Development of anti-MUC1 DNA aptamers for the imaging and radiotherapy of breast cancer

Aptamers are novel oligonucleotide-based recognition molecules which can bind to almost any target, including extracellular proteins, antibodies, peptides and small molecules. Aptamers can be rapidly generated, and offer reduced immunogenicity, good tumour penetration, rapid uptake and clearance, and can thus be used as alternatives to monoclonal antibodies in molecular targeted radiotherapy and diagnostic imaging

Development of anti-MUC1 DNA aptamers for the imaging and radiotherapy of breast cancer

Background Aptamers have shown great potential as novel targeted radiopharmaceutical entities for the diagnosis and imaging of disease. They offer reduced immunogenicity, good tumour penetration, rapid uptake and clearance compared with their monoclonal antibody counterparts. In previous work we have reported the labelling of such aptamers against breast-cancer-related biomarkers with radionuclide ligands. Methods We have now conjugated previously selected aptamers against the protein core of the MUC1 glycoprotein tumour marker with chelating agents and labelled them with 99mTc, for the diagnostic imaging of breast cancer. The conjugation is achieved using standard peptide coupling reactions between an amino modification on the aptamer and the carboxylic group on the ligands. Labelling with 99mTc used tin chloride as the reducing agent, and analysis was by HPLC where both the UV and the gamma emission was monitored. Radiolabelled aptamer conjugates were separated from free, unconjugated 99mTc using microcon filters. For the analysis of the pharmacokinetic properties of the aptamer–radionucleotide conjugate we used gamma-camera imaging in MCF-7 breast cancer tumour model systems. Results We coupled the aptamer with the highest affinity for the MUC1 glycoprotein to different ligands (MAG2 or meso-2,3-dimercaptosuccinic acid) and labelled it with active 99mTc to obtain stable complexes that were used in pharmacokinetic studies. This allows us to compare the properties of a single conjugate with a biaptamer conjugate, as two of the DMSA–aptamer conjugates can coordinate the metal core. An efficient and convenient labelling of the aptamer with short half-life radioisotopes was achieved as the last step of the synthesis (postconjugation labelling). The labelled aptamers were separated from free 99mTc using microcon filter separation and were monitored by HPLC at all stages, to ensure that only radiolabelled aptamers were injected and imaged for their pharmacokinetic properties. Conclusion The aptamer–chelator conjugates have strong 99mTc binding properties and the resulting complexes are highly stable in vivo both in terms of nuclease degradation and leaching of the metal. The presence of more than one molecule of aptamer per complex alters the binding and pharmacokinetic properties of the radiolabelled products, allowing the complex to remain longer in circulation and thus offering improved tumour imaging properties, without affecting the tumour penetration of the aptamer. Furthermore, different ligands affect accumulation of the aptamer in different organs, as they alter the lipophilic properties of the conjugate. These results aim to open new possibilities for the diagnostic imaging of, and potentially the targeted radiotherapy of, breast cancer. </br

Origin of magnetism and quasiparticles properties in Cr-doped TiO2_2

Combining LSDA+$U$ and an analysis of superexchange interactions beyond DFT, we describe the magnetic ground states in rutile and anatase Cr-doped TiO$_2$. In parallel, we correct our LSDA+$U$ ground state through GW corrections ($GW$@LSDA+$U$) that reproduce the position of impurity states and the band gaps in satisfying agreement with experiments. Because of the different topological coordinations of Cr-Cr bonds in the ground states of rutile and anatase, superexchange interactions induce either ferromagnetic or antiferromagnetic couplings of Cr ions. In Cr-doped anatase, this interaction leads to a new mechanism which stabilizes a ferromagnetic ground state, in keeping with experimental evidence, without the need to invoke F-center exchange.Comment: 5<pages, 4 figure

Novel Aptamer-Nanoparticle Bioconjugates Enhances Delivery of Anticancer Drug to MUC1-Positive Cancer Cells In Vitro

MUC1 protein is an attractive target for anticancer drug delivery owing to its overexpression in most adenocarcinomas. In this study, a reported MUC1 protein aptamer is exploited as the targeting agent of a nanoparticle-based drug delivery system. Paclitaxel (PTX) loaded poly (lactic-co-glycolic-acid) (PLGA) nanoparticles were formulated by an emulsion/evaporation method, and MUC1 aptamers (Apt) were conjugated to the particle surface through a DNA spacer. The aptamer conjugated nanoparticles (Apt-NPs) are about 225.3 nm in size with a stable in vitro drug release profile. Using MCF-7 breast cancer cell as a MUC1-overexpressing model, the MUC1 aptamer increased the uptake of nanoparticles into the target cells as measured by flow cytometry. Moreover, the PTX loaded Apt-NPs enhanced in vitro drug delivery and cytotoxicity to MUC1+ cancer cells, as compared with non-targeted nanoparticles that lack the MUC1 aptamer (P<0.01). The behavior of this novel aptamer-nanoparticle bioconjugates suggests that MUC1 aptamers may have application potential in targeted drug delivery towards MUC1-overexpressing tumors

Water Vapor Vertical Profiles on Mars in Dust Storms Observed by TGO/NOMAD

It has been suggested that dust storms efficiently transport water vapor from the near‐surface to the middle atmosphere on Mars. Knowledge of the water vapor vertical profile during dust storms is important to understand water escape. During Martian Year 34, two dust storms occurred on Mars: a global dust storm (June to mid‐September 2018) and a regional storm (January 2019). Here we present water vapor vertical profiles in the periods of the two dust storms (Ls = 162–260° and Ls = 298–345°) from the solar occultation measurements by Nadir and Occultation for Mars Discovery (NOMAD) onboard ExoMars Trace Gas Orbiter (TGO). We show a significant increase of water vapor abundance in the middle atmosphere (40–100 km) during the global dust storm. The water enhancement rapidly occurs following the onset of the storm (Ls~190°) and has a peak at the most active period (Ls~200°). Water vapor reaches very high altitudes (up to 100 km) with a volume mixing ratio of ~50 ppm. The water vapor abundance in the middle atmosphere shows high values consistently at 60°S‐60°N at the growth phase of the dust storm (Ls = 195°–220°), and peaks at latitudes greater than 60°S at the decay phase (Ls = 220°–260°). This is explained by the seasonal change of meridional circulation: from equinoctial Hadley circulation (two cells) to the solstitial one (a single pole‐to‐pole cell). We also find a conspicuous increase of water vapor density in the middle atmosphere at the period of the regional dust storm (Ls = 322–327°), in particular at latitudes greater than 60°S

No detection of methane on Mars from early ExoMars Trace Gas Orbiter observations

The detection of methane on Mars has been interpreted as indicating that geochemical or biotic activities could persist on Mars today. A number of different measurements of methane show evidence of transient, locally elevated methane concentrations and seasonal variations in background methane concentrations. These measurements, however, are difficult to reconcile with our current understanding of the chemistry and physics of the Martian atmosphere, which-given methane's lifetime of several centuries-predicts an even, well mixed distribution of methane. Here we report highly sensitive measurements of the atmosphere of Mars in an attempt to detect methane, using the ACS and NOMAD instruments onboard the ESA-Roscosmos ExoMars Trace Gas Orbiter from April to August 2018. We did not detect any methane over a range of latitudes in both hemispheres, obtaining an upper limit for methane of about 0.05 parts per billion by volume, which is 10 to 100 times lower than previously reported positive detections. We suggest that reconciliation between the present findings and the background methane concentrations found in the Gale crater would require an unknown process that can rapidly remove or sequester methane from the lower atmosphere before it spreads globally

Martian dust storm impact on atmospheric H₂O and D/H observed by ExoMars Trace Gas Orbiter

Global dust storms on Mars are rare but can affect the Martian atmosphere for several months. They can cause changes in atmospheric dynamics and inflation of the atmosphere, primarily owing to solar heating of the dust. In turn, changes in atmospheric dynamics can affect the distribution of atmospheric water vapour, with potential implications for the atmospheric photochemistry and climate on Mars. Recent observations of the water vapour abundance in the Martian atmosphere during dust storm conditions revealed a high-altitude increase in atmospheric water vapour that was more pronounced at high northern latitudes, as well as a decrease in the water column at low latitudes. Here we present concurrent, high-resolution measurements of dust, water and semiheavy water (HDO) at the onset of a global dust storm, obtained by the NOMAD and ACS instruments onboard the ExoMars Trace Gas Orbiter. We report the vertical distribution of the HDO/H O ratio (D/H) from the planetary boundary layer up to an altitude of 80 kilometres. Our findings suggest that before the onset of the dust storm, HDO abundances were reduced to levels below detectability at altitudes above 40 kilometres. This decrease in HDO coincided with the presence of water-ice clouds. During the storm, an increase in the abundance of H2O and HDO was observed at altitudes between 40 and 80 kilometres. We propose that these increased abundances may be the result of warmer temperatures during the dust storm causing stronger atmospheric circulation and preventing ice cloud formation, which may confine water vapour to lower altitudes through gravitational fall and subsequent sublimation of ice crystals. The observed changes in H2O and HDO abundance occurred within a few days during the development of the dust storm, suggesting a fast impact of dust storms on the Martian atmosphere

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic