Purpose: We developed a novel systemic immune-inflammation index (SII) based on lymphocyte, neutrophil, and platelet counts and explored its prognostic value in hepatocellular carcinoma (HCC).Experimental Design: The SII was developed based on a retrospective study of 133 patients with HCC undergoing resection between 2005 and 2006, and validated in a prospective study of 123 patients enrolled from 2010 to 2011. The circulating tumor cell (CTC) level in the validation cohort was measured using the CellSearch system. Prediction accuracy was evaluated with area under the receiver operating characteristic curve (AUC).Results: An optimal cutoff point for the SII of 330 Â 10 9 stratified the patients with HCC into high (!330) and low SII (<330) groups in the training cohort. Univariate and multivariate analyses revealed the SII was an independent predictor for overall survival and relapse-free survival, and prognostic for patients with negative a-fetoprotein and Barcelona Clinic Liver Cancer stage 0þA. The AUCs of the SII for survival and recurrence were higher than other conventional clinical indices. An SII ! 330 was significantly associated with vascular invasion, large tumors, and early recurrence. CTC levels were significantly higher in the SII ! 330 group (1.71 AE 0.34 vs. 4.37 AE 1.04, P ¼ 0.029). In patients with detectable CTCs, those with SII ! 330 had higher recurrence rates and shorter survival time than patients with SII < 330. Conclusion:The SII was a powerful prognostic indicator of poor outcome in patients with HCC and is a promising tool for HCC treatment strategy decisions. The dismal outcome in patients with high SII scores might be related to higher CTC levels. Clin Cancer Res; 20(23); 6212-22. Ó2014 AACR.

In Saccharomyces cerevisiae, ribosomal biogenesis takes place primarily in the nucleolus, in which a single 35S precursor rRNA (pre-rRNA) is first transcribed and sequentially processed into 25S, 5.8S, and 18S mature rRNAs, leading to the formation of the 40S and 60S ribosomal subunits. Although many components involved in this process have been identified, our understanding of this important cellular process remains limited. Here we report that one of the evolutionarily conserved DEAD-box protein genes in yeast, DBP3, is required for optimal ribosomal biogenesis. DBP3 encodes a putative RNA helicase, Dbp3p, of 523 amino acids in length, which bears a highly charged amino terminus consisting of 10 tandem lysine-lysine-X repeats ([KKX] repeats). Disruption of DBP3 is not lethal but yields a slow-growth phenotype. This genetic depletion of Dbp3p results in a deficiency of 60S ribosomal subunits and a delayed synthesis of the mature 25S rRNA, which is caused by a prominent kinetic delay in pre-rRNA processing at site A 3 and to a lesser extent at sites A 2 and A 0 . These data suggest that Dbp3p may directly or indirectly facilitate RNase MRP cleavage at site A 3 . The direct involvement of Dbp3p in ribosomal biogenesis is supported by the finding that Dbp3p is localized predominantly in the nucleolus. In addition, we show that the [KKX] repeats are dispensable for Dbp3p's function in ribosomal biogenesis but are required for its proper localization. The [KKX] repeats thus represent a novel signaling motif for nuclear localization and/or retention.In eukaryotes, ribosomal biogenesis takes place primarily in a specialized subnuclear compartment termed the nucleolus, where rRNA genes are localized and first transcribed into a single precursor rRNA (pre-rRNA). In Saccharomyces cerevisiae, this pre-rRNA is rapidly associated with a large number of ribosomal and nonribosomal proteins and sequentially processed through a number of intermediates by both exo-and endonucleases into mature 25S, 18S, and 5.8S rRNAs which are found in 60S (25S and 5.8S rRNAs) and 40S (18S rRNA) ribosomal subunits (reviewed in reference 79). During transcription and processing, pre-rRNA is also chemically modified by methylation on base and ribose moieties and by pseudouridylation. Although this highly complicated rRNA-processing pathway has been studied with many organisms, the genetically tractable yeast system has so far provided the most extensive information regarding the various cis-and trans-acting factors crucial to this process.In yeast, rRNA is first transcribed by RNA polymerase I as a 35S pre-rRNA which contains the mature 18S, 5.8S, and 25S rRNAs separated by two internal transcribed spacers, ITS1 and ITS2, and flanked by two external transcribed spacers, 5Ј ETS and 3Ј ETS (Fig. 1) (reviewed in reference 74). Processing of this 35S pre-rRNA occurs initially at sites A 0 , A 1 , and A 2 to yield the 20S pre-rRNA and the 27SA 2 pre-rRNA. Processing of the 20S pre-rRNA takes place in the cytoplasm, where site D is cleaved to form the ...

The Saccharomyces cerevisiae NOP4 gene was isolated by screening a lambda gt11 yeast genomic DNA library with a monoclonal antibody against a yeast nucleolar protein. NOP4 encodes a 78 kDa protein that contains two prototypical RNA recognition motifs (RRMs) flanking an imperfect RRM lacking characteristic RNP1 and RNP2 motifs. In addition, there is a fourth incomplete RRM. NOP4 is a single copy essential gene present on chromosome XVI, between RAD1 and PEP4. To examine the function of Nop4p, we constructed a conditional null allele of NOP4 by placing this gene under the control of the glucose‐repressible GAL1 promoter. When cells are shifted from galactose‐containing medium to glucose‐containing medium, NOP4 transcription is terminated, Nop4 protein is depleted and cell growth is impaired. Nop4 protein depletion results in diminished accumulation of 60S ribosomal subunits, assignable to a defect in ribosome biogenesis arising from a lack of production of mature 25S rRNA from 27S precursor rRNA.

This study was designed to investigate the effect of vascular endothelial growth factor 164 adenovirus (Ad-VEGF 164 )-transfected mesenchymal stem cells (MSC) on improving erectile function in diabetic rats. Forty-five male Sprague-Dawley rats were injected with streptozotocin to develop type 1 diabetes, whereas 10 served as normal controls. Diabetic rats were randomly divided into 3 groups: rats that underwent intracavernous injection with phosphatebuffered saline (DM+PBS), unmodified MSCs (DM+MSC), and Ad-VEGF 164 -transfected MSCs (DM+VMSC). Normal controls received intracavernous injection of PBS. Four weeks after injection, erectile function was measured by cavernous nerve electrostimulation. Penile tissue was harvested for histology and enzyme-linked immunoassay. Prior to injection, high expression of VEGF was confirmed in Ad-VEGF 164 -transfected MSCs by enzyme-linked immunoassay. Four weeks after injection, the erectile function, as well as the content of smooth muscle and endothelium in corpus cavernosum increased significantly in the MSC-injected groups compared with the DM+PBS group. There was a significant improvement of erectile function, the content of smooth muscle and endothelium, and the VEGF concentration in the corpus cavernosum in the DM+VMSC group compared with the DM+MSC group. Our study validates the effect of intracavernous injection of MSCs for diabetes-associated erectile dysfunction in an animal model. The combined strategy of MSC injection with VEGF gene therapy-enhanced therapy of MSCs for the treatment of diabetesassociated erectile dysfunction.

BackgroundTripartite Motif Containing 11 (TRIM11), a member of TRIM proteins, is overexpressed in high-grade gliomas and plays an oncogenic function in glioma biology. However, little is known about the role of TRIM11 in lung cancer.MethodsWe analyzed TRIM11 mRNA expression in lung cancer tissues and adjacent non-neoplastic tissues by real-time PCR. We then explored the function of TRIM11 in lung cancer cells by small interfering RNA-mediated downregulation of this protein followed by analyses of cell proliferation, migration and invasion.ResultsTRIM11 was highly expressed in lung cancer tissues and lung cancer cell lines. The higher expression of TRIM11 was correlated with the poorer prognosis of patients. Suppressing of TRIM11 expression in lung cancer cells with higher expression of TRIM11 (A549 and NCI-H446 cells) significantly reduced cell growth, motility and invasiveness. We further demonstrated that knockdown of TRIM11 affected the expression of cell proliferation-related proteins (Cyclin D1 and PCNA), and epithelial-mesenchymal transformation-related proteins (VEGF, MMP-2, MMP-9, Twist1, Snail and E-cadherin). The activity of ERK and PI3K/AKT was also suppressed in TRIM11 knocked down cells. Further experiments in lung cells with lower expression of TRIM11 (NCI-H460 and NCI-H1975 cells) with AKT inhibitor suggested that TRIM11 may promote cell motility and invasiveness through AKT pathway.ConclusionsOur results indicate that TRIM11 acts as an oncogene in lung cancer through promoting cell growth, migration and invasion. Our findings may have important implication for the detection and treatment of lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0379-y) contains supplementary material, which is available to authorized users.

Traumatic neuropathic pain caused by traumatic neuroma has long been bothering both doctors and patients, the mechanisms of traumatic neuropathic pain are widely discussed by researchers and the treatment is challenging. Clinical treatment of painful neuroma is unclear. Numerous treatment modalities have been introduced by experts in this field. However, there is still no single standard recognized treatment.Different forms of treatments have been tested in animals and humans, but pharmacotherapies (antidepressants, antiepileptics) remain the basis of traumatic neuropathic pain management. For intractable cases, nerve stump transpositions into a muscle, vein or bone are seen as traditional surgical procedures which provide a certain degree of efficacy. Novel surgical techniques have emerged in recent years, such as tube guided nerve capping, electrical stimulation and adipose autograft have substantially enriched the abundance of the treatment for traumatic neuropathic pain.Several treatments show advantages over the others in terms of pain relief and prevention of neuroma formation, making it difficult to pick out a single modality as the reference. An effective and standardized treatment for traumatic neuropathic pain would provide better choice for researchers and clinical workers.In this review, we summarized current knowledge on the treatment of traumatic neuropathic pain, and found a therapeutic strategy for this intractable pain. We tried to provide a useful guideline for choosing the right modality in management of traumatic neuropathic pain.

Our results suggest that iPS cells are able to differentiate into male germ cells in vitro and that reconstituted seminiferous tubules may provide a functional niche for exogenous iPS cell-derived male germ cells. Derivation of male germ cells from iPS cells has potential application for treating male infertility and provides an ideal platform for elucidating molecular mechanisms of male germ-cell development.

Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors. Here we describe a strategy to deplete polyamines through host–guest encapsulation using a peptide-pillar[5]arene conjugate (P1P5A, P1 = RGDSK(N 3 )EEEE) as a supramolecular trap. The RGD in the peptide sequence allows the molecule to bind to integrin α v β 3 -overexpressing tumor cells. The negative charged glutamic acid residues enhance the inclusion affinities between the pillar[5]arene and cationic polyamines via electrostatic interactions and facilitate the solubility of the conjugate in aqueous media. The trap P1P5A efficiently encapsulates polyamines with association constants of 10 5 –10 6 M −1 . We show that P1P5A has a wide spectrum of antitumor activities, and induces apoptosis via affecting the polyamine biosynthetic pathway. Experiments in vivo show that P1P5A effectively inhibits the growth of breast adenocarcinoma xenografts in female nude mice. This work reveals an approach for suppressing tumor growth by using supramolecular macrocycles to trap polyamines in tumor cells.