Recurrent frameshift neoantigen vaccine elicits protective immunity with reduced tumor burden and improved overall survival in a Lynch syndrome mouse model

BACKGROUND AND AIMS: DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far. METHODS: A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression and mutation frequency. In silico prediction, in vivo immunogenicity testing and epitope mapping was used to identify candidates for FSP vaccination. RESULTS: We identified four shared FSP neoantigens [Nacad(FSP-1), Maz(FSP-1), Senp6(FSP-1), Xirp1(FSP-1)] that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only four FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth and prolonged survival even more effectively than FSP vaccination alone. CONCLUSION: Our pre-clinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.Supplementary Data 1: Data of the supra-hexagonal plot in Figure 2ASupplementary Data 2: Complete dataset of all MMV PRB compounds’ activity on Plasmodium life cycle stagesSupplementary Data 3: Full SMFA dataset to support Figure 5CSupplementary Data 4: Transcriptome analysis of MMV1580488 (ML324) treated parasites to support Figure 6C.The Medicines for Malaria Venture and South African Technology Innovation Agency (TIA). This project was in part supported by the South African Medical Research Council with funds received from the South African Department of Science and Innovation, in partnership with the Medicines for Malaria Venture; and the DST/NRF South African Research Chairs Initiative Grant; and CSIR Parliamentary Grant funding as well as the Bill and Melinda Gates Foundation and the Australian NHMRC (APP1072217).http://www.nature.com/ncommshj2021BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

Die ontwerp en evaluering van die sekondere rekenaar in SUNSAT

Tesis (M. Ing.) -- Universiteit van Stellenbosch, 1996.Een kopie mikrofiche.Full text to be digitised and attached to bibliographic record

Persepsi Guru dan Siswa terhadap E-Module Praktikum Kimia Sebelum dan pada Saat Pandemi Covid-19

Pandemi COVID-19 mempengaruhi kebijakan pemerintah Republik Indonesia diberbagai sektor termasuk pendidikan. Kebijakan social distancing atau physical distancing dalam upaya memutus penyebaran COVID-19 berpengaruh terhadap proses pembelajaran, salah satunya pembelajaran kimia di laboratorium. solusi yang dipilih dalam rangka mengimplementasikan kebijakan tersebut yakni dengan menerapkan online learning, seperti pemanfaatan e-module. Pada penelitian ini, dianalisis dan diinterpretasi persepsi guru dan siswa terhadap e-module praktikum kimia sebelum dan pada saat pandemi COVID-19. Berdasarkan hasil penelitian, persepsi siswa terhadap e-module praktikum kimia sebelum pandemi COVID-19 sebesar 3,382 (skala 4) pada kategori baik dan pada saat pandemi COVID-19 sebesar 3,414 (skala 4) pada kategori baik. Persepsi guru terhadap e-module praktikum kimia sebelum pandemi COVID-19 sebesar 3,30 (skala 4) pada kategori baik dan pada saat pandemi COVID-19 sebesar 3,43 (skala 4) pada kategori baik. Pengembangan e-modul praktikum kimia sangat penting dilakukan, e-module berperan besar ketika pembelajaran tidak memungkinkan untuk dilakukan secara langsung dan penerapan online learning