KiTZ Publications

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Abstract: Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; < 1 × 10) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, , , , , , and associated with MM risk ( = 4.47 × 10-5.79 × 10). Mechanistically, we found that the SNP correlated with circulating concentrations of vitamin D3 ( = 4.0 × 10), whereas the SNP correlated with the number of transitional CD24CD38 B cells ( = 4.8 × 10) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 ( = 3.6 × 10). We also found that the SNP correlated with numbers of CD19 B cells, CD19CD3 B cells, CD5IgD cells, IgM cells, IgDIgM cells, and CD4CD8 PBMCs ( = 4.9 × 10-8.6 × 10) and circulating concentrations of interleukin (IL)-20 ( = 0.00082). Finally, we observed that the SNP correlated with levels of CD4EMCD45ROCD27 cells ( = 9.3 × 10). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3, MCP-2, and IL20-dependent pathways.

Authors: Esther Clavero, José Manuel Sanchez-Maldonado, Angelica Macauda, Rob Ter Horst, Belém Sampaio-Marques, Artur Jurczyszyn, Alyssa Clay-Gilmour, Angelika Stein, Michelle A T Hildebrandt, Niels Weinhold, Gabriele Buda, Ramón García-Sanz, Waldemar Tomczak, Ulla Vogel, Andrés Jerez, Daria Zawirska, Marzena Wątek, Jonathan N Hofmann, Stefano Landi, John J Spinelli, Aleksandra Butrym, Abhishek Kumar, Joaquín Martínez-López, Sara Galimberti, María Eugenia Sarasquete, Edyta Subocz, Elzbieta Iskierka-Jażdżewska, Graham G Giles, Malwina Rybicka-Ramos, Marcin Kruszewski, Niels Abildgaard, Francisco García Verdejo, Pedro Sánchez Rovira, Miguel Inacio da Silva Filho, Katalin Kadar, Małgorzata Razny, Wendy Cozen, Matteo Pelosini, Manuel Jurado, Parveen Bhatti, Marek Dudzinski, Agnieszka Druzd-Sitek, Enrico Orciuolo, Yang Li, Aaron D Norman, Jan Maciej Zaucha, Rui Manuel Reis, Miroslaw Markiewicz, Juan José Rodríguez Sevilla, Vibeke Andersen, Krzysztof Jamroziak, Kari Hemminki, Sonja I Berndt, Vicent Rajkumar, Grzegorz Mazur, Shaji K Kumar, Paula Ludovico, Arnon Nagler, Stephen J Chanock, Charles Dumontet, Mitchell J Machiela, Judit Varkonyi, Nicola J Camp, Elad Ziv, Annette Juul Vangsted, Elizabeth E Brown, Daniele Campa, Celine M Vachon, Mihai G Netea, Federico Canzian, Asta Försti, Juan Sainz

Published: May 2023 / Journal: International journal of molecular sciences

Details at PubMed

Desorption Kinetics Evaluation for the Development of Validated Desorption Electrospray Ionization-Mass Spectrometric Assays for Drug Quantification in Tissue Sections.

Abstract: The development of desorption/ionization (DI) mass spectrometric (MS) assays for drug quantification in tissue sections and their validation according to regulatory guidelines would enable their universalization for applications in (clinical) pharmacology. Recently, new enhancements in desorption electrospray ionization (DESI) have highlighted the reliability of this ion source for the development of targeted quantification methods that meet requirements for method validation. However, it is necessary to consider subtle parameters leading to the success of such method developments, such as the morphology of desorption spots, the analytical time, and sample surface, to cite but a few. Here, we provide additional experimental data highlighting an additional important parameter, based on the unique advantage of DESI-MS on continuous extraction during analysis. We demonstrate that considering desorption kinetics during DESI analyses would largely help (i) reducing analytical time during profiling analyses, (ii) verifying solvent-based drug extraction using the selected sample preparation method for profiling and imaging modes, and (iii) predicting the feasibility of imaging assays using samples in a given expected concentration range of the targeted drug. These observations will likely serve as precious guidance for the development of validated DESI-profiling and imaging methods in the future.

Authors: Margaux Fresnais, Siwen Liang, Deniz Seven, Nevena Prodanovic, Julia Sundheimer, Walter E Haefeli, Jürgen Burhenne, Rémi Longuespée

Published: May 2023 / Journal: International journal of molecular sciences

Details at PubMed

Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells.

Abstract: We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy.

Authors: Gintvile Valinciute, Jonas Ecker, Florian Selt, Thomas Hielscher, Romain Sigaud, Johannes Ridinger, Venu Thatikonda, Charlotte Gatzweiler, Sarah Robinson, Julie Talbot, Flavia Bernardi, Daniel Picard, Mirjam Blattner-Johnson, Simone Schmid, David T Jones, Cornelis M van Tilburg, David Capper, Marcel Kool, Marc Remke, Ina Oehme, Stefan M Pfister, Martine F Roussel, Olivier Ayrault, Olaf Witt, Till Milde

Published: Jun 2023 / Journal: Journal of neuro-oncology

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Survival in gastric and esophageal cancers in the Nordic countries through a half century.

Abstract: Gastric cancer (GC) and esophageal cancer (EC) are among the most fatal cancers and improving survival in them is a major clinical challenge. Nordic cancer data were recently released up to year 2019. These data are relevant for long-term survival analysis as they originate from high-quality national cancer registries from countries with practically free access to health care, thus documenting 'real-world' experience for entire populations.

Authors: Kari Hemminki, Filip Tichanek, Asta Försti, Otto Hemminki, Akseli Hemminki

Published: May 2023 / Journal: Cancer medicine

Details at PubMed