NOD/scid IL-2Rgnull mice: a preclinical model system to evaluate human dendritic cell-based vaccine strategies in vivo

<p>Abstract</p> <p>Background</p> <p>To date very few systems have been described for preclinical investigations of human cellular therapeutics <it>in vivo</it>. However, the ability to carry out comparisons of new cellular vaccines <it>in vivo </it>would be of substantial interest for design of clinical studies. Here we describe a humanized mouse model to assess the efficacy of various human dendritic cell (DC) preparations. Two reconstitution regimes of NOD/scid IL2Rg^null(NSG) mice with adult human peripheral blood mononuclear cells (PBMC) were evaluated for engraftment using 4-week and 9-week schedules. This led to selection of a simple and rapid protocol for engraftment and vaccine evaluation that encompassed 4 weeks.</p> <p>Methods</p> <p>NSG recipients of human PBMC were engrafted over 14 days and then vaccinated twice with autologous DC via intravenous injection. Three DC vaccine formulations were compared that varied generation time <it>in vitro </it>(3 days versus 7 days) and signals for maturation (with or without Toll-like receptor (TLR)3 and TLR7/8 agonists) using MART-1 as a surrogate antigen, by electroporating mature DC with <it>in vitro </it>transcribed RNA encoding full length protein. After two weekly vaccinations, the splenocyte populations containing human lymphocytes were recovered 7 days later and assessed for MART-1-specific immune responses using MHC-multimer-binding assays and functional assessment of specific killing of melanoma tumor cell lines.</p> <p>Results</p> <p>Human monocyte-derived DC generated <it>in vitro </it>in 3 days induced better MART-1-specific immune responses in the autologous donor T cells present in the humanized NSG mice. Moreover, consistent with our <it>in vitro </it>observations, vaccination using mature DC activated with TLR3 and TLR7/8 agonists resulted in enhanced immune responses <it>in vivo</it>. These findings led to a ranking of the DC vaccine effects <it>in vivo </it>that reflected the hierarchy previously found for these mature DC variations <it>in vitro</it>.</p> <p>Conclusions</p> <p>This humanized mouse model system enables comparisons among different DC vaccine types to be rapidly assessed <it>in vivo</it>. In addition, <it>ex vivo </it>analyses of human CD3⁺T cells recovered from the spleens of these mice are also possible, including studies on lymphocyte subsets, Th1/Th2 polarization, presence of regulatory T cells and the impact of DC vaccination on their functions.</p

Clinical effectiveness of pit and fissure sealants in primary and permanent teeth of children and adolescents: an umbrella review.

PURPOSE This umbrella review aimed to critically appraise the evidence published in systematic reviews (SRs) on the clinical effectiveness of sealants compared with each other/the non-use in primary/permanent teeth of children and adolescents with at least 12-month follow-up. METHODS A systematic literature search on 4 electronic databases was conducted up to January 18th, 2023. Following handsearching, two review authors independently screened retrieved articles, extracted data, and assessed the risk of bias (RoB) using the risk of bias in systematic reviews (ROBIS) tool. Based on a citation matrix, the overlap was interpreted by the corrected covered area (CCA). RESULTS Of 239 retrieved records, 7 SRs met the eligibility criteria with a moderate overlap among them (CCA = 7.4%). For primary molars, in 1120 1.5- to 8-year-old children, data on the clinical effectiveness of sealants were inconclusive. For permanent molars, 3 SRs found a significant caries risk reduction for sealants versus non-use (≤ 36-month follow-up). There was insufficient evidence to proof superiority of sealants over fluoride varnish for caries prevention (3 SRs), and to rank sealant materials according to the best clinical effectiveness in permanent molars. One study was rated at low and 6 at high RoB, which did not allow for a valid quantitative synthesis. CONCLUSION Considering the limitations of this umbrella review, sealants are more effective for caries prevention in children's permanent molars compared to no treatment. Future well-implemented RCTs are needed to draw reliable conclusions on the clinical effectiveness of sealants in primary and permanent teeth of children and adolescents

Three-day dendritic cells for vaccine development: Antigen uptake, processing and presentation

<p>Abstract</p> <p>Background</p> <p>Antigen-loaded dendritic cells (DC) are capable of priming naïve T cells and therefore represent an attractive adjuvant for vaccine development in anti-tumor immunotherapy. Numerous protocols have been described to date using different maturation cocktails and time periods for the induction of mature DC (mDC) <it>in vitro</it>. For clinical application, the use of mDC that can be generated in only three days saves on the costs of cytokines needed for large scale vaccine cell production and provides a method to produce cells within a standard work-week schedule in a GMP facility.</p> <p>Methods</p> <p>In this study, we addressed the properties of antigen uptake, processing and presentation by monocyte-derived DC prepared in three days (3d mDC) compared with conventional DC prepared in seven days (7d mDC), which represent the most common form of DC used for vaccines to date.</p> <p>Results</p> <p>Although they showed a reduced capacity for spontaneous antigen uptake, 3d mDC displayed higher capacity for stimulation of T cells after loading with an extended synthetic peptide that requires processing for MHC binding, indicating they were more efficient at antigen processing than 7d DC. We found, however, that 3d DC were less efficient at expressing protein after introduction of <it>in vitro </it>transcribed (<it>ivt</it>)RNA by electroporation, based on published procedures. This deficit was overcome by altering electroporation parameters, which led to improved protein expression and capacity for T cell stimulation using low amounts of <it>ivt</it>RNA.</p> <p>Conclusions</p> <p>This new procedure allows 3d mDC to replace 7d mDC for use in DC-based vaccines that utilize long peptides, proteins or <it>ivt</it>RNA as sources of specific antigen.</p

Drainage Water Storage for Improved Resiliency and Environmental Performance of Agricultural Landscapes

Drained lands, which include some of the most productive lands in the world, can experience both water excess and water deficit within a year. Storing drained water within the landscape could increase the sustainability of water for agriculture, particularly as intense rainfall and prolonged summer drought continue to increase under future climate change. A team of researchers and extension specialists from nine states are currently working towards a vision of transforming the process of designing and implementing agricultural drainage to include storage through the use of controlled drainage, saturated buffers, and drainage water recycling (i.e. capture, storage, and reuse). Field research data from experimental drainage sites from across the U.S. Corn Belt have been brought together in a database to support synthesis and modeling to determine economic and environmental impacts of drainage water storage. Results from this effort will extend the strategies and tools to agricultural producers, the drainage industry, watershed managers, agencies, and policy makers, and educate the next generation of engineers and scientists to design drainage systems that include water storage in the landscape

The Pond 2 selenium volatilization study: A synthesis of five years of experimental results, 1990--1995

Microbial volatilization is a potential remedial measure to decrease the selenium inventory in Kesterson Reservoir soils. Past studies in both the field and the laboratory suggest that a significant percentage of the selenium inventory may be removed in this fashion. The objectives of this study include the quantification of selenium losses and a test of a pilot-scale design which in the future may be used in other parts of the Reservoir

International Trends and Practices on Sustainability Reporting in Higher Education Institutions

Sustainability reports are regarded as important tools in offering information about the environmental, social, economic, and institutional performance of an institution, and in demonstrating a commitment to matters related to sustainable development. But even though sustainability reporting has been used by a variety of higher education institutions to date, it is not as widely practiced as it should be. To further investigate this topic, a twofold approach was used: a study focusing on sustainability reporting approaches deployed in a sample of 30 universities across a set of countries; and a survey with a sample of 72 universities from different global regions to assess the extent to which they are deploying sustainability reporting as part of their activities. The scientific value of the paper resides in the fact that it offers a comprehensive overview of the subject matter of sustainability reporting, and how higher education institutions handle it. It also outlines the efforts in developing these documents which may catalyse further progress in this key area

Gender-specific differences in COPD symptoms and their impact for the diagnosis of cardiac comorbidities

Background In chronic obstructive pulmonary disease (COPD), gender-specifc diferences in the prevalence of symptoms and comorbidity are known. Research question We studied whether the relationship between these characteristics depended on gender and carried diag nostic information regarding cardiac comorbidities. Study design and methods The analysis was based on 2046 patients (GOLD grades 1–4, 795 women; 38.8%) from the COSYCONET COPD cohort. Assessments comprised the determination of clinical history, comorbidities, lung function, COPD Assessment Test (CAT) and modifed Medical Research Council dyspnea scale (mMRC). Using multivariate regres sion analyses, gender-specifc diferences in the relationship between symptoms, single CAT items, comorbidities and functional alterations were determined. To reveal the relationship to cardiac disease (myocardial infarction, or heart failure, or coronary artery disease) logistic regression analysis was performed separately in men and women. Results Most functional parameters and comorbidities, as well as CAT items 1 (cough), 2 (phlegm) and 5 (activities), dif fered signifcantly (p<0.05) between men and women. Beyond this, the relationship between functional parameters and comorbidities versus symptoms showed gender-specifc diferences, especially for single CAT items. In men, item 8 (energy), mMRC, smoking status, BMI, age and spirometric lung function was related to cardiac disease, while in women primarily age was predictive. Interpretation Gender-specifc diferences in COPD not only comprised diferences in symptoms, comorbidities and func tional alterations, but also diferences in their mutual relationships. This was refected in diferent determinants linked to cardiac disease, thereby indicating that simple diagnostic information might be used diferently in men and women. Clinical trial registration The cohort study is registered on ClinicalTrials.gov with identifer NCT01245933 and on Ger manCTR.de with identifer DRKS00000284, date of registration November 23, 2010. Further information can be obtained on the website http://www.asconet.net