Survivin the battle against immunosuppression

Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to “escape” protective immunity. One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors

Mamu-A⁎01/Kb transgenic and MHC Class I knockout mice as a tool for HIV vaccine development

AbstractWe have developed a murine model expressing the rhesus macaque (RM) Mamu-A⁎01 MHC allele to characterize immune responses and vaccines based on antigens of importance to human disease processes. Towards that goal, transgenic (Tg) mice expressing chimeric RM (α1 and α2 Mamu-A⁎01 domains) and murine (α3, transmembrane, and cytoplasmic H-2Kb domains) MHC Class I molecules were derived by transgenesis of the H-2KbDb double MHC Class I knockout strain. After immunization of Mamu-A⁎01/Kb Tg mice with rVV-SIVGag–Pol, the mice generated CD8+ T-cell IFN-γ responses to several known Mamu-A⁎01 restricted epitopes from the SIV Gag and Pol antigen sequence. Fusion peptides of highly recognized CTL epitopes from SIV Pol and Gag and a strong T-help epitope were shown to be immunogenic and capable of limiting an rVV-SIVGag–Pol challenge. Mamu-A⁎01/Kb Tg mice provide a model system to study the Mamu-A⁎01 restricted T-cell response for various infectious diseases which are applicable to a study in RM

Computationally restoring the potency of a clinical antibody against Omicron.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1-3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4-6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities

Impact of Cultural Tourism Upon Urban Economies: An Econometric Exercise

In recent years, interest in tourism has spread rapidly throughout many small and medium European cities, which previously have not necessarily considered themselves as tourist destinations. Tourism is increasingly seen as a potential lever towards high economic growth, measured both in terms of income and employment. In the present Working Paper we report the analysis on the economic impact undertaken in the framework of the PICTURE Project, showing the results of a novel econometric exercise to statistically assess the impacts of cultural tourism upon European municipalities. More precisely the analysis aims at estimating the effects of tourism specialisation on local income and prices. The Working Paper is built as follows. Section 1 presents and discusses secondary data about tourism facts and figures, including the economic impact of tourism upon European economies, with a focus on cultural tourism. An extensive review of literature, which identifies the main categories of impacts and the currently available methodologies to assess them, is undertaken. Section 2 focuses on the state of the art. Section 3 describes the database built for the analysis, sources and variables. In order to visually represent the spatial variability of the main parameters, a series of thematic maps at NUTS 3 level(Maps of European tourism), using GIS (Geographical Information System) are also included in the Working Paper. Section 4 shows the results of the econometric analysis of European panel data for the estimation of the effects of tourism specialisation on both local incomes and prices. Section 5 concludes

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article