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Toxins, Volume 2, Issue 9 (September 2010), Pages 2213-2332

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Research

Jump to: Review

Open AccessArticle SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model
Toxins 2010, 2(9), 2242-2257; doi:10.3390/toxins2092242
Received: 23 July 2010 / Revised: 20 August 2010 / Accepted: 26 August 2010 / Published: 27 August 2010
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Abstract
SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models [...] Read more.
SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 106 cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
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Open AccessArticle Staphylococcal Superantigen (TSST-1) Mutant Analysis Reveals that T Cell Activation Is Required for Biological Effects in the Rabbit Including the Cytokine Storm
Toxins 2010, 2(9), 2272-2288; doi:10.3390/toxins2092272
Received: 2 August 2010 / Revised: 1 September 2010 / Accepted: 7 September 2010 / Published: 9 September 2010
Cited by 5 | PDF Full-text (281 KB) | XML Full-text
Abstract
Staphylococcal superantigens (sAgs), such as toxic shock syndrome toxin 1 (TSST-1), induce massive cytokine production, which may result in toxic shock syndrome (TSS) and sepsis. Recently, we reported that in vitro studies in human peripheral blood mononuclear cells (PBMC) do not reflect [...] Read more.
Staphylococcal superantigens (sAgs), such as toxic shock syndrome toxin 1 (TSST-1), induce massive cytokine production, which may result in toxic shock syndrome (TSS) and sepsis. Recently, we reported that in vitro studies in human peripheral blood mononuclear cells (PBMC) do not reflect the immunological situation of the host, because after exposure to superantigens (sAgs) in vivo, mononuclear cells (MNC) leave the circulation and migrate to organs, e.g., the spleen, liver and lung. Our experimental model of choice is the rabbit because it is comparable to humans in its sensitivity to sAg. T cell activation has been assessed by lymphocyte proliferation and IL-2 gene expression after in vivo challenge with TSST-1 and the mutant antigens; expression of the genes of proinflammatory cytokines were taken as indicators for the inflammatory reaction after the combined treatment with TSST-1 and LPS. The question as to whether the biological activities of TSST-1, e.g., lymphocyte extravasation, toxicity and increased sensitivity to LPS, are mediated by T cell activation or activation by MHC II-only, are unresolved and results are contradictory. We have addressed this question by studying these reactions in vivo, with two TSST-1 mutants: one mutated at the MHC binding site (G31R) with reduced MHC binding with residual activity still present, and the other at the T cell binding site (H135A) with no residual function detectable. Here, we report that the mutant G31R induced all the biological effects of the wild type sAg, while the mutant with non-functional TCR binding did not retain any of the toxic effects, proving the pivotal role of T cells in this system. Full article
(This article belongs to the Special Issue Enterotoxins)

Review

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Open AccessReview Cure and Curse: E. coli Heat-Stable Enterotoxin and Its Receptor Guanylyl Cyclase C
Toxins 2010, 2(9), 2213-2229; doi:10.3390/toxins2092213
Received: 15 July 2010 / Revised: 12 August 2010 / Accepted: 24 August 2010 / Published: 26 August 2010
Cited by 10 | PDF Full-text (461 KB) | HTML Full-text | XML Full-text
Abstract
Enterotoxigenic Escherichia coli (ETEC) associated diarrhea is responsible for roughly half a million deaths per year, the majority taking place in developing countries. The main agent responsible for these diseases is the bacterial heat-stable enterotoxin STa. STa is secreted by ETEC and [...] Read more.
Enterotoxigenic Escherichia coli (ETEC) associated diarrhea is responsible for roughly half a million deaths per year, the majority taking place in developing countries. The main agent responsible for these diseases is the bacterial heat-stable enterotoxin STa. STa is secreted by ETEC and after secretion binds to the intestinal receptor guanylyl cyclase C (GC-C), thus triggering a signaling cascade that eventually leads to the release of electrolytes and water in the intestine. Additionally, GC-C is a specific marker for colorectal carcinoma and STa is suggested to have an inhibitory effect on intestinal carcinogenesis. To understand the conformational events involved in ligand binding to GC-C and to devise therapeutic strategies to treat both diarrheal diseases and colorectal cancer, it is paramount to obtain structural information on the receptor ligand system. Here we summarize the currently available structural data and report on physiological consequences of STa binding to GC-C in intestinal epithelia and colorectal carcinoma cells. Full article
(This article belongs to the Special Issue Enterotoxins)
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Open AccessReview Rapid Visual Tests: Fast and Reliable Detection of Ochratoxin A
Toxins 2010, 2(9), 2230-2241; doi:10.3390/toxins2092230
Received: 2 August 2010 / Revised: 13 August 2010 / Accepted: 23 August 2010 / Published: 26 August 2010
Cited by 22 | PDF Full-text (394 KB) | HTML Full-text | XML Full-text
Abstract
This paper reviews the early detection strategies that have been employed for the rapid monitoring of ochratoxin A (OTA) contamination of food. OTA, a mycotoxin mainly produced by some Aspergillus and Penicillium species, is found in cereals, coffee, wine, pork and grapes. [...] Read more.
This paper reviews the early detection strategies that have been employed for the rapid monitoring of ochratoxin A (OTA) contamination of food. OTA, a mycotoxin mainly produced by some Aspergillus and Penicillium species, is found in cereals, coffee, wine, pork and grapes. To minimize the entry of this mycotoxin into the food chain, rapid diagnostic tools are required. To this end, the potential use of lateral flow devices has also been developed. In this study, we analyze the robustness of test strips using published methods for colorimetric detection. Different test formats are discussed, and challenges in the development of lateral flow devices for on-site determination of OTA, with requirements such as robustness, speed, and cost-effectiveness, are discussed. Full article
(This article belongs to the Special Issue Ochratoxins)
Open AccessReview Development of Treatment Concepts for the Use of Botulinum Toxin A in Children with Cerebral Palsy
Toxins 2010, 2(9), 2258-2271; doi:10.3390/toxins2092258
Received: 23 July 2010 / Revised: 24 August 2010 / Accepted: 26 August 2010 / Published: 27 August 2010
Cited by 7 | PDF Full-text (947 KB) | HTML Full-text | XML Full-text
Abstract
The treatment of children with cerebral palsy with Botulinum toxin A injections is well established, safe and effective. However, a standardized injection strategy is still missing and the used dosage has escalated over the years. In the recent past, the recommended dosages [...] Read more.
The treatment of children with cerebral palsy with Botulinum toxin A injections is well established, safe and effective. However, a standardized injection strategy is still missing and the used dosage has escalated over the years. In the recent past, the recommended dosages in Europe were, however, reduced due to a better understanding of the relationship between dosage, severe side effects and the kind of anesthesia used. To combine safety and efficacy, the trend tends to a lower dosage, but combined with a more specific selection of injected muscles. The treatment of these key-muscles takes into account the best support for motor development to attain each individual motor milestone. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessReview Naturally Occurring Food Toxins
Toxins 2010, 2(9), 2289-2332; doi:10.3390/toxins2092289
Received: 12 August 2010 / Revised: 2 September 2010 / Accepted: 13 September 2010 / Published: 20 September 2010
Cited by 15 | PDF Full-text (633 KB) | HTML Full-text | XML Full-text
Abstract
Although many foods contain toxins as a naturally-occurring constituent or, are formed as the result of handling or processing, the incidence of adverse reactions to food is relatively low. The low incidence of adverse effects is the result of some pragmatic solutions [...] Read more.
Although many foods contain toxins as a naturally-occurring constituent or, are formed as the result of handling or processing, the incidence of adverse reactions to food is relatively low. The low incidence of adverse effects is the result of some pragmatic solutions by the US Food and Drug Administration (FDA) and other regulatory agencies through the creative use of specifications, action levels, tolerances, warning labels and prohibitions. Manufacturers have also played a role by setting limits on certain substances and developing mitigation procedures for process-induced toxins. Regardless of measures taken by regulators and food producers to protect consumers from natural food toxins, consumption of small levels of these materials is unavoidable. Although the risk for toxicity due to consumption of food toxins is fairly low, there is always the possibility of toxicity due to contamination, overconsumption, allergy or an unpredictable idiosyncratic response. The purpose of this review is to provide a toxicological and regulatory overview of some of the toxins present in some commonly consumed foods, and where possible, discuss the steps that have been taken to reduce consumer exposure, many of which are possible because of the unique process of food regulation in the United States. Full article
(This article belongs to the Special Issue The Toxicity of Natural Products)

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