IgE immunotherapy: A novel concept with promise for the treatment of cancer

The importance of antibodies in activating immune responses against tumors is now better appreciated with the emergence of checkpoint blockade antibodies and with engineered antibody Fc domains featuring enhanced capacity to focus potent effector cells against cancer cells. Antibodies designed with Fc regions of the IgE class can confer natural, potent, long-lived immune surveillance in tissues through tenacious engagement of high-affinity cognate Fc receptors on distinct, often tumor-resident immune effector cells, and through ability to activate these cells under tumor-induced Th2-biased conditions. Here, we review the properties that make IgE a contributor to the allergic response and a critical player in the protection against parasites, which also support IgE as a novel anti-cancer modality. We discuss IgE-based active and passive immunotherapeutic approaches in disparate in vitro and in vivo model systems, collectively suggesting the potential of IgE immunotherapies in oncology. Translation toward clinical application is now in progress.     

Comparative reactivity of human IgE to cynomolgus monkey and human effector cells and effects on IgE effector cell potency

Background: Due to genetic similarities with humans, primates of the macaque genus such as the cynomolgus monkey are often chosen as models for toxicology studies of antibody therapies. IgE therapeutics in development depend upon engagement with the FcεRI and FcεRII receptors on immune effector cells for their function. Only limited knowledge of the primate IgE immune system is available to inform the choice of models for mechanistic and safety evaluations.   Methods: The recognition of human IgE by peripheral blood lymphocytes from cynomolgus monkey and man was compared. We used effector cells from each species in ex vivo affinity, dose-response, antibody-receptor dissociation and potency assays. Results: We report cross-reactivity of human IgE Fc with cynomolgus monkey cells, and comparable binding kinetics to peripheral blood lymphocytes from both species. In competition and dissociation assays, however, human IgE dissociated faster from cynomolgus monkey compared with human effector cells. Differences in association and dissociation kinetics were reflected in effector cell potency assays of IgE-mediated target cell killing, with higher concentrations of human IgE needed to elicit effector response in the cynomolgus monkey system. Additionally, human IgE binding on immune effector cells yielded significantly different cytokine release profiles in each species. Conclusion: These data suggest that human IgE binds with different characteristics to human and cynomolgus monkey IgE effector cells. This is likely to affect the potency of IgE effector functions in these two species, and so has relevance for the selection of biologically-relevant model systems when designing pre-clinical toxicology and functional studies.     

A new callose function: Involvement in differentiation and function of fern stomatal complexes

Callose in polypodiaceous ferns performs multiple roles during stomatal development and function. This highly dynamic (1→3)-β-D-glucan, in cooperation with the cytoskeleton, is involved in: (a) stomatal pore formation, (b) deposition of local GC wall thickenings and (c) the mechanism of stomatal pore opening and closure. This behavior of callose, among others, probably relies on the particular mechanical properties as well as on the ability to form and degrade rapidly, to create a scaffold or to serve as a matrix for deposition of other cell wall materials and to produce fibrillar deposits in the periclinal GC walls, radially arranged around the stomatal pore. The local callose deposition in closing stomata is an immediate response of the external periclinal GC walls experiencing strong mechanical forces induced by the neighboring cells. The radial callose fibrils transiently co-exist with radial cellulose microfibrils and, like the latter, seem to be oriented via cortical MTs.Key words: callose, cytoskeleton, fern stomata, guard cell wall thickening, stomatal function, stomatal pore formationCallose represents a hemicellulosic matrix cell wall component, usually of temporal appearance, which is synthesized by callose synthases, enzymes localized in the plasmalemma and degraded by (1→3)-β-glucanases.^1–4 It consists of triple helices of a linear homopolymer of (1→3)-β-glucose residues.^5–7 The plant cell is able to form and degrade callose in a short time. On the surface of the plasmolyzed protoplast a thin callose surface film may arise within seconds.⁸ Callose is the only cell wall component that is implicated in a great variety of developmental plant processes, like cell plate formation,^9–11 microspore development,^12–14 trafficking through plasmodesmata,^15,16 formation and closure of sieve pores,¹⁶ response of the plant cells to multiple biotic and abiotic stresses,^4,5 establishment of distinct “cell cortex domains”,¹⁷ etc.Despite the widespread occurrence of callose, its general function(s) is (are) not well understood (reviewed in refs. ⁴ and ⁵). It may serve as: a matrix for deposition of other cell wall materials, as in developing cell plates;⁹ a cell wall-strengthening material, as in cotton seed hairs and growing pollen tubes;¹⁸ a sealing or plugging material at the plasma membrane of pit fields, plasmodesmata and sieve plate pores;¹⁶ a mechanical obstruction to growth of fungal hyphae or a special permeability barrier, as in pollen mother cell walls and muskmelon endosperm envelopes.^4,19,20 The degree of polymerization, age and thickness of callose deposits may cause variation in its physical properties.⁵Evidence accumulated so far showed that a significant number of ferns belonging to Polypodiales and some other fern classes forms intense callose deposits in the developing GC wall thickenings.^21–28 This phenomenon has not been observed in angiosperm stomata, although callose is deposited along the whole surface of the young VW and in the VW ends of differentiating and mature stomata (our unpublished data; reviewed in refs ²⁹ and ³⁰).Stomata are specialized epidermal bicellular structures (Fig. 1A) regulating gas exchange between the aerial plant organs and the external environment. Their appearance in the first land plants was crucial for their adaptation and survival in the terrestrial environment. The constituent GCs have the ability to undergo reversible changes in shape, leading to opening and closure of the stomatal pore (stomatal movement). The mechanism by which GCs change shape is based on: (a) the particular mechanical properties of GC walls owed to their particular shape, thickening, fine structure and chemical composition and (b) the reversible changes in vacuole volume, in response to environmental factors, through fairly complicated biochemical pathways.^30–33Open in a separate windowFigure 1(A) Diagrammatic representation of an elliptical stoma. (B–E) Diagram to show the process of stomatal pore formation in angiosperms (B and C) and Polypodiales ferns (D and E). The arrows in (B) indicate the forming stomatal pore. DW, dorsal wall; EPW, external periclinal wall; GC, guard cell; IPW, internal periclinal wall; ISP, internal stomatal pore; PE polar ventral wall end; VW, ventral wall.The present review is focused on the multiple-role of callose in differentiating and functioning fern stomata, as they are substantiated by the available information, including some unpublished data, and in particular in: stomatal pore formation, deposition of GC wall thickenings and opening and closure of the stomatal pore. The mode of deposition of fibrillar callose deposits in GC walls and the mechanism of their alignment are also considered.     

Characterization of novel elongated Parvulin isoforms that are ubiquitously expressed in human tissues and originate from alternative transcription initiation

Background  

The peptidyl prolyl cis/trans isomerase (PPIase) Parvulin (Par14/PIN4) is highly conserved in all metazoans and is assumed to play a role in cell cycle progression and chromatin remodeling. It is predominantly localized to the nucleus and binds to chromosomal DNA as well as bent oligonucleotides in vitro.     

Nonlinear analysis of biomagnetic signals recorded from uterine myomas

Objective

To determine if there is any non-linearity in the biomagnetic recordings of uterine myomas and to find any differences that may be present in the mechanisms underlying their signal dynamics.

Methods

Twenty-four women were included in the study. Sixteen of them were characterised with large myomas and 8 with small ones. Uterine artery waveform measurements were evaluated by use of Pulsatility Index (PI) (normal value PI<1.45).

Results

Applying nonlinear analysis to the biomagnetic signals of the uterine myomas, we observed a clear saturation value for the group of large ones (mean = 11.35 ± 1.49) and no saturation for the small ones.

Conclusion

The comparison of the saturation values in the biomagnetic recordings of large and small myomas may be a valuable tool in the evaluation of functional changes in their dynamic behavior.

     

Effect of biotic and abiotic factors on reproductive parameters of the synovigenic endoparasitoid Venturia canescens

Abstract.  The main effects and interactions of adult age, access to food and host deprivation, on the egg load of Venturia canescens (Gravenhorst) (Hymenoptera: Ichneumonidae), a larval parasitoid of Ephestia kuehniella (Lepidoptera: Pyralidae) and other pyralids, were studied in the laboratory. Intraspecific variation in the number of ovarioles was also studied. There was a positive and significant correlation between wasp size and both egg load and ovariole number, with the reproductive system of large wasps containing significantly more ovarioles and mature eggs than small wasps. Newly emerged adult wasps contained 27 ± 2.4 ovulated (mature) eggs in their lateral oviducts. Access to food and host deprivation were the only conditions under which egg load increased with parasitoid age. Wasps that had access to hosts immediately after emergence showed a significant decline in their egg complement, irrespective of food presence. Under conditions of both host and food deprivation, there was practically no alteration of egg load with parasitoid age. A three-way analysis of variance revealed that egg load varies significantly with food or host access but not with parasitoid age. All interactions among the three factors were significant. It is confirmed that there is no egg resorption in V. canescens and that egg production stops in the absence of food.     

Bacterial diversity of the outflows of a Polichnitos (Lesvos,Greece) hot spring,laboratory studies of a <Emphasis Type="Italic">Cyanobacterium</Emphasis> sp. strain and potential medical applications

The bacterial diversity of the outflows of Polichnitos (Lesvos, Greece) hot spring has been investigated. Cyanobacteria showing high sequence homologies with Phormidium sp. and Cyanobacterium aponinum were found. Members of the Alphaproteobacteria closely related to Rhodobium sp. Albidovulum sp., Rhodobacter sp., Microvigra sp., Nitratireductor sp. and Phaeobacter sp. Gammaproteobacteria, Betaproteobacteria and Firmicutes were represented by members of Idiomarina sp., Marinobacter sp., Shinella sp., Bacillus sp. and Clostridium sp. with sequence homologies ranging from 92% to 100%. Members of the Bacteroidetes and Planctomycetes were represented by sequences of novel phylogenetic linkages exhibiting 87–90% sequence homology with type strains. When the hot spring consortium was cultivated in bioreactor repeated batch culture under photo-autotrophic growth conditions at temperature < 30 °C, Cyanobacterium sp. dominated over Phormidium sp. Cyanobacterium sp. seems to have biotechnological potential since its extracellular broth exhibited a strong insecticidal activity against larvae of Aedes aegypti (a vector of important human diseases) and significant anti-cancer activity against the PC3 human prostate cancer cell line, while its toxicity against human endothelial cells was relatively low.     

Functional analysis of the two cyclophilin isoforms of <Emphasis Type="Italic">Sinorhizobium meliloti</Emphasis>

The nitrogen fixing Sinorhizobium meliloti possesses two genes, ppiA and ppiB, encoding two cyclophilin isoforms which belong to the superfamily of peptidyl prolyl cis/trans isomerases (PPIase, EC: 5.2.1.8). Here, we functionally characterize the two proteins and we demonstrate that both recombinant cyclophilins are able to isomerise the Suc-AAPF-pNA synthetic peptide but neither of them displays chaperone function in the citrate synthase thermal aggregation assay. Furthermore, we observe that the expression of both enzymes increases the viability of E. coli BL21 in the presence of abiotic stress conditions such as increased heat and salt concentration. Our results support and strengthen previous high-throughput studies implicating S. meliloti cyclophilins in various stress conditions.     

Dual antioxidant structures with potent anti-inflammatory,hypolipidemic and cytoprotective properties

Novel amide derivatives of trolox, 3,5-di-tert-butyl-4-hydroxybenzoic acid, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid and cinnamic acid with cysteamine and l-cysteine ethyl ester were synthesised. In four cases, the disulfide derivatives were also isolated and tested. All compounds were examined for antioxidant activity, expressed as their ability to inhibit lipid peroxidation and to scavenge free radicals. They were found to demonstrate up to 17-fold better activity than that of the parent antioxidant acids. They could reduce acute inflammation up to 87%. The most active antioxidant compounds were further tested for their in vivo hypolipidemic effect, which ranged from 47% to 73%, and for their ability to protect the liver against oxidative toxicity caused by high paracetamol dose. The disulfide derivatives of 3,5-di-tert-butyl-4-hydroxybenzoic acid and cinnamic acid had no antioxidant activity and presented equal or lower anti-inflammatory effect than their thiol analogues, indicating that their molecular characteristics may not permit biological barrier penetration.