Tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs

Certain carbohydrate antigens of malignantly transformed cells have been identified as markers for the onset of cancer and have become targets for the development of anticancer vaccine therapies. For tumor antigens, many carbohydrate antigens belong to T-independent (TI) antigens. Carbohydrate conjugated to protein carriers can switch TI antigen to a T-dependent (TD) antigen. Attempts to add an innate immune response element (such as Toll-like receptor ligand) to carbohydrate TI-antigens have also been studied. Glycosylation inhibitors or small interfering RNA have also been used for antitumor and/or antiviral agents. This review aims at describing the vast spectrum of tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs.     

Calculation of the intracellular elastic modulus based on an atomic force microscope micro-cutting system

Better understanding of variations in the mechanical properties of cancer cells could help to provide novel solutions for the diagnosis,prevention,and treatment of cancers.We therefore developed a calculation model of the intracellular elastic modulus based on the contact pressure between the silicon tip of an atomic force microscope and the target cells,and cutting depth.Ovarian cells(UACC-1598) and colon cancer cells(NCI-H716) were cut into sequential layers using an atomic force microscope silicon tip.The cutting area on the cells was 8μm×8μm,and the loading force acting on the cells was increased from 17.523 to 32.126μN.The elastic modulus distribution was measured after each cutting process.There were significant differences in contact pressure and cutting depth between different cells under the same loading force,which could be attributed to differences in their intrinsic structures and mechanical properties.The differences between the average elastic modulus and surface elastic modulus for UACC-1598 and NCI-H716 cells were 0.288±0.08 kPa and 0.376±0.16 kPa,respectively.These results demonstrate that this micro-cutting method can be used to measure intracellular mechanical properties,which could in turn provide a more accurate experimental basis for the development of novel methods for the diagnosis and treatment of various diseases.     

Critical role of Toll-like receptor signaling in NK cell activation

Toll-like receptors (TLRs) and NK cell receptors are the most important receptor superfamilies in innate immunity. TLRs act as the sensor of external pathogens, while NK cells detect alterations in endogenous protein expression on target cells through activating and inhibitory receptors. Accumulating data has demonstrated that TLRs and NK cell receptors can coordinate and regulate each other during immune responses, which contributes to the initiation of innate response and the priming of adaptive responses. TLRs can activate NK cell function directly or with the help of accessory cells in a cytokine or cell-to-cell contact dependent manner. More understanding of the recognition of innate receptors and interactions between them may provide important insights into the design of effective strategies to combat tumor and microbial infections. In this review, we summarize how TLRs and NK cells discriminate the self or non-self components respectively. And importantly, we pay more attention to the role of TLR sig-naling in induction of NK cell activation, responses and the crosstalk between them.     

Connective tissue growth factor induces transformation of renal fibroblasts into myofibroblasts

Connective tissue growth factor (CTGF) is thought to be a specific mediator of TGF-β profibrogenic effect, but the role of CTGF in the transformation of renal fibroblasts to myofibroblasts, which are the most important host cells in the renal chronic fibrosis, is still unknown. Aimed at observing the biological effect of CTGF, we set up a cell line overexpressing CTGF, and analyzed the amount of myofibroblast and the level of extracellular matrix Collagen Ⅲ mRNA in cultured cells. Our results show that CTGF can directly induce myofibroblasts formation, and increase the level of Collagen Ⅲ mRNA. This suggests that CTGF may be a novel pharmacotherapeutical target protein for the interference with renal fibrosis, thus providing useful theoretic possibility for clinical prevention of chronic progression of kidney disease.     

Construction and anti-tumor effects of recombinant fowlpox virus expressing Newcastle disease virus hemagglutinin-neuramidinase gene

Hemagglutinin-neuramidinase (HN), a Newcastle disease virus-derived protein, not only mediates receptor recognition but also possesses neuraminidase (NA) activity, the ability to cleave a component of those receptors, N-acetylneuraminic acid (NAcneu, sialic acid). It is known that this protein in mammalian species, including human beings, has interesting anti-neoplastic as well as immune stimulating properties. To explore the use of the HN gene in cancer gene therapy, we constructed a recombi-nant fowlpox virus expressing the HN protein (vFV-HN) and compared the anti-tumor activity of the recombinant virus with that of wild-type fowlpox virus (FPV) in vivo and in vitro. Here we found that although B16 cells were somewhat resistant to the basal cytotoxic effect of wild-type fowlpox virus, infection with vFV-HN caused a pronounced cytotoxic effect and, the survival of tumor-bearing mice immunized with vFV-HN was significantly increased compared with the survival of mice immunized with the FPV alone. Furthermore, the immunization of mice with vFV-HN elicited a B16 tumor-specific cytotoxic T lymphocyte (CTL) response and clonal expansion of both CD4 and CD8 T cell populations in vivo. In addition, T cells from lymph nodes of mice vaccinated with vFV-HN secreted high levels of the Th1 cytokine IL-2 and IFN-γ, indicating that the regression of tumor cells is related to a Th1-type dominant immune response. These results demonstrate that vaccination with vFV-HN may be a potential strategy for cancer gene therapy.     

A monosaccharide transporter is localized to sieve plate and plasmodesmal channel in developing apple fruit

Two major classes of plant sugar transporters, sucrose and monosaccharide transporters, may be localized to tonoplast or plasma membrane. The monosaccharide transporters may also be localized in plastid. However, whether these transporters reside in other subcellular compartments remains unclear. We recently detected in apple fruit a 52 kD plasma membrane-localized monosaccharide transporter, and showed that this transporter may be functional in phloem unloading in the fruit. In this paper, we report that this monosaccharide transporter is also localized to sieve plate and plasmodesmal channel in apple fruit. The amount of this sieve plate- and plasmodesma-associated transporter changes during fruit development. This amount of the transporter expression may be altered in the phloem sieve elements but not in the parenchyma cells by a photoassimilate deficiency applied by the shoot girdling treatment, suggesting that the monosaccharide transporter of the special sub-cellular localization may be of biological significance.     

Three Candidate Epitope—Vaccines in Combination Inducing High Levels of Multiantibodies Against HIV—1

HIV-1 mutation results in immune evasion, which presents a serious challenge for conventional strategies for developing effective vaccines. So far, much experimental evidence indicates that HIV-1 particles in the blood of patients can be cleaned principally by neutralizing antibodies. Based on these facts, we prepared triple combination of epitope-vaccines with the objective of inducing antibodies with predefined multi-epitope-specificity against HW-1. According to the sequences of three neutralizing epitopes (RILAVERYLKD, ELDKWA and GPGRAFY, designated El, E2, and E3, respectively) on HIV-1 envelope proteins, three epitope-peptides ((E1)2: C-(RILAVERYLKDG)2; (E2)4: C-(ELDKWAG)4; and (E3)2:C-(GPGRAFY)2) were synthesized and then conjugated with carrier protein keyhole limpet hemocyanin (KLH) or bovine serum albumin (BSA), and used for immunizing rabbits. After the vaccine course, the triple combination of epitope-vaccines induced high levels of predefined multi-epitope-specific antibodies. An immunoblotting-analysis demonstrated that the antibodies could recognize the native epitopes on both gp41 protein and V3 loop peptide. Furthermore, we compared the immune responses of three doses of epitope-peptides in the candidate epitope-vaccine. Strong antibody responses to three epitopes were observed in a dose dependent manner, with increasing dose raising the immune response. This result indicated that immunotolerance did not occur using an epitope vaccine dose of 80 ~tg. Thus, our results demonstrate that epitope-vaccines in combination can synchronously induce high levels of antibodies with predefined multi-epitope-specificity against HIV-1, and may be used to develop effective vaccines against HIV as a new strategy.     

Metformin targets liver tumor-initiating cells through the PI3K/Akt/mTOR survival pathway

Liver tumor-initiating cells （T-ICs） are thought to be inherently resistant to the cytotoxic effects of chemo- therapy, and can self-renewal and maintain tumor-initiating potential. Therefore, effective anticancer research strategies should target the unique properties of T-ICs. In this study, we found that metformin, a first-line drug of choice for the treatment of type 2 diabetes, inhibited liver T-ICs both in vivo and in vitro. Metformin inhibited the formation of hepato- spheres and epithelial-specific antigen-positive （ESA, CD133＋） cell colonies by hepatocellular carcinoma （HCC） cell lines. Metformin also downregulated the expression of several T-IC-related genes which are involved in the signal- ing pathways, governing the self-renewal, proliferation and differentiation of T-ICs. Furthermore, the targeting of liver T-ICs by metformin was PI-3-kinase-Akt-mTOR （PI3K/Akt/ mTOR）-pathway dependent. The PI3K/Akt/mTOR inhibitorLY294002 and rapamycin abolished the inhibitory effect of metformin on CD133＋ cells, and the PI3K/Akt/mTOR stimulator EGF promoted the inhibitory effect of mefformin on CD 133＋ cells. Metformin also dramatically decreased the tumor volume and number of CD133 expressing tumor cells in a xenograft mouse model. Mefformin exerted a synergistic effect with cisplatin to target both T-ICs and non-T-ICs, and resulted in the smallest tumor volume and lowest number of CD133 expressing tumor cells. This study indicates that the antidiabetic drug metformin could potentially be used in combination therapy with chemotherapeutic agents to improve the treatment of liver cancer.     

A Study of Interface Pressure at the Seamed Area of Pressure Garments

Pressure garments constructed with elastic fabric play an important role in burn rehabilitation by helping to prevent or reduce the formation of hypertrophic scars. For clinical effectiveness, these garments are made in appropriate size for individual patient in order to provide an appropriate amount of skin-and-garment interface pressure on the patient.The seam area of pressure garments has marked impact on the comfort and durability of the pressure garments.Comments from the patients and occupational therapists have indicated that discomfort arose in the seam zone.Line marks appeared on the skin of patients under the seamed areas of pressure garments. This may be caused by uneven or Iocalised interface pressure at the seamed area. In this paper, the changes of interface pressure between the seamed and unseamed areas were investigated. The aim is to provide an understanding of the effect of seams on the interface pressure in order to assist the therapists and/or garment makers to choose an appropriate s     

Advances in identification and application of tumor antigen inducing anti-cancer responses

Tumor antigen is one of the important bases of tumor immunotherapy . With the discovery of novel tumor antigens, interest in specific immunotherapy for treatment of malignancies has increased substantially. Nowadays more and more scientists paid close attention to various tumor antigens with their roles or/and applications in anti-cancer immune responses, immune tolerance, tumor markers,     

Innate immune recognition and regulation in liver injury: A brief report from a series of studies

The discovery of innate immune receptors and the emergence of liver immunology （high content of NK and NKT cells in liver） led to the second research summit in innate immunity since the finding of NK cells in the middle 1970s. Liver disease is one of the most dangerous threats to humans, and the progress in innate immunology and liver immunology made it possible to re-explain the cellular and mo- lecular immune mechanisms of liver disease. In the past ten years, we have found that innate recognition of hepatic NK and NKT subsets were involved in murine liver injury. We established a novel NK cell-dependent acute murine hepatitis model by activating Toll-like receptor-3 （TLR-3） with an injection of poly I：C, which may mimic mild viral hepatitis （such as Chronic Hepatitis B）. We observed that a network of innate immune cells including NK, NKT and Kupffer cells is involved in liver immune injury in our established NK cell-dependent murine,model. We noted that TLR-3 on Kupffer cells activated by pretreatment with poly I： C might protect against bacterial toxin （LPS）-induced fulminant hepatitis by down-regulating TLR-4 function, while TLR-3 pre-activation of NK cells might reduce Con A-induced NKT cell-mediated fulminant hepatitis by blocking NKT cell recruitment to the liver. We also found that the oversensitivity to injury by immune stimulation in HBV （hepatitis B virus） transgenic mice （full HBV gene-tg or HBs-tg） correlated to the over-expression of Real, an NKG2D （natural killer cell group 2D） ligand of NK cells or CDld, a ligand of TCR-V14 of NKT cells, on HBV＋ hepatocytes, which leads to an innate immune response against hepatocytes and is critical in liver immune injury and regeneration.     

Formation mechanism of ferromagnetic minerals in loess of China： TEM investigation

The results of TEM investigation indicate that magnetite and maghemite are the major ferromagnetic minerals in loess-paleosol sequences. Primary magnetite has the similar morphology and surface characteristics as eolian detrital particles. The magnetite can be classified into two categories, high-titaninm and low-titanium, which may be the indicators of magmatic rocks and metamorphic rocks,respectively. TEM investigation at nanometer scale shows that primary detrital magnetite of micron scale had been partially weathered to magnetite of 5-20 nanometer during the pedogenic process, which maintain the pseudomorphism of the aeolian debris. Some chlorite particles were also weathered to nanometer scale magnetite or maghemite in the pedogenic process. So weathering of the two minerals leads to formation of superparamagnetism, which may be the important mechanism of magnelic-susceptibnlty increase in paleosols. The mgnelite or maghhemite resulting from the weathering of chlorite contains a small amount of P and S,which is the signal of microbe-mineral interaction, and indicates that microbes may play a certain role in chlorite weathering and formation of Superparamagnetic particles.     

Xenogeneic homologous genes, molecular evolution and cancer therapy

Cancer is one of the main causes for death of human beings to date, and cancer biotherapy (mainlyimmunotherapy and gene therapy) has become the most promising approach after surgical therapy, radiotherapy andchemotherapy. However, there are still many limitations on cancer immunotherapy and gene therapy; therefore great ef-fort is being made to develop new strategies. It has been known that, in the process of evolution, a number of genes, theso-called xenogeneic homologous genes, are well-conserved and show the structural and/or functional similarity betweenvarious species to some degree. The nucleotide changes between various xenogeneic homologous genes are derived frommutation, and most of them are neutral mutations. Considering that the subtle differences in xenogeneic homologousgenes can break immune tolerance, enhance the immunogenicity and induce autologous immune response so as to elimi-nate tumor cells, we expect that a strategy of inducing autoimmune response using the property of xenogeneic homologousgenes will become a new therapy for cancer. Moreover, this therapy can also be used in the treatment of other diseases,such as autoimmune diseases and AIDS. This article will discuss the xenogeneic homologous genes, molecular evolutionand cancer therapy.     

In vitro assay of cytoskeleton nanomechanics as a tool for screening potential anticancer effects of natural plant extract, tubeimoside I on human hepatoma (HepG2) cells

Cytoskeleton nanomechanics characterizes cancer cell’s physical behaviors such as how it spread and invade. For anticancer drug, cytoskeleton nanomechanics may be a target to inhibit invasiveness and metastasis of cancer cells. Therefore, in vitro assay of cytoskeleton nanomechanics may be used to evaluate the effects of potential anticancer drug on various cancer types. Here, we investigated the effects of tubeimoside I (TBMS I) on human hepatoma (HepG2) cells by using optical magnetic twisting cytometry, a well-established technique for measuring nanomechanics of the Factin cytoskeleton. TBMS I is a natural compound extracted from a traditional Chinese herbal medicine, and is reported with antitumor effect. In this study, we demonstrated that the cytoskeleton stiffness (G) of HepG2 cells was affected by TBMS I. G′ exhibited a typical power law with respect to the loading frequency (f), i.e. G~f . The magnitude of G′ and the value of exponent (α) of the HepG2 cells decreased consistently with the increase of concentration for TBMS I exposure. In addition, the HepG2 cells responded to TBMS I much faster than the normal liver (L-02) cells. Such alteration of cytoskeleton nanomechanics induced by TBMS I was reported for the first time, which was further corroborated by assays of Factin cytoskeleton structure and cell migration. Taken together, these results suggest that in vitro assay of cytoskeleton nanomechanics may have a great potential as an additional tool in screening of anticancer drug candidates.     

Neutron Capture Therapy （NCT） ＆ In-Hospital Neutron Irradiator （IHNI）-a new technology on binary targeting radiation therapy of cancer

BNCT is finally becoming ＂a new option against cancer＂. The difficulties for its development progress of that firstly is to improve the performance of boron compounds, secondly, it is the requirements of quantification and accuracy upon radiation dosimetry evaluation in clinical trials. Furthermore, that is long anticipation on hospital base neutron sources. It includes dedicated new NCT reactor, accelerator based neutron sources, and isotope source facilities. In ad- dition to reactors, so far, the technology of other types of sources for clinical trials is not yet completely proven. The In- Hospital Neutron lrradiator specially designed for NCT, based on the MNSR successfully developed by China, can be installed inside or near the hospital and operated directly by doctors. The Irradiator has two neutron beams for respective treatment of the shallow and deep tumors. It is expected to initiate operation in the end of this year. It would provide a safe, low cost, and effective treatment tool for the NCT routine application in near future.     

Advances in research of sulphide ore textures and their implications for ore genesis

Important advances in research of sulphide ore textures in recent years have deepened our understanding of ore genesis of related mineral deposits. Pressure solution of sulphide minerals has been suggested as a mechanism for remobilization of ore materials, whereas pressure solution of the gangues is believed to raise the grade of the primary ores. We have known that precipitation of base metal sulphides from fluids prefers crystal and crack surfaces of pyrite to form overgrowth. Therefore, pyrite-bearing embryo beds in a sedimentary sequence can be acted as effective crystal seed beds and are favorable for fluid overprinting to form huge statabound deposits. Texture studies of various sulphides can be used to interpret the entire history of sedimentation, diagenesis, deformation and metamorphism of the ores. The study of chalcopyrite disease in sphalerite has brought about the idea of zone refining, and given a new explanation to metal zonation in massive sulphide deposits. Ductile shearing of sulphide ores may form ore mylonites, which will become oreshoots enriched in Cu, Au and Ag during late-stage fluid overprinting. Despite that various modern analytical techniques are being rapidly developed, ore microscopy remains to be an unreplaceable tool for ore geologists. Combined with these modern techniques, this tool will help accelerate the development of theories on ore genesis.     

Calculation model of military aircraft survivability to a missile

Since missiles are main threat against aircrafts in air war, a model is proposed for calculating the aircraft survivability to a missile. The hit characteristic of aircraft to a missile is analyzed, and then Monte Carlo method is applied to generate missile detonation location according to its distribution rule. In addition, based on the analysis of fragment trajectory and critical components, the in- tersection point of these two is determined. Then the kill probability of critical component to a fragment can be calculated, and the aircraft survivability to a missile is obtained accordingly. Finally, the feasibility of the proposed method is demonstrated. Simulation results show that this method captures the basic effects of missile detonation locations on aircraft survivability, which may provide an effective reference to aircraft survivability research.     

CD8<Superscript>+</Superscript> T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model

The role of anti-tumor immune responses in oncolytic adenoviral therapy has not been well studied due to lack of efficacious tu- mor model in immunocompetent mice.Here,we evaluated the contributions of immune components to the therapeutic effects of oncolytic adenoviruse in an immunocompetent murine tumor model permissive for infection and replication of adenovirus.We found that CD8+T cells were critical mediator for antitumor efficacy by oncolytic adenovirus.Intratumoral viral therapy induced intensive infiltration of CD8+T cells in tumor,increased tumor-specific IFN-?(interferon-?)production and CTL(cytotoxic T lymphocyte)activity of lymphocytes,and generated a long-term tumor-specific immune memory.Boosting CD8+T cell responses by agonistic anti-4-1BB(cluster differentiation 137,CD137)antibody showed synergistic anticancer effects with oncolytic viro- therapy.Our results provide insight into antitumor mechanisms of oncolytic adenovirus in addition to their direct oncolytic effect.