Safety and Immunogenicity of a Human Papillomavirus Peptide Vaccine (CIGB-228) in Women with High-Grade Cervical Intraepithelial Neoplasia: First-in-Human, Proof-of-Concept Trial

Objective. CIGB-228 is a novel therapeutic vaccine consisting of HLA-restricted HPV16 E7 epitope adjuvated with VSSP. This trial was designed to evaluate the toxicity, safety, immunogenicity, HPV clearance, and lesion regression. Methods. Seven women were entered. All were HLA-A2 positive, had biopsy-proven high-grade CIN, histologically positive for HPV16, and beared persistent postbiopsy lesions visible by digital colposcopy. HLA-A2 women with biopsy-proven high-grade CIN, HPV16-positive, and beared persistent postbiopsy lesions visible by digital colposcopy were vaccinated. One weekly injections of CIGB-228 vaccine was given for four weeks. Then, loop electrosurgical excision procedure (LEEP) of the transformation zone was performed. Study subjects were followed for 1 year after LEEP. Results. No toxicity beyond grade 1 was observed during and after the four vaccinations. Five of seven women had complete and partial regression. Cellular immune response was seen in all patients. HPV was cleared in three of the patients with complete response. Conclusion. CIGB-228 vaccination was well tolerated and capable to induce IFNγ-associated T-cell response in women with high-grade CIN. In several patients, lesion regression and HPV clearance were observed

Envelope: interactive software for modeling and fitting complex isotope distributions

<p>Abstract</p> <p>Background</p> <p>An important aspect of proteomic mass spectrometry involves quantifying and interpreting the isotope distributions arising from mixtures of macromolecules with different isotope labeling patterns. These patterns can be quite complex, in particular with <it>in vivo </it>metabolic labeling experiments producing fractional atomic labeling or fractional residue labeling of peptides or other macromolecules. In general, it can be difficult to distinguish the contributions of species with different labeling patterns to an experimental spectrum and difficult to calculate a theoretical isotope distribution to fit such data. There is a need for interactive and user-friendly software that can calculate and fit the entire isotope distribution of a complex mixture while comparing these calculations with experimental data and extracting the contributions from the differently labeled species.</p> <p>Results</p> <p>Envelope has been developed to be user-friendly while still being as flexible and powerful as possible. Envelope can simultaneously calculate the isotope distributions for any number of different labeling patterns for a given peptide or oligonucleotide, while automatically summing these into a single overall isotope distribution. Envelope can handle fractional or complete atom or residue-based labeling, and the contribution from each different user-defined labeling pattern is clearly illustrated in the interactive display and is individually adjustable. At present, Envelope supports labeling with ²H, ¹³C, and ¹⁵N, and supports adjustments for baseline correction, an instrument accuracy offset in the m/z domain, and peak width. Furthermore, Envelope can display experimental data superimposed on calculated isotope distributions, and calculate a least-squares goodness of fit between the two. All of this information is displayed on the screen in a single graphical user interface. Envelope supports high-quality output of experimental and calculated distributions in PNG or PDF format. Beyond simply comparing calculated distributions to experimental data, Envelope is useful for planning or designing metabolic labeling experiments, by visualizing hypothetical isotope distributions in order to evaluate the feasibility of a labeling strategy. Envelope is also useful as a teaching tool, with its real-time display capabilities providing a straightforward way to illustrate the key variable factors that contribute to an observed isotope distribution.</p> <p>Conclusion</p> <p>Envelope is a powerful tool for the interactive calculation and visualization of complex isotope distributions for comparison to experimental data. It is available under the GNU General Public License from <url>http://williamson.scripps.edu/envelope/</url>.</p

Benchmarking solutions to the T-cell receptor epitope prediction problem: IMMREP22 workshop report

Many different solutions to predicting the cognate epitope target of a T-cell receptor (TCR) have been proposed. However several questions on the advantages and disadvantages of these different approaches remain unresolved, as most methods have only been evaluated within the context of their initial publications and data sets. Here, we report the findings of the first public TCR-epitope prediction benchmark performed on 23 prediction models in the context of the ImmRep 2022 TCR-epitope specificity workshop. This benchmark revealed that the use of paired-chain alpha-beta, as well as CDR1/2 or V/J information, when available, improves classification obtained with CDR3 data, independent of the underlying approach. In addition, we found that straight-forward distance-based approaches can achieve a respectable performance when compared to more complex machine-learning models. Finally, we highlight the need for a truly independent follow-up benchmark and provide recommendations for the design of such a next benchmark

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

SiPM-matrix readout of two-phase argon detectors using electroluminescence in the visible and near infrared range

Proportional electroluminescence (EL) in noble gases is used in two-phase detectors for dark matter searches to record (in the gas phase) the ionization signal induced by particle scattering in the liquid phase. The “standard” EL mechanism is considered to be due to noble gas excimer emission in the vacuum ultraviolet (VUV). In addition, there are two alternative mechanisms, producing light in the visible and near infrared (NIR) ranges. The first is due to bremsstrahlung of electrons scattered on neutral atoms (“neutral bremsstrahlung”, NBrS). The second, responsible for electron avalanche scintillation in the NIR at higher electric fields, is due to transitions between excited atomic states. In this work, we have for the first time demonstrated two alternative techniques of the optical readout of two-phase argon detectors, in the visible and NIR range, using a silicon photomultiplier matrix and electroluminescence due to either neutral bremsstrahlung or avalanche scintillation. The amplitude yield and position resolution were measured for these readout techniques, which allowed to assess the detection threshold for electron and nuclear recoils in two-phase argon detectors for dark matter searches. To the best of our knowledge, this is the first practical application of the NBrS effect in detection science

Design and construction of a new detector to measure ultra-low radioactive-isotope contamination of argon

Large liquid argon detectors offer one of the best avenues for the detection of galactic weakly interacting massive particles (WIMPs) via their scattering on atomic nuclei. The liquid argon target allows exquisite discrimination between nuclear and electron recoil signals via pulse-shape discrimination of the scintillation signals. Atmospheric argon (AAr), however, has a naturally occurring radioactive isotope, 39Ar, a β emitter of cosmogenic origin. For large detectors, the atmospheric 39Ar activity poses pile-up concerns. The use of argon extracted from underground wells, deprived of 39Ar, is key to the physics potential of these experiments. The DarkSide-20k dark matter search experiment will operate a dual-phase time projection chamber with 50 tonnes of radio-pure underground argon (UAr), that was shown to be depleted of 39Ar with respect to AAr by a factor larger than 1400. Assessing the 39Ar content of the UAr during extraction is crucial for the success of DarkSide-20k, as well as for future experiments of the Global Argon Dark Matter Collaboration (GADMC). This will be carried out by the DArT in ArDM experiment, a small chamber made with extremely radio-pure materials that will be placed at the centre of the ArDM detector, in the Canfranc Underground Laboratory (LSC) in Spain. The ArDM LAr volume acts as an active veto for background radioactivity, mostly γ-rays from the ArDM detector materials and the surrounding rock. This article describes the DArT in ArDM project, including the chamber design and construction, and reviews the background required to achieve the expected performance of the detector