Treatment of human hepatocellular carcinoma by the oncolytic herpes simplex virus G47delta

Background: Oncolytic herpes simplex virus (HSV) can replicate in and kill cancer cells while sparing the adjacent normal tissue. Hepatocellular carcinoma (HCC) is amongst the most common and lethal cancers, especially in Third World countries. In this study, the cytotoxicity of a third-generation oncolytic HSV, G47Δ, was investigated in different human HCC cell lines and in an immortalized human hepatic cell line. Additionally, subcutaneous models of HCC were established to evaluate the in vivo anti-tumor efficacy of G47Δ. Methods: The HepG2, HepB, SMMC-7721, BEL-7404, and BEL-7405 human HCC cell lines and the HL-7702 human hepatic immortalized cell lines were infected with G47Δ at different multiplicities of infection (MOIs). The viability of infected cells was determined, and the G47Δ replication was identified by X-gal staining for LacZ expression. Two subcutaneous (s.c.) HCC tumor models of HCC were also established in Balb/c nude mice, which were intratumorally(i.t.) treated with either G47Δ or mock virus. Tumor volume and mouse survival times were documented. Results: More than 95% of the HepG2, Hep3B,and SMMC-7721 HCC cells were killed on by day 5 after infection with a MOI’s of 0.01. For the HL-7702 human hepatic immortalized cells, 100% of the cells were killed on by day 5 after infection with a MOI’s of 0.01. The BEL-7404 HCC cell line was less susceptible with about 70% cells were killed by day 5 after infection with a MOI’s of 0.01. Whereas the BEL-7405 HCC cells were the least susceptible, with only 30% of the cells were killed. Both the SMMC-7721 and BEL-7404 cells form aggressive sc tumor models. G47Δ replicates in the tumors, such that most of the tumors regressed after the G47Δ-treatment, and treated tumor-bearing mice survived much longer than the control animals. Conclusions: G47Δ effectively kills human HCC cells and an immortalized hepatic cell line at low MOI. Intra-tumor injection of G47Δ can induce a therapeutic effect and prolong the survival of treated mice bearing SMMC-7721 and BEL-7404 subcutaneously (s.c.) tumors. Thus, G47Δ may be useful as a novel therapeutic agent for HCC

Photoactive platinum(IV) complex conjugated to a cancer-cell-targeting cyclic peptide

A conjugate of cancer-cell targeting cyclic disulphide non a-peptide c(CRWYDENAC) consisting of nine L-amino acids with the photoactive succinate platinum(IV)complex trans, trans-[Pt(N3)2(py)2(OH)(succinate)] (Pt-cP) has been synthesised and characterised. The conjugate was stable in dark, but released succinate–peptide and Pt(II) species upon irradiation with visible light, and formed photoproducts with guanine. Conjugate Pt-cP exhibited higher photocytotoxicity than parent complextrans, trans, trans-[Pt(N3)2(OH)2(py)2] (FM-190) towards cancer cells, including ovarian A2780, lung A549 and prostate PC3 human cancer cells upon irradiation with blue light (465 nm, 17.28 J cm−2) with IC50values of 2.8–22.4μM and the highest potency for A549 cells. Even though the dark cellular accumulation of Pt-cP in A2780 cells was lower than that of parent FM-190, Pt from Pt-cP accumulated in cancer cells upon irradiation to a level >3× higher than that fromFM-190. In addition, the cellular accumulation of Pt from Pt-cPwas enhanced ca. 47× after irradiation

Immunization with Fc-based recombinant Epstein-Barr virus gp350 elicits potent neutralizing humoral immune response in a BALB/c mice model

Epstein-Barr virus (EBV) was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers, however the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared to wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody and binding to its receptor by ELISA and SPR. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared to gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent neutralizing antibodies against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications. Please click Additional Files below to see the full abstract

Trapping dielectric Rayleigh particles with tightly focused pin-like vortex beam

Optical force exerted on the dielectric Rayleigh particles and tightly focused properties of circular polarized pin-like vortex beam are studied numerically in this paper. Firstly, we drive the expressions study the tightly focused properties of pin-like vortex beam. The numerical results show that the focal length keeps almost unchanged and the maximum intensity decreases with the increase of scaling factor. Then, the optical force exerted on the Rayleigh particle is studied based on the Rayleigh scattering model. The results show that smaller topological charges number and scaling factor of the pin-like vortex beams have greater longitudinal gradient force, transverse gradient force and trapping stiffness. Meanwhile, the trapping position in the beam propagation direction remains almost unchanged. The exponential parameter of the pin-like vortex beams has great influence on the propagation properties and tightly focused characteristics. Therefore, the stability of particle manipulation can be improved by changing the topological charges and scaling factor of the pin-like beams. These results have potential applications for optical trapping, optical storage and optical imaging

Ultra-Wideband and Wide-Angle Perfect Solar Energy Absorber Based on Titanium and Silicon Dioxide Colloidal Nanoarray Structure

In this paper, we designed an ultra-wideband solar energy absorber and approved it numerically by the finite-difference time-domain simulation. The designed solar energy absorber can achieve a high absorption of more than 90% of light in a continuous 3.506 μm (0.596 μm–4.102 μm) wavelength range. The basic structure of the absorber is based on silicon dioxide colloidal crystal and Ti. Since the materials have a high melting point, the designed solar energy absorber can work normally under high temperature, and the structure of this solar energy absorber is simpler than most solar energy absorbers fabricated with traditional metal. In the entire wavelength band researched, the average absorption of the colloidal crystal-based solar energy absorber is as high as 94.3%, demonstrating an excellent performance under the incidence light of AM 1.5 solar spectrum. In the meantime, the absorption spectrum of the solar energy absorber is insensitive to the polarization of light. In comparison to other similar structures, our designed solar energy absorber has various advantages, such as its high absorption in a wide spectrum range and that it is low cost and easy to make

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era

Abstract Background Systemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL). Methods We retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels. Results Multivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p < 0.001) and OS (p < 0.001). The 3-year OS for patients with ICPS =0, ICPS =1, ICPS =2 and ICPS =3 were 95.6, 88.2, 76.0 and 62.2%, respectively (p < 0.001). The 3-year PFS for patients with ICPS = 0–1, ICPS = 2 and ICPS = 3 were 84.8, 71.6 and 54.5%, respectively (p < 0.001). Conclusions The prognostic value of the ICPS model indicated that the degree of systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies

Human Papillomavirus Oncoprotein E6 Inactivates the Transcriptional Coactivator Human ADA3

High-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. The HPV oncoprotein E6 is essential for oncogenic transformation. We identify here hADA3, human homologue of the yeast transcriptional coactivator yADA3, as a novel E6-interacting protein and a target of E6-induced degradation. hADA3 binds selectively to the high-risk HPV E6 proteins and only to immortalization-competent E6 mutants. hADA3 functions as a coactivator for p53-mediated transactivation by stabilizing p53 protein. Notably, three immortalizing E6 mutants that do not induce direct p53 degradation but do interact with hADA3 induced the abrogation of p53-mediated transactivation and G(1) cell cycle arrest after DNA damage, comparable to wild-type E6. These findings reveal a novel strategy of HPV E6-induced loss of p53 function that is independent of direct p53 degradation. Given the likely role of the evolutionarily conserved hADA3 in multiple coactivator complexes, inactivation of its function may allow E6 to perturb numerous cellular pathways during HPV oncogenesis

Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry

We report the synthesis and characterisation of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product from amide coupling of Ir-I to dibenzocyclooctyne-amine (Ir-II), and its conjugate with the cyclic nona-peptide c(CRWYDENAC) (Ir-CP). The familiar three-legged ‘piano-stool’ configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to a amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes