Monoclonal antibodies (mAbs) blocking immune checkpoint molecules, especially programmed cell death 1 (PD-1) and its ligands programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2), are currently been investigated for treatment of various tumors [1-3]. PD-L1 and PD-L2 are usually upregulated on the surface of multiple tumor cells to mediate immune tolerance through the interaction with inhibitory PD-1 molecule [4]. Thus, blocking PD-1/PD-Ls interaction has brought promising future for tumor immunotherapy. To date, several PD-1/ PD-L1 blockade antibodies have been approved for clinical use or under phase III clinical trials (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab and BMS-936559, etc.) [4]. The PD-1 targeting therapeutic antibodies block the PD-1/PD-L1 or PD-1/PD-L2 interaction to restore tumor-specific T cell reactivity, without mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Recently, the structural basis of hPD-1/pembrolizumab (a PD-1 targeting therapeutic antibody developed by Merck & Co., Inc., USA) has been revealed, providing a molecular insight into blocking PD-1-mediated immune suppression by antibody [5]. PD-L1 targeting therapeutic antibodies possess PD-1/ PD-L1 blockade activity with or without ADCC activity. As one of the PD-L1 targeting antibodies, avelumab is a human IgG1 antibody with ADCC activity developed by Merck (Darmstadt, Germany) and Pfizer, which is now in multiple phase III clinical trials against non-small cell lung cancer (NCT02395172), advanced renal cell cancer (NCT02684006) and gastric cancer (NCT02625610) [6]. The crystal structures of PD-L1 couplexed with its receptor PD-1 have been extensively studied, including human PD-L1 (hPD-L1) alone, mouse PD-1 (mPD-1) complexed with hPD-L1 and human PD-1 (hPD-1) complexed with hPD-L1 [7-9]. Though the complex structure of hPD-1 with a commercial mAb pembrolizumab has been solved very recently [5], hPD-L1/mAb complex structure has not been investigated. In this study, we expressed the single chain Fv frag

Resistin is expressed in human placenta and has been postulated to play a role in regulating energy metabolism in pregnancy. However, changes in serum resistin levels in normal pregnancy and in the setting of pre-eclampsia are far from understood. The purpose of the present study was to clarify the alterations in serum resistin level in normal pregnancy and pre-eclampsia. Blood samples were taken from 28 healthy non-pregnant women, 27 women in the first, 26 in the second and 26 in the third trimesters of normal pregnancy and 25 women with pre-eclampsia. Serum resistin concentrations were determined by using an ELISA, and mean serum resistin levels were compared with one-way ANOVA. Serum resistin levels were not significantly different among non-pregnant women and women in the first and second trimesters of pregnancy (P>0.05 for all). Serum resistin was significantly elevated in the third trimester of normal pregnancy compared with non-pregnant women (P<0.01) and women in the first (P<0.001) and second (P<0.001) trimesters of pregnancy. Serum resistin level was significantly lower in women with pre-eclampsia than women in the third trimester of normal pregnancy (P<0.001), but was comparable with those of non-pregnant women and women in the first and second trimesters of pregnancy (P>0.05 for all). In conclusion, we found an increase in serum resistin in the third trimester of normal pregnancy, but this increase was not present in pre-eclampsia. We postulate that these associations may offer insight into the mechanisms of maternal adaptation to pregnancy and the pathogenesis of pre-eclampsia.

Cutaneous fatty acid-binding protein (C-FABP), a cancer promoter and metastasis inducer, is overexpressed in the majority of prostatic carcinomas. Investigation of molecular mechanisms involved in tumor-promoting activity of C-FABP has established that there is a fatty acid-initiated signaling pathway leading to malignant progression of prostatic cancer cells. Increased C-FABP expression plays an important role in this novel signaling pathway. Thus, when C-FABP expression is increased, excessive amounts of fatty acids are transported into the nucleus where they act as signaling molecules to stimulate their nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). The activated PPARγ then modulates the expression of its downstream target regulatory genes, which eventually lead to enhanced tumor expansion and aggressiveness caused by an overgrowth of cells with reduced apoptosis and an increased angiogenesis.

In previous work, it is suggested that the excessive amount of fatty acids transported by FABP5 may facilitate the malignant progression of prostate cancer cells through a FABP5-PPARγ-VEGF signal transduction axis to increase angiogenesis. To further functionally characterise the FABP5-PPARγ-VEGF signal transduction pathway, we have, in this work, investigated the molecular mechanisms involved in its tumorigenicity promoting role in prostate cancer. Suppression of PPARγ in highly malignant prostate cancer cells produced a significant reduction (up to 53%) in their proliferation rate, invasiveness (up to 89%) and anchorage-independent growth (up to 94%) in vitro. Knockdown of PPARγ gene in PC3-M cells by siRNA significantly reduced the average size of tumours formed in nude mice by 99% and tumour incidence by 90%, and significantly prolonged the latent period by 3.5 fold. Results in this study combined with some previous results suggested that FABP5 promoted VEGF expression and angiogenesis through PPARγ which was activated by fatty acids transported by FABP5. Further investigations showed that PPARγ up-regulated VEGF expression through acting with the PPAR-responsive elements in the promoter region of VEGF gene in prostate cancer cells. Although androgen can modulate VEGF expression through Sp1/Sp3 binding site on VEGF promoter in androgen-dependent prostate cancer cells, this route, disappeared as the cells gradually lost their androgen dependency; was replaced by the FABP5-PPARγ-VEGF signalling pathway. These results suggested that the FABP5-PPARγ-VEGF signal transduction axis, rather than androgen modulated route, may be a more important novel therapeutic target for angiogenesis-suppression treatment of castration resistant prostate cancer.