Timing the initiation of multiple myeloma

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2nd-3rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection

Plasma Proteome Profiles Associated with Inflammation, Angiogenesis, and Cancer

Tumor development is accompanied by a complex host systemic response, which includes inflammatory and angiogenic reactions. Both tumor-derived and systemic response proteins are detected in plasma from cancer patients. However, given their non-specific nature, systemic response proteins can confound the detection or diagnosis of neoplasia. Here, we have applied an in-depth quantitative proteomic approach to analyze plasma protein changes in mouse models of subacute irritant-driven inflammation, autoreactive inflammation, and matrix associated angiogenesis and compared results to previously described findings from mouse models of polyoma middle T-driven breast cancer and Pdx1-Cre KrasG12D Ink4a/Arf lox/lox -induced pancreatic cancer. Among the confounding models, approximately 1/3 of all quantified plasma proteins exhibited a significant change in abundance compared to control mice. Of the proteins that changed in abundance, the majority were unique to each model. Altered proteins included those involved in acute phase response, inflammation, extracellular matrix remodeling, angiogenesis, and TGFβ signaling. Comparison of changes in plasma proteins between the confounder models and the two cancer models revealed proteins that were restricted to the cancer-bearing mice, reflecting the known biology of these tumors. This approach provides a basis for distinguishing between protein changes in plasma that are cancer-related and those that are part of a non-specific host response

The regulation of IL-10 expression

Interleukin (IL)-10 is an important immunoregulatory cytokine and an understanding of how IL-10 expression is controlled is critical in the design of immune intervention strategies. IL-10 is produced by almost all cell types within the innate (including macrophages, monocytes, dendritic cells (DCs), mast cells, neutrophils, eosinophils and natural killer cells) and adaptive (including CD4(+) T cells, CD8(+) T cells and B cells) immune systems. The mechanisms of IL-10 regulation operate at several stages including chromatin remodelling at the Il10 locus, transcriptional regulation of Il10 expression and post-transcriptional regulation of Il10 mRNA. In addition, whereas some aspects of Il10 gene regulation are conserved between different immune cell types, several are cell type- or stimulus-specific. Here, we outline the complexity of IL-10 production by discussing what is known about its regulation in macrophages, monocytes, DCs and CD4(+) T helper cells

Appendix to Integrated Criteria Document Asbestos

Dit rapport bevat een systematisch overzicht en een kritische evaluatie van de belangrijkste gegevens over de prioritaire stof asbest ten behoeve van het effectgericht milieubeleid.<br

Integrated Criteria Document Asbestos

Separaat verschenen bijlage: Appendix Integrated Criteria Document Asbestos, Effects. Met rapportnummer 758473006-A&lt;br&gt;Dit rapport bevat een systematisch overzicht en een kritische evaluatie van de belangrijkste gegevens over de prioritaire stof asbest ten behoeve van het effectgericht milieubeleid.DGMH/SR Cornet J

Basisdocument Asbest

Dit rapport betreft een vertaling van het basisdocument asbest met rapportnummer 75843006. Bij dit rapport behoort een losse bijlage getiteld Appendix to report no 758473013. Integrated Criteria Document Asbestos Effects.&lt;br&gt;Dit rapport bevat een systematisch overzicht en een kritische evaluatie van de belangrijkste gegevens over de prioritaire stof asbest ten behoeve van het effectgericht milieubeleid.DGM/S

Basisdocument Asbest Appendix

Dit rapport bevat een systematisch overzicht en een kritische evaluatie van de belangrijkste gegevens over de prioritaire stof asbest ten behoeve van het effectgericht milieubeleid.DGMH/SR Cornet J

Ontwerp-basisdocument benzeen

Onderhavig document omvat gegevens over benzeen inzake de bronnen en het verspreidingspatroon (bodem, water, lucht, biota), de risico's op basis van afweging van blootstellingsconcentraties en -routes enerzijds en schadelijke concentraties voor mens, (onderdelen van) ecosystemen en materialen anderzijds, en de technische mogelijkheden en economische gevolgen met betrekking tot reductie van deze risico's. Deze informatie dient als wetenschappelijke basis voor het formuleren van het effectgericht normstellingsbeleid.<br

Benzeen Basisdocument

Betreft de engelse editie van rapport nr. 758476001 Bij dit rapport behoort een Appendix getiteld: &quot;Integrated Criteria Document Benzene Effects&quot; met rapportnummer 758476003&lt;br&gt;Dit rapport bevat een systematisch overzicht en een kritische evaluatie van de belangrijkste gegevens over de prioritaire stof benzeen ten behoeve van het effectgericht milieubeleid.DGM/SR /Cornet J