Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response

A major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. In keeping with this notion, HER-2/neu (neu)-targeted vaccines, which raise strong CD8+ T cell responses to a dominant peptide (RNEU420-429) in WT FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in MMTV-neu (neu-N) transgenic mice. However, treatment of neu-N mice with vaccine and cyclophosphamide-containing chemotherapy resulted in tumor protection in a proportion of mice. This effect was specifically abrogated by the transfer of neu-N–derived CD4+CD25+ T cells. RNEU420-429-specific CD8+ T cells were identified only in neu-N mice given vaccine and cyclophosphamide chemotherapy which rejected tumor challenge. Tetramer-binding studies demonstrated that cyclophosphamide pretreatment allowed the activation of high-avidity RNEU420-429-specific CD8+ T cells comparable to those generated from vaccinated FVB/N mice. Cyclophosphamide seemed to inhibit regulatory T (T reg) cells by selectively depleting the cycling population of CD4+CD25+ T cells in neu-N mice. These findings demonstrate that neu-N mice possess latent pools of high-avidity neu-specific CD8+ T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed by using approaches such as administration of cyclophosphamide before vaccination

Die blande Struma

Eine mechanische Teil-Indikation kann auch schon bei blander Struma des Stadium I bestehen. Die Indikation auf Wunsch des Patienten ist berechtigt, wenn die Schilddrüsenhormonbehandlung erfolglos oder wenig aussichtsreich ist. Die prophylaktischdiagnostische Operationsindikation wird nach Abwägung von statistischem und individuellem Malignom- und Operationsrisiko gestellt. Letztere Indikation überwiegt heute bei weitem. — Die Kropf-Prophylaxe mit jodiertem Speisesalz könnte die mittlere Strumafrequenz in der Bundesrepublick von 15 auf 3 % reduzieren.Surgical treatment can be justified already for nontoxic goiter stage I (WHO) because of tracheal stenosis. Surgery for cosmetic reasons may be adequate, if treatment with thyroid hormones is neither successful nor promising. Diagnostic (histologic) or prophylactic reasons are today the most frequent causes for surgery, in order to detect or avoid thyroid malignancies. — Iodine prophylaxis is advocated in the Federal Republic of Germany, where iodine deficiency and endemic goiter (15 %) are still prevalent

The Role of TLR4 in the Paclitaxel Effects on Neuronal Growth In Vitro

Paclitaxel (Pac) is an antitumor agent that is widely used for treatment of solid cancers. While being effective as a chemotherapeutic agent, Pac in high doses is neurotoxic, specifically targeting sensory innervations. In view of these toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression. However, it remains unclear if low doses of Pac retain its neurotoxic properties or might exhibit unusual effects on neuronal cells. The goal of this study was to analyze the concentration-dependent effect of Pac on isolated and cultured DRG neuronal cells from wild-type and TLR4 knockout mice. Three different morphological parameters were analyzed: the number of neurons which developed neurites, the number of neurites per cell and the total length of neurites per cell. Our data demonstrate that low concentrations of Pac (0.1 nM and 0.5 nM) do not influence the neuronal growth in cultures in both wild type and TLR4 knockout mice. Higher concentrations of Pac (1-100 nM) had a significant effect on DRG neurons from wild type mice, affecting the number of neurons which developed neurites, number of neurites per cell, and the length of neurites. In DRG from TLR4 knockout mice high concentrations of Pac showed a similar effect on the number of neurons which developed neurites and the length of neurites. At the same time, the number of neurites per cell, indicating the process of growth cone initiation, was not affected by high concentrations of Pac. Thus, our data showed that Pac in high concentrations has a significant damaging effect on axonal growth and that this effect is partially mediated through TLR4 pathways. Low doses of Pac are devoid of neuronal toxicity and thus can be safely used in a chemomodulation mode. © 2013 Ustinova et al

Diketopiperazine Formation in Fungi Requires Dedicated Cyclization and Thiolation Domains

Cyclization of linear dipeptidyl precursors derived from nonribosomal peptide synthetases (NRPSs) into 2,5‐diketopiperazines (DKPs) is a crucial step in the biosynthesis of a large number of bioactive natural products. However, the mechanism of DKP formation in fungi has remained unclear, despite extensive studies of their biosyntheses. Here we show that DKP formation en route to the fungal virulence factor gliotoxin requires a seemingly extraneous couplet of condensation (C) and thiolation (T) domains in the NRPS GliP. In vivo truncation of GliP to remove the CT couplet or just the T domain abrogated production of gliotoxin and all other gli pathway metabolites. Point mutation of conserved active sites in the C and T domains diminished cyclization activity of GliP in vitro and abolished gliotoxin biosynthesis in vivo. Verified NRPSs of other fungal DKPs terminate with similar CT domain couplets, suggesting a conserved strategy for DKP biosynthesis by fungal NRPSs

Integrating adverse effect analysis into environmental risk assessment for exotic generalist arthropod biological control agents: a three-tiered framework

Environmental risk assessments (ERAs) are required before utilizing exotic arthropods for biological control (BC). Present ERAs focus on exposure analysis (host/prey range) and have resulted in approval of many specialist exotic biological control agents (BCA). In comparison to specialists, generalist arthropod BCAs (GABCAs) have been considered inherently risky and less used in classical biological control. To safely consider exotic GABCAs, an ERA must include methods for the analysis of potential effects. A panel of 47 experts from 14 countries discussed, in six online forums over 12 months, scientific criteria for an ERA for exotic GABCAs. Using four case studies, a three-tiered ERA comprising Scoping, Screening and Definitive Assessments was developed. The ERA is primarily based on expert consultation, with decision processes in each tier that lead to the approval of the petition or the subsequent tier. In the Scoping Assessment, likelihood of establishment (for augmentative BC), and potential effect(s) are qualitatively assessed. If risks are identified, the Screening Assessment is conducted, in which 19 categories of effects (adverse and beneficial) are quantified. If a risk exceeds the proposed risk threshold in any of these categories, the analysis moves to the Definitive Assessment to identify potential non-target species in the respective category(ies). When at least one potential non-target species is at significant risk, long-term and indirect ecosystem risks must be quantified with actual data or the petition for release can be dismissed or withdrawn. The proposed ERA should contribute to the development of safe pathways for the use of low risk GABCAs