In situ redox reactions facilitate the assembly of a mixed-valence metal-organic nanocapsule

C-alkylpyrogallol[4]arenes (PgCs) have been studied for their ability to form metal-organic nanocapsules (MONCs) through coordination to appropriate metal ions. Here we present the synthesis and characterization of an MnII/MnIII-seamed MONC in addition to its electrochemical and magnetic behavior. This MONC assembles from 24 manganese ions and 6 PgCs, while an additional metal ion is located on the capsule interior, anchored through the introduction of bridging nitrite ions. The latter originate from an in situ redox reaction that occurs during the self-assembly process, thus representing a new route to otherwise unobtainable nanocapsules

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Heterozygosity for human () dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the promoter. The patients\u27 cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with DN mutations, ZNF341-deficient patients lack T helper 17 (T17) cells, have an excess of T2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the transcription-dependent autoinduction and sustained activity of STAT3

Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COlQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We present data on 15 COLQ -mutant CMS carrying 16 different mutations (9 novel ones identified) followed-up for an average period of 10 ears. The mean age at the first examination was 19 ears old (range from 3 to 48). We report relapses during short or long-term periods characterized by worsening of muscle weakness sometimes associated with respiratory crises. All the relapses ended spontaneously or with 3-4 DAP or ephedrine with no residual impairment. The triggering factors identified were esterase inhibitors, effort, puberty or pregnancy highlighting the importance of hormonal factors. There was no genotype-phenotype correlation. At the end of the follow-up, 80% of patients were ambulant and 87% of patients had no respiratory trouble in spite of severe relapses

Abstract 1319: Early tumor regression after endocrine and kinase inhibitor treatments in mammary carcinomas with different hormonal requirements

Abstract Two-thirds of diagnosed breasts cancers express either estrogen receptors (ER), progesterone receptors (PR) or both. Unlike most experimental breast cancer models, in the medroxyprogesterone acetate (MPA) model, MPA induces mammary carcinomas that express high levels of ER and PR. In this model we developed a tumor variant that depends on MPA to grow (C4-HD), and another one that grows without it (C4-HI). Previous studies showed that both types of tumors represent a useful tool to study mechanisms of regression after endocrine therapy, since both regress, albeit differently, after prolonged treatment (10 days) with the antiprogestin mifepristone. While regressive C4-HD tumors display extensive apoptosis, C4-HI tumors regress showing increased glandular differentiation. In order to investigate specific mechanisms of regression and to determine if these mechanisms are tumor specific or antitumor agent specific, we evaluated early steps of tumor regression caused by different agents in C4-HD and C4-HI tumors. We evaluated mifepristone (12mg/kg/day), ER modulators such as ICI182780 (25mg/kg) and tamoxifen (5mg/kg/day), and the PI3K/AKT inhibitor wortmannin (1 mg/kg/day). Mice carrying C4-HD or C4-HI tumors were treated for 48 hours and then sacrificed. Tumors were measured, excised and processed for histopathological and immunohistochemical studies as well as western blotting. We found that after 48 hs of treatment the size of C4-HD tumors was only reduced with mifepristone (p&amp;lt;0.001). However, even a short exposure of these tumors to any of the treatments increased apoptosis and necrosis index and stromal area, with mifepristone and tamoxifen being the most effective (p&amp;lt;0.001 and 0.01 respectively). In C4-HI tumors, we did not observe an increase in apoptosis or necrosis index neither a significant stromal reaction after 48 hs with any treatment tested. However, all treatments caused tissular reorganization and differentiation, being the most effective mifepristone and wortmannin. To study tissue reorganization we evaluated the expression of differentiation markers such as the apical marker MUC-1 and the luminal cell marker cytoqueratin 8 and found that these markers are increased in C4-HI tumors treated with wortmannin and mifepristone (p&amp;lt;0.01). Taken together, these results suggest that each tumor variant has its own mechanism of regression in response to endocrine or kinase inhibitor treatments. Such different mechanism of regression in each tumor type may arise as a result of specific tumor-stromal interactions. Understanding the particular cellular mechanisms that lead to each tumor type regression could provide the basis to develop more specific and selective new antitumor therapies or potentiate therapies that already exist. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1319. doi:10.1158/1538-7445.AM2011-1319</jats:p