A self-immolative linker for the pH-responsive release of amides

The administration of therapeutics using bioconjugation has been mainly limited to drugs containing amine, alcohol, or thiol functional groups. Here, we report a general procedure for the preparation of benzylic N-acyl carbamates suitable for masking the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon in good to acceptable yields. These N-acyl carbamates appear to be stable in plasma, while a qualitative analysis of further drug uncage demonstrates that, at pH values of 5.5, a classical 1,6-benzyl elimination mechanism takes place, releasing more than 80% of the drug in 24 h. © 2023 by the authors

A novel DNA/histone H4 peptide complex detects autoantibodies in systemic lupus erythematosus sera

Background: The detection of anti-dsDNA antibodies is critical for the diagnosis and follow-up of systemic lupus erythematosus (SLE) patients. The presently available assays are characterized by a non-optimal specificity (solid phase assays) or sensitivity (Crithidia Luciliae immunofluorescence test (CLIFT)). To overcome the limits of CLIFT and solid phase chromatin assays, we explored the diagnostic potential of an assay based on plasmid DNA containing a highly bent fragment of 211 bp from Crithidia Luciliae minicircles, complexed with histone peptides. Methods: Electrically neutral complexes of PK201/CAT plasmid (PK) DNA and histone 4 (H4) peptides were evaluated by electromobility shift assay. Complexes of H4 peptides and PK were absorbed to the solid phase to detect specific immunoglobulin G (IgG) in sera. Sera from 109 SLE patients, 100 normal healthy subjects, and 169 disease controls were tested. Results: H4(14-34) containing the consensus sequence for DNA binding interacts with PK, retarding its migration. H4(14-34)/PK complexes were used to test sera by ELISA. Anti-H4-PK antibodies were detected in 56 % of SLE sera (more frequently in patients with skin or joint involvement) versus 5.9 % in disease controls; inhibition assays show that sera react with epitopes present on DNA or on the complex, not on the peptide. Antibody titer is correlated with European Consensus Lupus Activity Measurement (ECLAM) score and anti-complement component 1q (C1q) antibodies, negatively with C3 levels. Anti-H4-PK antibodies compared with CLIFT and solid phase dsDNA assays display moderate concordance. Conclusions: The H4/PK assay is a simple and reliable test which is useful for the differential diagnosis and evaluation of disease activity in SLE patients

Documenting cultural heritage in an INSPIRE-based 3D GIS for risk and vulnerability analysis

Purpose The study, within the Increasing Resilience of Cultural Heritage (ResCult) project, aims to support civil protection to prevent, lessen and mitigate disasters impacts on cultural heritage using a unique standardised-3D geographical information system (GIS), including both heritage and risk and hazard information. Design/methodology/approach A top-down approach, starting from existing standards (an INSPIRE extension integrated with other parts from the standardised and shared structure), was completed with a bottom-up integration according to current requirements for disaster prevention procedures and risk analyses. The results were validated and tested in case studies (differentiated concerning the hazard and type of protected heritage) and refined during user forums. Findings Besides the ensuing reusable database structure, the filling with case studies data underlined the tough challenges and allowed proposing a sample of workflows and possible guidelines. The interfaces are provided to use the obtained knowledge base. Originality/value The increasing number of natural disasters could severely damage the cultural heritage, causing permanent damage to movable and immovable assets and tangible and intangible heritage. The study provides an original tool properly relating the (spatial) information regarding cultural heritage and the risk factors in a unique archive as a standard-based European tool to cope with these frequent losses, preventing risk

Oxygen investigation in the Galileian satellites using AFOSC

Spectroscopy in the visible range of the Galilean satellites is a suitable way to investigate the surface properties of these objects. In recent years, several species, like O_2, O_3, and SO_2, have been detected on the surfaces of these satellites, which were thought to be completely covered only by water ice. The recent detection of the O_2 absorption bands in the Ganymede trailing face \citep{spencer_1995} led to laboratory experiments in order to better constraint the O_2 phases trapped in the water ice surface \citep{vidal_1997}. The same features were observed also on Europa and Callisto surfaces \citep{spencer_2002}, although a better investigation of their properties and their variability with time is still not fully addressed. We proposed ground-based observations with the AFOSC instrument on the 1.8-m telescope in Asiago, to investigate the Galilean satellites? surface properties, focusing both on the leading and trailing faces of the satellites. We used the Volume Phase Holographic grism covering the spectral range 400-1000 nm, with a spectral resolution of about 5000. In this work, we show results of the observations acquired in November 2014, focusing on the leading faces of the satellites. Data were treated using standard methods of data reduction. Further observations with the same setup, scheduled for February 2015 to observe the trailing face of the Galileian satellites, will complement the program. These observations are in preparation to the future science we will be able to perform with the MAJIS spectrometer on the European JUICE mission

A pH-responsive crosslinker platform for antibody-drug conjugate (ADC) targeting delivery

We report a new 1-6 self-immolative, traceless crosslinker derived from the natural product gallic acid. The linker acts through a pH-dependent mechanism for drug release. This 5-(hydroxymethyl)pyrogallol orthoester derivative (HMPO) was stable for 24 hours at pH values of 7.4 and 6.6 and in plasma, releasing molecules bound to the hydroxymethyl moiety under acid-dependent stimuli at pH 5.5. The linker was non-toxic and was used for the conjugation of Doxorubicin (Doxo) or Combretastatin A4 with Cetuximab. The ADCs formed showed their pH responsivity reducing cell viability of A431 and A549 cancer cells better than Cetuximab alone. © 2022 The Royal Society of Chemistry

Dynamics investigation in the Venus upper atmosphere

The O_2 nightglow emissions in the infrared spectral range are important features to investigate dynamics at the mesospheric altitudes, in the planetary atmosphere. In this work, we analyzed the profiles obtained at limb by the VIRTIS spectrometer on board the Venus Express mission, acquired during the mission period from 2006-07-05 to 2008-08-15 to investigate possible gravity waves characteristics at the airglow altitudes. Indeed, several profiles present double peaked structures that can be interpreted as due to gravity waves. In analogy to the Earth's and Mars cases, we use a well-known theory to model the O_2 nightglow emissions affected by gravity waves propagation, in order to support this thesis and derive the waves properties. We discuss results from 30 profiles showing double peaked structures, focusing on vertical wavelength and wave amplitude of the possible gravity waves. On average, the double peaked profiles are compatible with the effects of gravity waves with a vertical wavelength ranging between 7 and 16 km, and wave amplitude of 3-14%. A comparison with gravity waves properties in the Mars and Earth's atmospheres, using the same theory, is also proposed \citep{altieri_2014}. \ The research is supported by ASI (contract ASI-INAF I/050/10/0)

Repeated SARS-CoV-2 vaccination in cancer patients treated with immune checkpoint inhibitors: induction of high-avidity anti-RBD neutralizing antibodies

BackgroundCancer patients are more vulnerable to COVID-19 and are thus given high priority in vaccination campaigns. In solid cancer patients treated with checkpoint inhibitors, we evaluated the amount of anti-RBD and neutralizing antibodies and antibody avidity after two or three doses of the vaccine.MethodsThirty-eight solid cancer patients, 15 untreated hematological patients and 21 healthy subjects were enrolled in the study. Blood was collected before the first dose (T0), 21 days after the second (T2) and in 18 solid cancer patients also 15 days after the third dose of vaccine (T3). IgG, IgM and IgA anti-RBD antibodies were detected by ELISA. Neutralizing antibodies were measured testing the inhibition of RBD binding to ACE2. Antibody avidity was evaluated in 18 patients by a urea avidity ELISA.ResultsIgG anti-RBD antibodies were produced in 65.8% of the cancer patients at T2, and in 60% of hematological patients at levels lower than healthy controls. IgM and IgA anti-RBD antibodies were also produced in 5.3% and 21% cancer patients, respectively. At T3, a significant increase in anti-RBD IgG levels was observed. Neutralizing antibodies were produced in 68.4% of cancer patients as compared with 93% of untreated hematological patients and 100% of controls, at titers lower than in healthy subjects. At T3, neutralizing antibodies and avidity of IgG anti-RBD increased; 6/18 patients negative at T2 developed neutralizing antibodies at T3.ConclusionThe data indicate that in cancer patients mRNA vaccine induces high avidity anti-RBD antibodies and neutralizing antibodies that increase after the third dose. The process of induction and selection of high-affinity antibodies is apparently unaffected by the treatment with anti-PD-1 or anti-PD-L1 antibodies