No abstract

Exosomes perform important functions for intercellular communication through extracellular signaling pathways, leading to the regulation of important biological processes, including cell proliferation, but also systemic dysfunctions such as preeclampsia (PE). However, the inhibitory effects of mesenchymal stem cell (MSCs)-derived exosomes in PE remain largely unknown. Thus, we assessed the possibility that exosomes could transport long non-coding RNA H19 and the correlation between H19 and the apoptosis of trophoblast cells. The expression of microRNA let-7b and forkhead box protein O1 (FOXO1) was characterized in placental tissues of PE patients. Gain-and lossof-function experiments were performed to examine the roles of FOXO1 and let-7b in trophoblast cells. Interactions between let-7b and H19 as well as between let-7b and FOXO1 were confirmed by a dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation. HTR-8/SVneo cells were co-cultured with exosomes derived from MSCs overexpressing H19, followed by invasion, migration, and apoptosis assessments of trophoblast cells. We found that let-7b was highly expressed and FOXO1 was poorly expressed in placental tissues of PE patients. Furthermore, H19 acts as a competitive endogenous RNA against let-7b, and let-7b directly targeted FOXO1. Moreover, H19 could be transferred to trophoblast cells via MSCsecreted exosomes. MSC-derived exosomes overexpressing H19 decreased let-7b, increased FOXO1, and activated the protein kinase B (AKT) signaling pathway, thus increasing invasion and migration and inhibiting apoptosis of trophoblast cells. These results suggest that MSC-derived exosomes overexpressing H19 may be a novel direction for therapeutic strategies against PE.

The inhibition of a prepotent response is an essential executive function which enables us to suppress inappropriate actions in a given context. Individuals with fencing expertise exhibit behavioral advantages on tasks with high demands on response inhibition. This study examines the electrophysiological basis for the superior response inhibition in experienced fencers. In the Go/Nogo task where frequent stimuli required a motor response while reaction had to be withheld to rare stimuli, the fencers, compared with the non-fencers, exhibited behavioral as well as electrophysiological advantages when suppressing prepotent responses. The superior response inhibition in the fencers was characterized by enhanced Nogo-N2 and reduced Nogo-P3. Single-trial analysis revealed that the amplitude difference of the Nogo-N2 between two groups was caused by lower single-trial latency variability in the fencers (may be due to low attentional fluctuation and/or stable neural processing speed) while the amplitude difference of the Nogo-P3 resulted from truly weaker neural activity in the fencers (may be because few cognitive sources are needed and few control efforts are made). The two inhibition-related components are distinct neurophysiological indexes that, on the one hand, provide effective guidance to titrate the level of executive function in fencers, and on the other hand, facilitate to monitor fencers’ improvement in the training process.

The symbiosis of host and intestinal microbiota constitutes a microecosystem and plays an important role in maintaining intestinal homeostasis and regulating the host's immune system. Eimeria tenella , an obligate intracellular apicomplexan parasite, can cause coccidiosis, a serious intestinal disease. In this study, the effects of E. tenella infection on development parameters (villus height, crypt depth, mucosa thickness, muscularis thickness, and serosa thickness) and microbiota in chicken cecum were investigated. Fourteen-day-old male Hy-Line Variety Brown layer chickens were inoculated with sporulated oocysts of E. tenella . Cecal tissues were collected 7 d after inoculation. Relative density of goblet cells and glycoproteins were determined by Alcian blue periodic acid–Schiff staining and periodic acid–Schiff staining, respectively. Intestinal development parameters were also evaluated. Cecal contents were extracted, and the composition of cecal microflora was examined by Illumine sequencing in the V3–V4 region of the 16S rRNA gene. Results indicated that E. tenella infection destroyed the structure of cecal tissue and reduced the relative density of goblet cells and glycoproteins. Sequencing analysis indicated that E. tenella infection altered the diversity and composition of cecal microbiota. The populations of Proteobacteria , Enterococcus , Incertae , and Escherichia–Shigella decreased, and those of Bacteroidales and Rikenella significantly increased in the infected group compared with those in the control group. Hence, the pathological damage caused by E. tenella infection is associated with cecal microbiota dysbiosis, and this finding may be used to develop an alternative measure for alleviating the effect of coccidiosis on the poultry industry.

No abstract

Background Immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC) have been rapidly evolving. ICIs are likely to be more effective but also lead to escalating healthcare costs. Objectives The aim of this study was to evaluate the cost effectiveness of immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC). Methods We searched the PubMed, Web of Science, and Cochrane Library for studies comparing the cost effectiveness of ICIs for NSCLC. Potential studies identified were independently checked for eligibility by two authors, with disagreement resolved by a third reviewer. Quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards checklists. Results A total of 22 economic studies were included. Overall reporting of the identified studies largely met CHEERS recommendations. In the first-line setting, for advanced or metastatic NSCLC patients with PD-L1 � 50%, pembrolizumab appeared cost-effective compared with platinum-based chemotherapy in the US and Hong Kong (China), but not in the UK and China. The cost-effectiveness of pembrolizumab versus chemotherapy for first-line treatment of NSCLC in PD-L1 � 1% patients remained obscure. Regardless of PD-L1 expression status, pembrolizumab in combination with chemotherapy could be a cost-effective first-line therapy in the US. On the contrary, addition of atezolizumab to the combination of

Holliday junction recognition protein (HJURP) refers to a histone H3 chaperone that has been implicated in different kinds of malignancies. Yet, its character in pancreatic cancer remains unclear. The expression of HJURP was assessed in PDAC tissues by RT-qPCR, immunoblotting, and immunohistochemistry. HJURP-deficient or overexpressed PDAC cell lines were constructed, using shRNA or plasmids with HJURP insert. MTT, sphere formation assay, migration, and invasion assays were performed to evaluate the viability, proliferation, migration, and invasion of PDAC cells. We used xenograft mice models to assess the tumor growth and metastasis in vivo. RNA-seq was applicated in search of the potential downstream target of HJURP in PDAC and subsequent verification were fulfilled via multiple assays, including immunofluorescence. Additionally, chromatin immunoprecipitation and luciferase reporter assay were conducted to explore the potential regulation of MDM2 expression by HJURP through H3K4me2. In this current research, we found that the expression of HJURP in PDAC cells and tissue was significantly higher than those of adjacent normal tissue, and high HJURP expression predicted poor survival. HJURP significantly promoted the viability, sphere formation, migration, and invasion of PDAC cells in vitro, HJURP also facilitated tumor growth and metastasis in vivo. Mechanically, MDM2/p53 axis is critical for HJURP-mediated malignant behaviors in PDAC, and HJURP regulates MDM2 expression through H3K4me2. HJURP could serve as a promising biomarker, and target for PDAC prognosis and treatment.

BackgroundOvarian cancer is the most common gynecological malignancies in women, with high mortality rates worldwide. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily which preferentially induces apoptosis of cancer cells. However, acquired resistance to TRAIL hampers its therapeutic application. Identification of compounds that sensitize cancer cells to TRAIL is vital in combating resistance to TRAIL. The effect of kaempferol, a flavonoid enhancing TRAIL-induced apoptosis in ovarian cancer cells, was investigated in this study.Material/MethodsThe cytotoxic effects of TRAIL (25 ng/mL) and kaempferol (20–100 μM) on human ovarian cancer cells OVCAR-3 and SKOV-3 were assessed. Effect of kaempferol on the expression patterns of cell survival proteins (Bcl-xL, Bcl-2, survivin, XIAP, c-FLIP) and apoptotic proteins (caspase-3, caspase-8, caspase-9, Bax) were studied. The influence of kaempferol on expression of DR4 and DR5 death receptors on the cell surface and protein and mRNA levels was also analyzed. Apoptosis following silencing of DR5 and CHOP by small interfering RNA (siRNA), and activation of MAP kinases were analyzed as well.ResultsKaempferol enhanced apoptosis and drastically up-regulated DR4, DR5, CHOP, JNK, ERK1/2, p38 and apoptotic protein expression with decline in the expression of anti-apoptotic proteins. Further transfection with siRNA specific to CHOP and DR5 indicated the involvement of CHOP in DR5 up-regulation and also the contribution of DR5 in kaempferol-enhanced TRAIL-induced apoptosis.ConclusionsKaempferol sensitized ovarian cancer cells to TRAIL-induced apoptosis via up-regulation of DR4 and DR5 through ERK/JNK/CHOP pathways.