Necroptosis in immuno-oncology and cancer immunotherapy

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To "break" cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy

Microleakage and Resin-to-Dentin Interface Morphology of Pre-Etching versus Self-Etching Adhesive Systems

The purpose of this study was to compare the microleakage and tissue-adhesive interface morphology from Class V restorations using different systems of dentin adhesives. Class V cavities were prepared on buccal surfaces of 27 extracted caries-free molars and premolars. Teeth were randomly assigned to one of three groups: (1) Prime & Bond NT, a 5th generation system using an initial step of total etch followed by a second step of application of a self bonding primer (2) Clearfil SE Bond, a 5th generation adhesive system employing two separate steps of self-etch priming and subsequent bonding (3) One-up Bond F, a 6th generation one step self-etching, self-priming and self-bonding adhesive. Microleakage and interface morphology of teeth restored with these adhesives and a composite resin were evaluated. Kruskal-Wallis Test (p = 0.05) was used to analyze the results. SEM analysis was used to relate interface morphology to microleakage. The mean and (SD) values of microleakage were: Prime and Bond NT: 0.15 (0.33), Clearfil SE Bond: 0.06 (0.17) and One-up Bond F: 2.96 (0.63). The mean microleakage for One-up Bond was significantly higher than for the other groups (p<0.05). Protruding tags in dentin channels were observed in Prime and Bond and Clearfil systems, but not in One-up Bond. The single step adhesive system, although more convenient for the clinician, uses a low viscosity formulation difficult to keep in place on cavity walls. It also tends to be too aggressive and hydrophilic to create an impermeable hybridized tissue-adhesive interfacial layer resistant to microleakage. Two-step adhesive systems, on the other hand, were retained on all segments of the cavosurface during application, and formed a hybridized interfacial layer resistant to microleakage

Ellenberg-type indicator values for European vascular plant species

Aims: Ellenberg-type indicator values are expert-based rankings of plant species according to their ecological optima on main environmental gradients. Here we extend the indicator-value system proposed by Heinz Ellenberg and co-authors for Central Europe by incorporating other systems of Ellenberg-type indicator values (i.e., those using scales compatible with Ellenberg values) developed for other European regions. Our aim is to create a harmonized data set of Ellenberg-type indicator values applicable at the European scale. Methods: We collected European data sets of indicator values for vascular plants and selected 13 data sets that used the nine-, ten- or twelve-degree scales defined by Ellenberg for light, temperature, moisture, reaction, nutrients and salinity. We compared these values with the original Ellenberg values and used those that showed consistent trends in regression slope and coefficient of determination. We calculated the average value for each combination of species and indicator values from these data sets. Based on species’ co-occurrences in European vegetation plots, we also calculated new values for species that were not assigned an indicator value. Results: We provide a new data set of Ellenberg-type indicator values for 8908 European vascular plant species (8168 for light, 7400 for temperature, 8030 for moisture, 7282 for reaction, 7193 for nutrients, and 7507 for salinity), of which 398 species have been newly assigned to at least one indicator value. Conclusions: The newly introduced indicator values are compatible with the original Ellenberg values. They can be used for large-scale studies of the European flora and vegetation or for gap-filling in regional data sets. The European indicator values and the original and taxonomically harmonized regional data sets of Ellenberg-type indicator values are available in the Supporting Information and the Zenodo repository

High-resolution local vibrational mode spectroscopy of the negatively charged oxygen-vacancy complex in germanium

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Comparative Sem and Tem Examination of the Ultrastructure of the Resin-dentin Interdiffusion Zone

The resin-dentin interdiffusion zone produced by a dentin-adhesive system that removes the smear layer and concurrently decalcifies superficial dentin was morphologically examined by both scanning and transmission electron microscopy. Cross-sectioned resin-bonded dentin discs were etched with an argon-ion beam to make the resin-dentin interface observable by SEM. For the TEM examination, the sections were partly decalcified by an aqueous EDTA solution to facilitate ultramicrotomy and to disclose the ultrastructure of the interdiffusion zone. Both SEM and TEM confirmed the presence of the resin-dentin interdiffusion zone as the junction between the deep unaltered dentin structure and the restorative resin. Within the interdiffusion zone, three sublayers with characteristic ultrastructure and staining were identified by TEM. An upper diffuse black layer contained few structural features. Underneath, partially-altered collagen fibrils were closely packed, mostly running parallel with the interface and perpendicular to the dentinal tubules. Their outline was electron-dense, forming tunnel-like structures. At the base of the upper layer, several stained projections were found to bulge out into the underlying collagen network and appeared to be confined by obstructive, parallel-running collagen fibrils. Finally, the third dense layer, containing hydroxyapatite crystals, demarcated the superficially demineralized dentin layer from the deeper unaltered dentin. Resin diffusion into the decalcified dentin surface layer was evident, but diminished with depth, presumably reducing deeper resin impregnation into the interfibrillar spaces. The citric acid dentin-pretreatment probably caused denaturation of the superficial collagen fibrils. Its decalcifying effect gradually weakened with depth, leaving behind hydroxyapatite crystals at the base of the interdiffusion zone. These crystals appeared to have been resistant to the EDTA TEM-sample decalcification procedure, which suggests that they were protected by resin encapsulation

The interaction of adhesive systems with human dentin

Purpose: To investigate the interaction of six experimental and commercial bonding systems with dentin in vivo. Materials and Methods: One-Step, Clearfil Liner Bond 2, OptiBond, Permagen with 10% phosphoric acid, Permagen with 35% phosphoric acid, and Prime & Bond were applied in standard Class I occlusal cavities in premolars scheduled for extraction for orthodontic reasons, combined either with a self-cured or with a light-cured resin composite. The teeth were carefully extracted 5 minutes after resin polymerization and fixed in 2.5% glutaraldehyde. After fixation, the specimens were dehydrated, sectioned, and processed for field-emission SEM. Results: Although some systems produced gap-free intact interfaces in specific specimens, all of them showed detachment at the transition between the resin-dentin interdiffusion zone and the fluid resin placed over it. It was apparent that the presence of air-bubbles and/or thick layers of polymerized-filled fluid resin resulted in less frequent separation areas at the resin-dentin interface, providing support for the concept of the elastic cavity wall. It was also confirmed that some dentin adhesive systems do not form a thick layer over the dentin, otherwise the resin composite would not have penetrated the dentin tubules

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To "break" cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.status: publishe