Gaseous TMO(CO)n+ (TM = Sc, Y, La) complex cations prepared via laser vaporization were mass-selected and studied by infrared photodissociation spectroscopy in the C-O stretching frequency region. The structures and vibrational frequencies were calculated by density functional theory to support and interpret the experimental results. The saturated coordination number of CO ligands for ScO(CO)n+, YO(CO)n+ and LaO(CO)n+ was demonstrated to be six, seven and nine, respectively, namely, the nominal 18-, 20- and 24-electron gaseous cation complexes were synthesized. Based on our analysis of the electronic structure, the YO(CO)7+ complex also obeys the 18-electron rule, since one of the occupied valence molecular orbitals is formed only by ligand orbitals. The contribution of 4f orbitals in LaO(CO)9+ accounts for its high coordination number with a 24-electron valence shell.

To explore an optimal frequency of whole-body low-dose radiation (LDR) to protect the kidney from diabetes, type 1 diabetic mice were induced with multiple injections of low-dose streptozotocin in male C57BL/6J mice. Diabetic or age-matched normal mice received whole-body exposure to 12.5 or 25 mGy either every other day or weekly for 4 or 8 weeks. Diabetes decreased the urinary creatinine and increased the microalbumin in urine, renal accumulation of 3-nitrotyrosine and 4-hydroxynonenal, and renal expression of collagen IV and fibronectin. All these renal pathological and functional changes in diabetic mice were significantly attenuated by exposure to LDR at all regimens. However, whole-body exposure of diabetic mice to 25 mGy weekly and to 12.5 mGy every other day for 8 weeks provided a better prevention of diabetic nephropathy than other LDR regimens. Furthermore, whole-body exposure to 25 mGy weekly for 8 weeks showed no detectable effect on the kidney of normal mice, but whole-body exposure to normal mice at 12.5 mGy every other day for 8 weeks increased urinary microalbumin and renal expression of collagen IV and fibronectin. These results suggest that whole-body exposure to LDR at 25 mGy weekly is the optimal condition of LDR to protect the kidney from diabetes.

COPS3 encodes the third subunit of the COP9 signalosome and its aberrant expression is associated with many RITE ("Region of Increased Tumor Expression") genes in lung cancer tissues.To elucidate the specific role of COPS3 in lung cancer, we examined its expression in lung cancer tissues by immunohistochemical staining.We found that COPS3 was overexpressed in most of the lung cancer samples examined, particularly in small cell carcinoma and squamous cell carcinoma.The expression of COPS3 protein was positively correlated with the level of Ki-67 cell proliferation index (p=0.001)and negatively related to the degree of tumor differentiation (p=0.012).In a xenograft tumor model in nude mice, shRNA-knockdown of COPS3 significantly reduced tumor growth.In lung adenocarcinoma A549 cells, shRNA-knockdown of COPS3 induced cell cycle arrest at G0/G1 phase by upregulating the cell cycle regulator protein P21 and downregulating cyclin B1 and CDK4.These data suggest that COPS3 may promote tumor growth by regulating cell-cycle associated proteins.

Cancer gene therapy has attracted increasing attention for its advantages over conventional therapy in specific killing of tumor cells. Here, we attempt to prove a novel therapeutic approach that targets tumors by harnessing the blood antigen immune response system, which is inherently present in patients with breast cancers. Breast cancer MDA-MB-231 cells expressed blood group H antigen precursor. After ectopic expression of blood group A glycosyltransferase, we found that the H precursor was converted into the group A antigen, appearing on the surface of tumor cells. Incubation with group B plasma from breast cancer patients activated the antigen-antibody-complement cascade and triggered tumor cell killing. Interestingly, expression of blood A antigen also reduced tumorigenesis in breast cancer cells by inhibiting cell proliferation, migration, and tumor sphere formation. Cell cycle analysis revealed that cancer cells were paused at S phase due to the activation of cell cycle regulatory genes. Furthermore, pro-apoptotic genes were unregulated by the A antigen, including BAX, P21, and P53, while the anti-apoptotic BCL2 was down regulated. Importantly, we showed that extracellular HMGB1 and ATP, two critical components of the immunogenic cell death pathway, were significantly increased in the blood A antigen-expressing tumor cells. Collectively, these data suggest that blood antigen therapy induces specific cancer cell killing by activating the apoptosis and immunogenic cell death pathways. Further translational studies are thereby warranted to apply this approach in cancer immuno-gene therapy.

It has been generally accepted that both natural and man‐made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low‐dose radiation (LDR) are different from those of high‐dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti‐cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application.

Insulin-like growth factor II (IGF2) is maternally imprinted in most tissues, but the epigenetic regulation of the gene in cancer stem cells (CSCs) has not been defined. To study the epigenetic mechanisms underlying self-renewal, we isolated CSCs and non-CSCs from colon cancer (HT29, HRT18, HCT116), hepatoma (Hep3B), breast cancer (MCF7) and prostate cancer (ASPC) cell lines. In HT29 and HRT18 cells that show loss of IGF2 imprinting (LOI), IGF2 was biallelically expressed in the isolated CSCs. Surprisingly, we also found loss of IGF2 imprinting in CSCs derived from cell lines HCT116 and ASPC that overall demonstrate maintenance of IGF2 imprinting. Using chromatin conformation capture (3C), we found that intrachromosomal looping between the IGF2 promoters and the imprinting control region (ICR) was abrogated in CSCs, in parallel with loss of IGF2 imprinting in these CSCs. Loss of imprinting led to increased IGF2 expression in CSCs, which have a higher rate of colony formation and greater resistance to chemotherapy and radiotherapy in vitro. These studies demonstrate that IGF2 LOI is a common feature in CSCs, even when the stem cells are derived from a cell line in which the general population of cells maintain IGF2 imprinting. This finding suggests that aberrant IGF2 imprinting may be an intrinsic epigenetic control mechanism that enhances stemness, self-renewal and chemo/radiotherapy resistance in cancer stem cells.

Background: A number of studies show that the pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of multiple myeloma (MM). However, whether MM risk is associated with IL-6 genetic variability remains uncertain. Objective: The aim of our study was to evaluate the association between two different IL-6 polymorphisms (located in the IL-6 promoter and receptor, respectively) and the risk of developing MM using a meta-analytic approach. Materials and Methods: A systematic search for studies on the association of IL-6/IL-6R single-nucleotide polymorphisms with susceptibility to MM was conducted in PubMed, Cochrane Library, Embase, CNKI (Chinese) and Wanfang (Chinese) Digital Dissertations Databases from inception through November 2014. A meta-analysis was performed and results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results: A total of eight case-control studies on the IL-6 promoter polymorphism and three studies on the IL-6 receptor (IL-6R) polymorphism were included. No significant association was found between the IL-6 promoter rs1800795 (G>C) polymorphism and MM susceptibility. A significantly increased risk of MM was observed with the IL-6R rs8192284 (A>C) polymorphism. In subgroup analyses, grouped by ethnicity, region, quality of studies, and Hardy-Weinberg equilibrium of control group, similar results were found. Conclusion: Unlike the IL-6 promoter rs1800795 (G>C) polymorphism, the IL-6R rs8192284 (A>C) polymorphism may be associated with MM risk. However, large-scale studies are needed to validate our findings since they are based on a relatively small number of studies.

Hormesis and adaptive responses are 2 important biological effects of low-dose ionizing radiation (LDR). In normal tissue, LDR induces hormesis as evinced by increased cell proliferation; however, whether LDR also increases tumor cell proliferation needs to be investigated. In this study, cell proliferation was assayed by total cell numbers and the Cell Counting Kit 8 assay. Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3′ -kinase(PI3K)-Akt (PI3K/AKT) phosphorylation were determined by Western blot analysis. Human embryonic lung fibroblast 2BS and lung cancer NCI-H446 cell lines were irradiated with LDR at different doses (20-100 mGy). In response to 20 to 75 mGy X-rays, cell proliferation was significantly increased in 2BS but not in NCI-H446 cells. In 2BS cells, LDR at 20 to 75 mGy also stimulated phosphorylation of MAPK/ERK pathway proteins including ERK, MEK, and Raf and of the PI3K/AKT pathway protein AKT. To test whether ERK1/2 and AKT pathway activation was involved in the stimulation of cell proliferation in 2BS cells, the MAPK/ERK and PI3K/AKT pathways were inhibited using their specific inhibitors, U0126 and LY294002. U0126 decreased the phosphorylation of ERK1/2, and LY294002 decreased the phosphorylation of AKT; each could significantly inhibit LDR-induced 2BS cell proliferation. However, LDR did not stimulate these kinases, and kinase inhibitors also did not affect cell proliferation in the NCI-H446 cells. These results suggest that LDR stimulates cell proliferation via the activation of both MAPK/ERK and PI3K/AKT signaling pathways in 2BS but not in NCI-H446 cells. This finding implies the potential for applying LDR to protect normal tissues from radiotherapy without diminishing the efficacy of tumor therapy.

Transplantation of hepatocytes is a promising therapy for end-stage liver disease, but the availability of functional cells currently precludes its clinical application. We now report a simple transient reprogramming approach to convert fibroblasts into hepatic-like cells. Human skin fibroblasts were treated with fish egg extracts to become the transiently remodeled cells (TRCs). After infected with retroviral EGFP, they were directly injected into the fetal monkey liver, where they underwent in situ differentiation in the hepatic niche. The hepatic-like cells were functional as shown by the synthesis of hepatic markers in vivo, including albumin, cytokeratin-18, and hepatic serum antigen. Similarly, when implanted in the mouse liver, the TRCs were differentiated into hepatic-like cells that synthesize albumin and CK18 and became completely integrated into the liver parenchyma. The potency of TRCs was mechanistically related to the activation of several signal pathways, which reactivate endogenous genes related to cell potency. This study demonstrates the feasibility of a simple and inexpensive epigenetic remodeling approach to convert human fibroblasts into therapeutic hepatic-like cells for the treatment of end-stage liver disease.

Interferons have been marketed to treat hematological malignancies, but their efficacy in the treatment of solid tumors has been significantly hindered by low antitumor efficacy and numerous side effects. We used a "cDNA in-frame fragment" library screening method to identify short cDNA peptides that potentiate the anti-tumor activity of interferons. In this study, we synthesized a hybrid molecule by fusing a short positively charged peptide derived from placental growth factor-2 to the C-terminus of human IFNγ. Using the human brain glioblastoma U87 cell line as a model system, we found that the hybrid interferon exhibited significantly higher activity than did the wild-type IFNγ in inhibiting tumor cell growth. As compared with the unmodified IFNγ, the hybrid interferon was better at inhibiting cell invasion in a matri-gel assay and at decreasing tumor colony formation. The enhanced antitumor activity of the synthetic interferon was correlated with the activation of interferon pathway genes and the blockade of tumor cell division at the S-G2/M phase. This study demonstrates the potential of a synthetic IFNγ for use as a novel antitumor agent.

Background Hepatitis B virus ( HBV ) infection is a major global public health concern. Although recent findings suggest an inverse relationship between HBV infection and multiple myeloma ( MM ), the true relationship between these two conditions remains unclear. Aim The primary aim of this meta‐analysis was to evaluate the association between HBV infection, defined as hepatitis B surface antigen positivity, and the incidence of MM . Methods We searched the PubMed /Medline, Cochrane Library and EMBASE databases from January 1975 to July 2014 and reviewed the reference lists of all retrieved articles. Odds ratios ( OR ) and 95% confidence intervals ( CI ) were calculated using fixed‐ and random‐effects models. Results We identified nine case–control studies involving 30 646 patients with MM and 379 837 controls. HBV infection was not significantly associated with the development of MM ( OR = 1.3; 95% CI : 0.92–1.82; P = 0.14). A similar risk of developing MM was present in different HBV ‐prevalent countries. However, significant heterogeneity was observed among studies ( P = 0.01). A statistically significant relationship between HBV infection and increased MM risk was detected in sub‐analyses evaluating high‐quality studies and those with hospital‐based controls ( P < 0.05). Conclusion HBV infection may be associated with an increased risk of MM . However, confirmation of this relationship and the specific molecular mechanisms involved in the association between HBV infection and the development of MM require further exploration.

Background aims. Despite the availability of multiple treatment strategies, patients with gastric carcinoma (GC) have a dismal prognosis. The aim of this study was to evaluate the efficacy and safety of cellular immunotherapy (CIT) with the use of autologous natural killer cells, gamma delta T cells and cytokine-induced killer cells in combination with chemotherapy in patients with GC. Methods. In this open-label pilot cohort study, patients were treated with the combination therapy (chemo/CIT group) or chemotherapy alone (control group). Progression-free survival (PFS), overall survival (OS), quality of life (QOL) and adverse events were investigated. Results. Fifty-eight patients were analyzed, 30 in the chemo/CIT group and 28 in the control group. The median PFS of the chemo/CIT group was significantly longer compared with the control group (P = 0.021). In subgroup analysis, in patients with stage III GC, node-positive metastasis or poorly differentiated carcinoma, the 2-year PFS rate in chemo/CIT versus control groups was 62.5% versus 26.7% (P = 0.022), 50% versus 27.3% (P = 0.016) and 56.3% versus 28.6% (P= 0.005), respectively. The median OS in either group has not yet been reached, and there was no significant difference in OS between the groups. The QOL was improved in the patients treated with chemo/CIT compared with the control group. CIT was well tolerated and not related to any significant adverse events. Conclusions. A combination of CIT and chemotherapy for patients with GC was safe, improved QOL, and might prevent recurrence, especially in GC patients with advanced stage, poorly differentiated carcinoma or lymph node metastasis.

Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency.

Localized prostate cancer and polycythemia vera (PV) are rare, and can be difficult to distinguish from bone marrow metastatic prostate cancer. The present study describes a case of prostate cancer occurring with PV. Magnetic resonance imaging revealed diffusely inhomogeneous bone marrow of the pelvis and a localized prostatic mass. The bone marrow biopsy indicated erythrocytosis and leukocytosis. The patient was treated with aspirin and twice-weekly phlebotomy procedures for two weeks, followed by a radical prostatectomy. Following the surgery, the patient was continually treated with interferon-α2b and aspirin, and demonstrated no abnormalities within the one-year follow-up period. The findings of the present study may aid in the future diagnosis and treatment of patients with prostate cancer and PV.

Small cell lung cancer (SCLC) relapses rapidly after the initial response to chemotherapy and shows drug-resistance. This study was to investigate the efficacy and safety of cellular immunotherapy (CIT) with autologous natural killer (NK), γδT, and cytokine-induced killer (CIK) cells as maintenance therapy for SCLC patients.

Pancreatic cancer is the most aggressive malignant disease, ranking as the fourth leading cause of cancer-related death among men and women in the United States. Interferon alpha (IFNα) has been used to treat pancreatic cancer, but its clinical application has been significantly hindered due to the low antitumor activity. We used a "cDNA in-frame fragment library" screening approach to identify short peptides that potentiate the antitumor activity of interferons. A short positively charged peptide derived from the C-terminus of placental growth factor-2 (PLGF-2) was selected to enhance the activity of IFNα. For this, we constructed a synthetic interferon hybrid molecule (SIFα) by fusing the positively charged PLGF-2 peptide to the C-terminus of the human IFNα. Using human pancreatic cell lines (ASPC and CFPAC1) as a model system, we found that SIFα exhibited a significantly higher activity than did the wild-type IFNα in inhibiting the tumor cell growth. The enhanced activity of the synthetic SIFα was associated with the activation of interferon pathway target genes and the increased binding of cell membrane receptor. This study demonstrates the potential of a synthetic SIFα as a novel antitumor agent.

The bacterial defense system CRISPR (clustered regularly interspaced short palindromic repeats) has been explored as a powerful tool to edit genomic elements. In this study, we test the potential of CRISPR Csy4 RNA endoribonuclease for targeting HIV-1. We fused human codon-optimized Csy4 endoribonuclease with VPR, a HIV-1 viral preintegration complex protein. An HIV-1 cell model was modified to allow quantitative detection of active virus production. We found that the trans-expressing VPR-Csy4 almost completely blocked viral infection in two target cell lines (SupT1, Ghost). In the MAGI cell assay, where the HIV-1 LTR β-galactosidase is expressed under the control of the tat gene from an integrated provirus, VPR-Csy4 significantly blocked the activity of the provirus-activated HIV-1 reporter. This proof-of-concept study demonstrates that Csy4 endoribonuclease is a promising tool that could be tailored further to target HIV-1.

This study was aimed to characterize clinicopathological features and prognosis of patients with adenosquamous lung carcinoma(ASC). Among the 2531 patients with lung cancer who underwent surgery between January 2000 and June 2012 in our hospital, 59 were histologically diagnosed as having ASC. The clinicopathological features and follow-up data of ASC patients were collected and analyzed statistically. Superior lobectomy was accomplished in 40 patients, middle and inferior lobectomy in 3, lobectomy plus partial resection of contralateral lung in 5, partial lung resection in 4, and pneumonectomy in 7. Moreover, 22 cases were found to be adenocarcinoma-predominant, and 18 to be squamous cell carcinoma-predominant. The median survival time was 13.6 months, and the 1-, 3-, and 5-year survival rates were 59.9%, 36.4% and 31.2%, respectively. Of the 52 cases with tissue specimens available, 11 had an EGFR mutation(21.2%) and 2 had a KRAS mutation(3.8%). Multivariate analysis showed that histology subtype, pleural invasion, TNM stage, and postoperative treatment were all independent prognostic factors. The data from the current study demonstrated that SCC-predominant histology represents a better prognosis of ASC. Histology subtype, pleural invasion, TNM stage, and postoperative treatment are independent prognostic factors for ASC and adjuvant therapy may help control the disease.

Correspondence: Guanjun Wang, Cancer Center, the First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, China. Tel: ( 86)043185167335. Fax: ( 86)0431-85166279. Email: guanjunwang2013@hotmail.com; Shibo Li, Department of Pediatrics, University of Oklahoma Health Sciences Center, 1122 NE 13th Street, Suite 1400, Oklahoma City, OK 73104, USA, Tel: 405-271-3589. Fax: 405-271-7117. E–mail: shibo–li@ouhsc.edu

The insulin-like growth factor II (IGF2) gene is aberrantly expressed in tumors as a result of loss of imprinting (LOI). Reactivation of the normally-suppressed maternal allele may lead to IGF2 upregulation and increased tumor growth, particularly in colon cancer. However, the mechanisms underlying IGF2 LOI in tumors are poorly defined. In this report, we identified polycomb repressive complex 2 (PRC2) docking factor SUZ12 as a critical factor in regulating IGF2 imprinting in tumors. Human colon cancer cell lines (HRT18 and HT29) show loss of IGF2 imprinting. Ectopic expression of SUZ12 restored normal monoallelic expression of IGF2 in these two colon cancer cell lines. Using chromatin immunoprecipitation (ChIP) and chromatin conformation capture (3C), we found that the virally-expressed SUZ12 bound to IGF2 promoters, coordinating with endogenous CTCF to orchestrate a long range intrachromosomal loop between the imprinting control region (ICR) and the IGF2 promoters. The histone methyltransferase EZH2 was recruited to the IGF2 promoters, where it induced H3K27 hypermethylation, suppressing one allele, leading to the restoration of IGF2 imprinting. These data demonstrate that SUZ12 is a key molecule in the regulation of monoallelic expression of IGF2, suggesting a novel epigenetic therapeutic strategy for modulating IGF2 production in human tumors.