Role of gangliosides in active immunotherapy with melanoma vaccine.

Among various tumor associated cell surface antigens, gangliosides, the glycosphingolipids that contain sialic acids, offer a variety of epitopes, some of which are preferentially expressed on melanoma cells. These surface components of the bilayered lipid membrane of tumor cells are the targets of active immunotherapy with melanoma vaccine. Purified gangliosides in aqueous solution form micelles and, at high density, form lactones. Their antigenic expression (physical conformation and orientation) on the cell surface is governed by the nature of the sphingosine and the fatty acids they contain. Evidence is accruing to show that the nature of the fatty acid moiety of gangliosides differs in normal and neoplastic cells. Gangliosides per se are not immunogenic and require extrinsic adjuvanticity. Preparation of a melanoma cell vaccine for active immunotherapy requires an understanding of the ganglioside profile of melanoma, the ganglioside-associated heterogeneity of melanoma, and the role of shed melanoma gangliosides in the immunosuppression of cell mediated and humoral immunity. In addition, the role of some of the anti-ganglioside antibodies in the elimination of shed gangliosides, the cytotoxic killing of tumor cells, as well as in the down-regulation of lymphocyte functions must be considered in the formulation of vaccine. Different strategies for augmenting the immunogenicity of melanoma associated gangliosides with melanoma vaccine are evaluated.     

Genetic and epigenetic insights into uveal melanoma

Uveal melanoma (UM) is the most frequent primary intraocular tumor in Caucasian adults and is potentially fatal if metastases develop. While several prognostic genetic changes have been identified in UM, epigenetic influences are now getting closer attention. Recent technological advances have allowed to exam the human genome to a greater extent and have improved our understanding of several diseases including malignant tumors. In this context, there has been tremendous progress in the field of UM pathogenesis. Herein, we review the literature with emphasis on genetic alterations, epigenetic modifications and signaling pathways as well as possible biomarkers in UM. In addition, different research models for UM are discussed. New insights and major challenges are outlined in order to evaluate the current status for this potentially devastating disease.     

An in vivo rat model to study epigenetic control of cell invasion

Due to it ability to invade deep into endometrium, as well as into other tissues at ectopic sites (testis, kidney capsule), throphoblast plays an important role in shaping the future placenta. To accomplish this task, it is necessary for throphoblast cells to differentiate into highly invasive throphoblast giant cells (TGC). The behaviour of TGC during implantation resembles that of cancer cells during metastasis. In both cases, the invasive phenotype is to a large degree controlled epigenetically, by DNA methylation, with resulting gene expression silencing. DNA demethylating agents, such as 5-azacitidine (5azaC), reverse the gene expression and change cell behaviour; already used in cancer therapy, 5azaC is also useful experimentally to elucidate epigenetic pathways in normal and malignant cells. In this paper we describe an in vivo rat model of throphoblast cell invasion, in which cells are exposed to 5azaC and transplanted ectopically under kidney capsule. We conclude that temporal variation in exposure to 5azaC, such as the gestation day, affects the throphoblast cells differentiation, and thus changes their invasive properties. We suggest that this in vivo model could be useful to study steps in epigenetic control of both the placental development and cancer cell spread.     

Pneumolysin as a vaccine and drug target in the prevention and treatment of invasive pneumococcal disease

Streptococcus pneumoniae (the pneumococcus) remains one of the major human pathogens and one of the most common causes of community-acquired pneumonia, otitis media, sinusitis, and meningitis. Aside from the threats posed by emerging antibiotic resistance and infection with the human immunodeficiency virus, the mortality rate among those patients with severe pneumococcal disease who receive seemingly appropriate antimicrobial chemotherapy remains unacceptably high. Because of its involvement in the pathogenesis of invasive disease, pneumolysin, one of the best-characterized virulence factors of the pneumococcus, represents not only a potential vaccine target, but also a target for adjunctive therapy to antibiotics in patients with acute pneumococcal disease. In this paper we review the cytolytic and pro-inflammatory properties of pneumolysin and their involvement in subversion of host defenses and extra-pulmonary dissemination of the pneumococcus, as well as strategies, both immunological and pharmacological, which may counter these harmful activities of the toxin.     

茶多酚的表遗传机制与肿瘤防治

茶多酚(tea polyphenols,TP)是绿茶中对人体有益的主要成分,其对多种不同类型的肿瘤发生可能具有防护作用,其中包括表遗传途径.表遗传指不改变DNA序列的情况下基因表达发生可遗传改变的机制,主要包括DNA甲基化、组蛋白修饰、染色质重塑、siRNA和miRNA调控等,在人类的大多数肿瘤中都观察到表修饰模式的异常.茶多酚具有抑制DNA甲基转移酶、改变组蛋白修饰和miRNA表达的生物学活性,对肿瘤的防护与治疗具有一定的价值.该文就茶多酚的表遗传机制的研究进展作一简要概述.

Abstract：

Tea polyphenols (TP) is one of components from green teas, beneficial to human health. They may help prevent different types of tumors, and are involved in epigenetic pathway. Epigenetics is defined as reversible heritable changes in gene expression that occur without alteration in DNA sequence, including DNA methylation, histone modification, chromatin remodeling, and RNA interference.Most of tumors in humans have shown the abnormal patterns of epigenetics. Tea polyphenols demonstrated some effects of epigenetic agents, inducing epigenetic changes through modifying methylation, histone modifications and expression of some miRNAs. It has potential to be used as an agent for tunor prevention.     

茶多酚的表遗传机制与肿瘤防治

茶多酚(tea polyphenols,TP)是绿茶中对人体有益的主要成分,其对多种不同类型的肿瘤发生可能具有防护作用,其中包括表遗传途径.表遗传指不改变DNA序列的情况下基因表达发生可遗传改变的机制,主要包括DNA甲基化、组蛋白修饰、染色质重塑、siRNA和miRNA调控等,在人类的大多数肿瘤中都观察到表修饰模式的异常.茶多酚具有抑制DNA甲基转移酶、改变组蛋白修饰和miRNA表达的生物学活性,对肿瘤的防护与治疗具有一定的价值.该文就茶多酚的表遗传机制的研究进展作一简要概述.     

Microwave applicator for hyperthermia treatment on in vivo melanoma model

In this article, we evaluated a planar microwave applicator for in vivo superficial hyperthermia treatments on small tumors in the mouse mimicking treatments for human neoplasms. The design of the applicator, was challenged by the small dimensions of the tumors and unwanted diffusion of heating in the tumor-bearing animals. The required solution was to limit the penetration of microwaves in the depth of the tissue maintaining the full efficacy of hyperthermia. The study was firstly performed by computer simulations of SAR distribution inside a flat homogeneous phantom, considering various thicknesses of the integrated water bolus. Simulations, validated by the measurements, were also used to evaluate the impedance matching. Further tests were performed on homogeneous agar phantom to simulate the temperature distribution in the biological tissue and to preliminary assess the possible modality and schedule of microwave hyperthermia delivery. The in vivo experiments showed the evidence of direct microwave-induced heating and damage of the melanoma tissue in a range of penetration coherent both with computer simulations and phantom studies. The described approach appears perspective for designing limited-microwave-delivery applicators tailored for treatments of human superficial tumors and pre-tumoral lesions.     

Synergistic effect of a combined DNA and peptide vaccine against gp100 in a malignant melanoma mouse model

Vaccination against tumors relies on tumor-associated antigens, and has been quite successful with synthetic peptides used as immunogens. Gp100 is a human melanoma-associated antigen (hgp100) with a highly homologous mouse counterpart, pmel17/gp100 (mgp100), that is expressed in melanocytes and highly tumorigenic B16 melanoma cells. Since mgp100 is poorly immunogenic in mice, we used a xenoimmunization approach and vaccinated with the hgp100 immunogene. To that end, plasmid DNA encoding hgp100 was applied as a vaccine in combination with three synthetic peptides corresponding to putative cytotoxic T cell epitopes of hgp100. Immunization with DNA and peptide-pulsed spleen cells had a synergistic effect and provided significant protection against a challenge with poorly immunogenic B16-F0 malignant melanoma cells in the syngeneic C57BL/6 mouse model. Vaccination with either plasmid DNA or peptides alone delayed the onset of tumor formation, and reduced tumor growth 2-fold and 30-fold, respectively. However, while all animals vaccinated with DNA encoding hgp100 or with peptides eventually developed tumors, 30% of the animals treated with both vaccines remained tumor free and survived for the entire observation period of 150 days. Depletion of T cell subsets revealed that the protective effect observed after vaccination with plasmid DNA was mediated by CD4+ and CD8+ T cells, while protection following vaccination with DNA encoding hgp100 in combination with peptides appears to depend on CD4+ T cells only. Furthermore, we could also demonstrate a therapeutic effect of the combined DNA/peptide regime. A single treatment cycle consisting of injections of plasmid DNA and peptide-pulsed spleen cells led to a fourfold reduction in the growth rate of preexisting tumors. The data presented demonstrate that immunization with xenoantigens induces cross-species priming leading to an immunological response against the tumor-specific antigens.     

An epigenetic,transgenerational model of increased mental health disorders in children,adolescents and young adults

Prevalence rates of mental health disorders in children and adolescents have increased two to threefold from the 1990s to 2016. Some increase in prevalence may stem from changing environmental conditions in the current generation which interact with genes and inherited genetic variants. Current measured genetic variant effects do not explain fully the familial clustering and high heritability estimates in the population. Another model considers environmental conditions shifting in the previous generation, which altered brain circuits epigenetically and were transmitted to offspring via non-DNA-based mechanisms (intergenerational and transgenerational effects). Parental substance use, poor diet and obesity are environmental factors with known epigenetic intergenerational and transgenerational effects, that regulate set points in brain pathways integrating sensory-motor, reward and feeding behaviors. Using summary statistics for eleven neuropsychiatric and three metabolic disorders from 128,989 families, an epigenetic effect explains more of the estimated heritability when a portion of parental environmental effects are transmitted to offspring alongside additive genetic variance.Subject terms: Genetic variation, ADHD, Addiction, Autism spectrum disorders, Genetic variation     

Role of primary care in the prevention of malignant melanoma.

One of the targets for health in the United Kingdom is the reduction in the year-on-year increase in the incidence of skin cancer. Most of the mortality associated with skin cancer is attributable to malignant melanoma. One possible way to reduce the incidence of malignant melanoma is to develop a strategy for prevention based in primary care. This paper considers the arguments for and against three possible strategies: giving general advice; identifying patients at high risk; and undertaking early diagnosis. It is concluded that elements of all three strategies are likely to prove useful, but that major studies need to be undertaken before any strategy is adopted on a national basis.     

Pertussis vaccine oedema: An experimental model for the action of penicillamine-like drugs

A delayed hypersensitivity response was induced in the rat paw using pertussis vaccine. Oedema was measured after the challenging injection.d-Penicillamine and levamisole enhanced the response, while indomethacin suppressed it. This model is useful to distinguish the effects of antiinflammatory drugs from those liked-penicillamine which have a specific activity in rheumatoid arthritis.     

An outer membrane vesicle vaccine for prevention of serogroup A and W-135 meningococcal disease in the African meningitis belt

The bacterium Neisseria meningitidis of serogroups A and W-135 has in the recent decade caused most of the cases of meningococcal meningitis in the African meningitis belt, and there is currently no efficient and affordable vaccine available demonstrated to protect against both these serogroups. Previously, deoxycholate-extracted outer membrane vesicle (OMV) vaccines against serogroup B meningococci have been shown to be safe and induce protection in humans in clonal outbreaks. The serogroup A and W-135 strains isolated from meningitis belt epidemics demonstrate strikingly limited variation in major surface-exposed protein structures. We have here investigated whether the OMV vaccine strategy also can be applied to prevent both serogroups A and W-135 meningococcal disease. A novel vaccine combining OMV extracted from recent African serogroup A and W-135 strains and adsorbed to aluminium hydroxide was developed and its antigenic characteristics and immunogenicity were studied in mice. The specificity of the antibody responses was analysed by immunoblotting and serum bactericidal activity (SBA) assays. Moreover, the bivalent A+W-135 vaccine was compared with monovalent A and W-135 OMV vaccines. The bivalent OMV vaccine was able to induce similar SBA titres as the monovalent A or W-135 OMV towards both serogroups. High SBA titres were also observed against a meningococcal serogroup C strain. These results show that subcapsular antigens may be of importance when developing broadly protective and affordable vaccines for the meningitis belt.     

An active model of immune complex glomerulonephritis in the rat employing cationized antigen.

An active model of in situ immune complex glomerulonephritis involving a cationic antigen was established. Three weeks after immunization with human IgG, the left kidneys of Wistar rats were perfused with 100 micrograms of cationized human IgG (pI greater than 9.5) via the left renal artery. At this time the animals exhibited a mean serum concentration of 0.58 +/- 0.33 mg anti-human IgG antibody per milliliter. Renal tissue was examined at regular intervals by immunofluorescence, light, and electron microscopy thereafter. Cationized human IgG and rat IgG were distributed along the glomerular capillary wall in a pattern that became increasingly granular with time; rat C3 was also present. Histologically, a severe proliferative lesion was seen with crescent formation in 10-20% of the glomeruli; adhesions of glomerular tufts to Bowman's capsule were common and with time spike formation in the glomerular basement membrane became very prominent. Extensive subepithelial dense deposits were seen by electron microscopy. Proteinuria was present in 19 of 26 animals within 24 hours, and in 30 of 31 by Day 7. Protein excretion fell from Day 14 onward, but some animals exhibited chronic proteinuria. The model described here represents another situation in which cationic antigens can induce subepithelial immune complexes, namely, the rapid release of small quantities of antigen into a previously sensitized host. This sequence could well mirror the events occurring in nature more closely than the previously described passive in situ model.     

An adaptive model simulating the somatic motility and the active hair bundle motion of the OHC

The outer hair cells (OHC) of the mammalian inner ear change the sensitivity and frequency selectivity of the filtering system of the cochlea using two kinds of mechanical activity: the somatic motility and the active hair bundle motion. We designed a non-linear adaptive model of the OHC employing both mechanisms of the mechanical activity.The modeling results show that the high sensitivity and frequency selectivity of the filtering system of the cochlea depend on the somatic motility of the OHC. However, both mechanisms of mechanical activity are involved in the adaptation to sound intensity and efferent-synaptic influence. The fast (alternating) component (AC) of the mechanical-electrical transduction signal controls the motor protein prestin and fast changes in axial length of the cell. The slow (direct) component (DC) appearing at high signal intensity affects the axial stiffness, the cell length and the position of the hair bundle. The efferent influence is realized by the same mechanism.