 mediate the invasion and migration of BeWo and JAR cells, and may play a potential role in early onset severe preeclampsia.

Resistance to radiotherapy and to EGFR tyrosine kinase inhibitors (EGFR‐TKIs), as well as therapy‐related lung toxicity, are serious problems in the treatment of lung cancer. NF‐κB has been reported to be associated with radioresistance. Therefore, we evaluated its effects on sensitivity to irradiation and to EGFR‐TKIs; irradiation‐induced lung toxicity; and the effects of irradiation on sensitivity to EGFR‐TKIs. We used IKKβ inhibitor IMD 0354 or p65 depletion to explore their effects on sensitivity to irradiation and to EGFR‐TKIs in vitro and in vivo. We evaluated the efficacy of IMD 0354 in a radiation‐induced pulmonary‐fibrosis mouse model. Irradiation enhanced activation and expression of MET and therefore suppressed the sensitivity of lung cancer cells to irradiation or EGFR‐TKIs. Inhibition of NF‐κB by IMD 0354 or by p65 depletion reversed irradiation‐induced MET activation and increased the sensitivity of lung cancer cells to irradiation, to EGFR‐TKIs and to the combination thereof in vitro and in vivo. In addition, IMD 0354 significantly reduced lung toxicity in a murine model of irradiation‐induced pneumonia and lung fibrosis. These findings indicated that NF‐κB inhibition can improve sensitivity to irradiation and to EGFR‐TKIs and can decrease irradiation‐induced lung toxicity in lung cancer.

No abstract

Solar-induced chlorophyll fluorescence (SIF) is increasingly known as an effective proxy for plant photosynthesis, and therefore, has great potential in monitoring gross primary production (GPP). However, the relationship between SIF and GPP remains highly uncertain across space and time. Here, we analyzed the SIF (reconstructed, SIFc)–GPP relationships and their spatiotemporal variability, using GPP estimates from FLUXNET2015 and two spatiotemporally contiguous SIFc datasets (CSIF and GOSIF). The results showed that SIFc had significant positive correlations with GPP at the spatiotemporal scales investigated (p < 0.001). The generally linear SIFc–GPP relationships were substantially affected by spatial and temporal scales and SIFc datasets. The GPP/SIFc slope of the evergreen needleleaf forest (ENF) biome was significantly higher than the slopes of several other biomes (p < 0.05), while the other 11 biomes showed no significant differences in the GPP/SIFc slope between each other (p > 0.05). Therefore, we propose a two-slope scheme to differentiate ENF from non-ENF biome and synopsize spatiotemporal variability of the GPP/SIFc slope. The relative biases were 7.14% and 11.06% in the estimated cumulative GPP across all EC towers, respectively, for GOSIF and CSIF using a two-slope scheme. The significantly higher GPP/SIFc slopes of the ENF biome in the two-slope scheme are intriguing and deserve further study. In addition, there was still considerable dispersion in the comparisons of CSIF/GOSIF and GPP at both site and biome levels, calling for discriminatory analysis backed by higher spatial resolution to systematically address issues related to landscape heterogeneity and mismatch between SIFc pixel and the footprints of flux towers and their impacts on the SIF–GPP relationship.