Tethered N-Heterocyclic Carbene-Carboranyl Silver Complexes for Cancer Therapy

Silver complexes of tethered N-heterocyclic carbene-carboranyl ligands have been prepared and fully characterized. The first example of silver bonded directly to the cage of o-carborane has been identified in the solid state. The presence of a carboranyl N substituent on the N-heterocyclic carbene significantly enhances the in vitro cytotoxicity of the silver complex against HCT116 p53+/+ and HCT116 p53–/– colon cancer cells in comparison to a phenyl derivative. Conversely, the presence of a carboranyl on the backbone of a xanthine-derived N-heterocyclic carbene decreases the in vitro cytotoxicity of the silver complex in comparison to its phenyl derivative. Stability studies on the xanthine-derived ligands and complexes show that decomposition via deboronation occurs in hydrous dimethyl sulfoxide, which may attribute to the contrasting in vitro behaviors of the carborane-containing complexes

Competitive aminal formation during the synthesis of a highly soluble, isopropyl-decorated imine porous organic cage.

The synthesis of a new porous organic cage decorated with isopropyl moieties (CC21) was achieved from the reaction of triformylbenzene and an isopropyl functionalised diamine. Unlike structurally analogous porous organic cages, its synthesis proved challenging due to competitive aminal formation, rationalised using control experiments and computational modelling. The use of an additional amine was found to increase conversion to the desired cage

A minimally invasive immunocytochemical approach to early detection of oral squamous cell carcinoma and dysplasia

Squamous dysplasia of the oral cavity indicates increased risk of progression to squamous cell carcinoma (SCC). An important advance would be the development of a minimally invasive assay for identification of oral SCC and dysplasia. We have investigated the suitability in this context of immunostaining oral smears for minichromosome maintainance proteins (MCMs), sensitive and specific biomarkers of cell cycle entry. Immunohistochemical examination of 66 oral tissue samples showed a greater frequency of Mcm-2 expression in surface layers of moderate/severe dysplasia and SCC compared to benign keratosis/mild dysplasia. Immunocytochemistry for Mcm-2/Mcm-5 was performed on 101 oral smears. Conventional smears included 23 from normal mucosa, benign proliferative disease and mild dysplasia, all of which were MCM negative. Of 52 conventional smears of SCC tissue samples, 18 were inadequate. However, MCM-positive cells were present in 33/34 adequate samples. Of 26 liquid-based cytology smears, 19 out of 20 smears from SCC were adequate and all were MCM positive. Six smears from benign lesions were adequate and MCM negative. We conclude that MCMs are promising markers for early detection of oral SCC and dysplasia, particularly in a liquid-based cytology platform. Detection of MCMs would be amenable to automation and potentially applicable in the developing world. Further studies are now warranted

Functional diversity of marine ecosystems after the Late Permian mass extinction event

Article can be accessed from http://www.nature.com/ngeo/journal/v7/n3/full/ngeo2079.htmlThe Late Permian mass extinction event was the most severe such crisis of the past 500 million years and occurred during an episode of global warming. It is assumed to have had significant ecological impact, but its effects on marine ecosystem functioning are unknown and the patterns of marine recovery are debated. We analysed the fossil occurrences of all known Permian-Triassic benthic marine genera and assigned each to a functional group based on their inferred life habit. We show that despite the selective extinction of 62-74% of marine genera there was no significant loss of functional diversity at the global scale, and only one novel mode of life originated in the extinction aftermath. Early Triassic marine ecosystems were not as ecologically depauperate as widely assumed, which explains the absence of a Cambrian-style Triassic radiation in higher taxa. Functional diversity was, however, significantly reduced in particular regions and habitats, such as tropical reefs, and at these scales recovery varied spatially and temporally, probably driven by migration of surviving groups. Marine ecosystems did not return to their pre-extinction state, however, and radiation of previously subordinate groups such as motile, epifaunal grazers led to greater functional evenness by the Middle Triassic

Diagnosis of bladder cancer by immunocytochemical detection of minichromosome maintenance protein-2 in cells retrieved from urine.

BACKGROUND: We tested the accuracy of immunocytochemistry (ICC) for minichromosome maintenance protein-2 (MCM-2) in diagnosing bladder cancer, using cells retrieved from urine. METHODS: Adequate samples were obtained from 497 patients, the majority presenting with gross haematuria (GH) or undergoing cystoscopic surveillance (CS) following previous bladder cancer. We performed an initial study of 313 patients, followed by a validation study of 184 patients. In all cases, presence/absence of bladder cancer was established by cystoscopy/biopsy. RESULTS: In the initial study, receiver operator characteristic analysis showed an area under the curve of 0.820 (P<0.0005) for the GH group and 0.821 (P<0.01) for the CS group. Optimal sensitivity/specificity were provided by threshold values of 50+ MCM-2-positive cells in GH samples and 200+ cells in CS samples, based on a minimum total cell number of 5000. Applying these thresholds to the validation data set gave 81.3% sensitivity, 76.0% specificity and 92.7% negative predictive value (NPV) in GH and 63.2% sensitivity, 89.9% specificity and 89.9% NPV in CS. Minichromosome maintenance protein-2 ICC provided clinically relevant improvements over urine cytology, with greater sensitivity in GH and greater specificity in CS (P=0.05). CONCLUSIONS: Minichromosome maintenance protein-2 ICC is a reproducible and accurate test that is suitable for both GH and CS patient groups

Immunohistochemical estimation of cell cycle phase in laryngeal neoplasia

We previously developed an immunohistochemical method for estimating cell cycle state and phase in tissue samples, including biopsies that are too small for flow cytometry. We have used our technique to examine whether primary abnormalities of the cell cycle exist in laryngeal neoplasia. Antibodies against the markers of cell cycle entry, minichromosome maintenance protein-2 (Mcm-2) and Ki67, and putative markers of cell cycle phase, cyclin D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis) were applied to paraffin-embedded sections of normal larynx (n=8), laryngeal dysplasia (n=10) and laryngeal squamous cell carcinoma (n=10). Cells expressing each marker were determined as a percentage of total cells, termed the labelling index (LI), and as a percentage of Mcm-2-positive cells, termed the labelling fraction (LF). The frequency of coexpression of each putative phase marker was investigated by confocal microscopy. There was a correlation between Mcm-2 and Ki67 LIs (ρ=0.93) but Mcm-2 LIs were consistently higher. All cells expressing a phase marker coexpressed Mcm-2, whereas Ki67 was not expressed in a proportion of these cells. The putative phase markers showed little coexpression. Labelling index values increased on progression from normal larynx through laryngeal dysplasia to squamous cell carcinoma for Mcm-2 (P=0.001), Ki67 (P=0.0002), cyclin D1 (P=0.015), cyclin A (P=0.0001) and cyclin B1 (P=0.0004). There was no evidence of an increase in the LF for any phase marker. Immunohistochemistry can be used to estimate cell cycle state and phase in laryngeal biopsies. Our data argues against primary cell cycle phase abnormalities in laryngeal neoplasia

Accelerated robotic discovery of type II porous liquids

Porous liquids are an emerging class of materials and to date little is known about how to best design their properties. For example, bulky solvents are required that are size-excluded from the pores in the liquid, along with high concentrations of the porous component, but both of these factors may also contribute to higher viscosities, which are undesirable. Hence, the inherent multivariate nature of porous liquids makes them amenable to high-throughput optimisation strategies. Here we develop a high-throughput robotic workflow, encompassing the synthesis, characterisation and property testing of highly-soluble, vertex-disordered porous organic cages dissolved in a range of cavity-excluded solvents. As a result, we identified 29 cage–solvent combinations that combine both higher cage-cavity concentrations and more acceptable carrier solvents than the best previous examples. The most soluble materials gave three times the pore concentration of the best previously reported scrambled cage porous liquid, as demonstrated by increased gas uptake. We were also able to explore alternative methods for gas capture and release, including liberation of the gas by increasing the temperature. We also found that porous liquids can form gels at higher concentrations, trapping the gas in the pores, which could have potential applications in gas storage and transportation

Magnetostratigraphy of Permian/Triassic boundary sequences in the Cis-Urals, Russia : no evidence for a major temporal hiatus

During the last five years there has been considerable doubt over the age of the continental uppermost Permian Russian stages, the Kazanian and Tatarian. Traditionally they have been regarded as Late Permian but were re-dated as Middle Permian in the 2004 international time scale, despite fossil evidence that the Tatarian, at least, is Late Permian. These debated ages are tested by magnetostratigraphic study of five sections spanning the Permian Triassic Boundary (PTB) of the SE Urals in the Orenburg region of Russia. The Upper Permian and Lower Triassic of this region have a well documented vertebrate fauna whose evolution has a significant bearing on our understanding of the PTB mass extinction event. If the Tatarian is viewed as Mid Permian, then the Late Permian in Russia is marked by a 9–10 Ma stratigraphic gap. The palaeomagnetic data yield a distinct series of polarity zones that provide clear local and regional correlation and are readily tied to a recently compiled global magnetostratigraphic record. On the basis of this correlation the sampled sections span the upper Guadalupian to Induan stages without any obvious break, so confirming the traditional view that the Tatarian is Late Permian in age. Anomalies in the magnetic inclination are consistent with sediment compaction (inclination shallowing, a common phenomenon of red beds) but declination anomalies between these sites and elsewhere in Russia may suggest localised vertical axis rotation