IgE-antibody-dependent immunotherapy of solid tumors: cytotoxic and phagocytic mechanisms of eradication of ovarian cancer cells

Abs have a paramount place in the treatment of certain, mainly lymphoid, malignancies, although tumors of nonhemopoietic origin have proved more refractory ones. We have previously shown that the efficacy of immunotherapy of solid tumors, in particular ovarian carcinoma, may be improved by the use of IgE Abs in place of the conventional IgG. An IgE Ab (MOv18 IgE) against an ovarian-tumor-specific Ag (folate binding protein), in combination with human PBMC, introduced into ovarian cancer xenograft-bearing mice, greatly exceeded the analogous IgG1 in promoting survival. In this study, we analyzed the mechanisms by which MOv18 IgE may exert its antitumor activities. Monocytes were essential IgE receptor-expressing effector cells that mediated the enhanced survival of tumor-bearing mice by MOv18 IgE and human PBMC. Monocytes mediated MOv18 IgE-dependent ovarian tumor cell killing in vitro by two distinct pathways, cytotoxicity and phagocytosis, acting respectively through the IgE receptors FcepsilonRI and CD23. We also show that human eosinophils were potent effector cells in MOv18 IgE Ab-dependent ovarian tumor cell cytotoxicity in vitro. These results demonstrate that IgE Abs can engage cell surface IgE receptors and activate effector cells against ovarian tumor cells. Our findings offer a framework for an improved immunotherapeutic strategy for combating solid tumors.     

Fused in Sarcoma (FUS) Protein Lacking Nuclear Localization Signal (NLS) and Major RNA Binding Motifs Triggers Proteinopathy and Severe Motor Phenotype in Transgenic Mice

Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1–359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1–359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5–4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1–359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice.     

Findings from the Peutz-Jeghers Syndrome Registry of Uruguay

Background

Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients.

Methods

Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed.

Results and discussion

25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000.

Conclusion

The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation.     

Assessment of Local Public Health Workers' Willingness to Respond to Pandemic Influenza through Application of the Extended Parallel Process Model

Background

Local public health agencies play a central role in response to an influenza pandemic, and understanding the willingness of their employees to report to work is therefore a critically relevant concern for pandemic influenza planning efforts. Witte''s Extended Parallel Process Model (EPPM) has been found useful for understanding adaptive behavior in the face of unknown risk, and thus offers a framework for examining scenario-specific willingness to respond among local public health workers. We thus aim to use the EPPM as a lens for examining the influences of perceived threat and efficacy on local public health workers'' response willingness to pandemic influenza.

Methodology/Principal Findings

We administered an online, EPPM-based survey about attitudes/beliefs toward emergency response (Johns Hopkins∼Public Health Infrastructure Response Survey Tool), to local public health employees in three states between November 2006 – December 2007. A total of 1835 responses were collected for an overall response rate of 83%. With some regional variation, overall 16% of the workers in 2006-7 were not willing to “respond to a pandemic flu emergency regardless of its severity”. Local health department employees with a perception of high threat and high efficacy – i.e., those fitting a ‘concerned and confident’ profile in the EPPM analysis – had the highest declared rates of willingness to respond to an influenza pandemic if required by their agency, which was 31.7 times higher than those fitting a ‘low threat/low efficacy’ EPPM profile.

Conclusions/Significance

In the context of pandemic influenza planning, the EPPM provides a useful framework to inform nuanced understanding of baseline levels of – and gaps in – local public health workers'' response willingness. Within local health departments, ‘concerned and confident’ employees are most likely to be willing to respond. This finding may allow public health agencies to design, implement, and evaluate training programs focused on emergency response attitudes in health departments.     

Electrogenic Cl<Superscript>−</Superscript> secretion does not occur in the ileum of the Australian common brushtail possum, <Emphasis Type="Italic">Trichosurus vulpecula</Emphasis>, due to low levels of expression of the NaK2Cl cotransporter,NKCC1

The colon of the brushtail possum does not have an electrogenic secretory response. Given the functional significance of electrogenic Cl⁻ secretion in the intestine of eutherian mammals, we have investigated the secretory response in the small intestine of this marsupial. In the Ussing chamber cAMP-dependent secretagogues stimulated a sustained increase in ileal short-circuit current (Isc), whereas Ca²⁺-dependent secretagogues induced a transient increase. Both the responses were inhibited by mucosal addition of the anion channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (100 μmol l⁻¹), consistent with an anion secretory response. However, the responses were not inhibited by serosal bumetanide (10 μmol l⁻¹) and were independent of bath Cl⁻, indicating that the stimulated ileal Isc does not involve electrogenic Cl⁻ secretion driven by the NaK2Cl cotransporter, NKCC1. Consistent with this, there were low levels of NKCC1 expression in the ileal epithelium. In particular, NKCC1 expression in the ileal crypt cells was comparable to that of the villous cells. This differs from eutherian mammals where high levels of NKCC1 expression in the ileal crypt cells are associated with their role in Cl⁻ secretion. The cAMP- and Ca²⁺-dependent secretory responses were inhibited by the removal of HCO₃ ⁻ suggesting that these responses were due to electrogenic HCO₃ ⁻ secretion. We conclude that the ileum of the possum does not secrete Cl⁻ due to low levels of NKCC1 expression. It does however appear to secrete HCO₃ ⁻. These results are further significant examples of differences in the transport function of the possum intestinal epithelium compared with eutherian mammals.     

Assessment of regional and local biodiversity in tropical and subtropical coastal habitats in the East African Marine Ecoregion

The transboundary networks of Marine Protected Areas (MPAs) project, TRANSMAP, assessed local turnover and regional biodiversity across the East African Marine Ecoregion, where inter-governmental co-operation has been working to connect local MPAs. The benthic fauna in the three most dominant habitats on this coastline??beaches, mangroves and seagrasses??were studied in two Regions (Northern Region, 10?C13°S; Southern Region, 25?C28°S). Meiofaunal taxa were used as the model faunal group owing to their diversity and abundance across habitat types and environmental conditions. Meiofaunal abundance averaged 2,500 individuals 10 cm^?2 and was generally higher in mangrove and seagrass sediments than on the beaches, and was significantly different between habitats × Regions. In total, 18 taxa were recorded with highest diversity in the beach samples. Diversity indices and assemblage structure were significantly different between habitats, but also Regions. Specific granulometric 1?? size classes, shore-height and number of rain days were the factors most significantly correlating with the observed assemblage patterns. Additionally, the size of a MPA and latitude (which correlated with MPA age, but not number of rain days), were the factors fitting best with meiofaunal assemblage patterns across the beaches, the habitat for which the most comprehensive data were generated. Sample diversity was higher in the Southern Region, and although within- and across-habitats diversity were similar across the Regions, the two Regions appeared to provide complementary habitats and supported different assemblages. Within the Regions, beaches (the only habitat for which more than one location was sampled) were significantly different between Locations, supporting the establishment of multiple protected locations of the same habitat within each transboundary MPA.