Multiple myeloma (MM) evolves from a highly prevalent premalignant condition termed MGUS. The factors underlying the malignant transformation of MGUS are unknown. We report a MGUS/MM phenotype in ...transgenic mice with Eμ-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Eμ-XBP-1s elicited elevated serum Ig and skin alterations. With age, Eμ-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Eμ-xbp-1s lymphoid and MM cells show aberrant expression of known human MM dysregulated genes. The similarities of this model with the human disease, coupled with documented frequent XBP-1s overexpression in human MM, serve to implicate XBP-1s dysregulation in MM pathogenesis.
Land cover mapping of large areas is challenging due to the significant volume of satellite data to acquire and process, as well as the lack of spatial continuity due to cloud cover. Temporal ...aggregation—the use of metrics (i.e., mean or median) derived from satellite data over a period of time—is an approach that benefits from recent increases in the frequency of free satellite data acquisition and cloud-computing power. This enables the efficient use of multi-temporal data and the exploitation of cloud-gap filling techniques for land cover mapping. Here, we provide the first formal comparison of the accuracy between land cover maps created with temporal aggregation of Sentinel-1 (S1), Sentinel-2 (S2), and Landsat-8 (L8) data from one-year and test whether this method matches the accuracy of traditional approaches. Thirty-two datasets were created for Wales by applying automated cloud-masking and temporally aggregating data over different time intervals, using Google Earth Engine. Manually processed S2 data was used for comparison using a traditional two-date composite approach. Supervised classifications were created, and their accuracy was assessed using field-based data. Temporal aggregation only matched the accuracy of the traditional two-date composite approach (77.9%) when an optimal combination of optical and radar data was used (76.5%). Combined datasets (S1, S2 or S1, S2, and L8) outperformed single-sensor datasets, while datasets based on spectral indices obtained the lowest levels of accuracy. The analysis of cloud cover showed that to ensure at least one cloud-free pixel per time interval, a maximum of two intervals per year for temporal aggregation were possible with L8, while three or four intervals could be used for S2. This study demonstrates that temporal aggregation is a promising tool for integrating large amounts of data in an efficient way and that it can compensate for the lower quality of automatic image selection and cloud masking. It also shows that combining data from different sensors can improve classification accuracy. However, this study highlights the need for identifying optimal combinations of satellite data and aggregation parameters in order to match the accuracy of manually selected and processed image composites.
Several components of the Wnt signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway ...in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances beta-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling.
Multiple myeloma (MM) is an invariably fatal form of cancer characterized by clonal proliferation of malignant plasma cells in the bone marrow. The canonical Wnt signaling pathway is activated in MM ...cells through constitutively active β-catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. The identification of a number of small molecular compounds, such as PKF115-584, which disrupt the interaction of the transcriptionally active β-catenin/TCF protein complex, provides valuable new therapeutic tools to target an alternative pathway in MM independent of the proteasome. Here we evaluated the transcriptional, proteomic, signaling changes, and biological sequelae associated with the inhibition of Wnt signaling in MM by PKF115-584. The compound blocks expression of Wnt target genes and induces cytotoxicity in both patient MM cells and MM cell lines without a significant effect in normal plasma cells. In xenograft models of human MM, PKF115-584 inhibits tumor growth and prolongs survival. Taken together, these data demonstrate the efficacy of disrupting the β-catenin/TCF transcriptional complex to exploit tumor dependence on Wnt signaling as a therapeutic approach in the treatment of MM.
Humans may have evolved a need to connect with nature, and nature provides substantial cultural and social values to humans. However, quantifying the connection between humans and nature at a global ...scale remains challenging. We lack answers to fundamental questions: how do humans experience nature in different contexts (daily routines, fun activities, weddings, honeymoons, other celebrations, and vacations) and how do nature experiences differ across countries? We answer these questions by coupling social media and artificial intelligence using 31,534 social media photographs across 185 countries. We find that nature was more likely to appear in photographs taken during a fun activity, honeymoon, or vacation compared to photographs of daily routines. More importantly, the proportion of photographs with nature taken during fun activities is associated with national life satisfaction scores. This study provides global evidence of the biophilia hypothesis by showing a connection between humans and nature that contributes to life satisfaction and highlights how nature serves as background to many of our positive memories.
To quantify known and unknown microorganisms at species-level resolution using shotgun sequencing data, we developed a method that establishes metagenomic operational taxonomic units (mOTUs) based on ...single-copy phylogenetic marker genes. Applied to 252 human fecal samples, the method revealed that on average 43% of the species abundance and 58% of the richness cannot be captured by current reference genome-based methods. An implementation of the method is available at http://www.bork.embl.de/software/mOTU/.
Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of ...PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF–induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED50 = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5nM) and MM patients. It decreased SDF-1–induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell–induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.
To identify genetic events underlying the genesis and progression of multiple myeloma (MM), we conducted a high-resolution analysis of recurrent copy number alterations (CNAs) and expression profiles ...in a collection of MM cell lines and outcome-annotated clinical specimens. Attesting to the molecular heterogeneity of MM, unsupervised classification using nonnegative matrix factorization (NMF) designed for array comparative genomic hybridization (aCGH) analysis uncovered distinct genomic subtypes. Additionally, we defined 87 discrete minimal common regions (MCRs) within recurrent and highly focal CNAs. Further integration with expression data generated a refined list of MM gene candidates residing within these MCRs, thereby providing a genomic framework for dissection of disease pathogenesis, improved clinical management, and initiation of targeted drug discovery for specific MM patients.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances protection against tumors and infections, but GM-CSF-deficient mice develop inflammatory disease. Here we show that GM-CSF is ...required for the expression of milk fat globule EGF 8 (MFG-E8) in antigen-presenting cells, and that MFG-E8-mediated uptake of apoptotic cells is a key determinant of GM-CSF-triggered tolerance and immunity. Upon exposure to apoptotic cells, GM-CSF-deficient antigen-presenting cells (APCs) produce an altered cytokine profile that results in decreased Tregs and increased Th1 cells, whereas concurrent ablation of IFN-gamma promotes Th17 cells. In wild-type mice, MFG-E8 attenuates the vaccination activity of GM-CSF-secreting tumor cells through Treg induction, whereas a dominant-negative MFG-E8 mutant potentiates GM-CSF-stimulated tumor destruction through Treg inhibition. These findings clarify the immunoregulatory effects of apoptotic cells and suggest new therapeutic strategies to modulate CD4(+) T cell subsets in cancer and autoimmunity.
Activated phosphoinositide 3-kinase (PI3K)-AKT signaling appears to be an obligate event in the development of cancer. The highly related members of the mammalian FoxO transcription factor family, ...FoxO1, FoxO3, and FoxO4, represent one of several effector arms of PI3K-AKT signaling, prompting genetic analysis of the role of FoxOs in the neoplastic phenotypes linked to PI3K-AKT activation. While germline or somatic deletion of up to five FoxO alleles produced remarkably modest neoplastic phenotypes, broad somatic deletion of all FoxOs engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas, demonstrating that the mammalian FoxOs are indeed bona fide tumor suppressors. Transcriptome and promoter analyses of differentially affected endothelium identified direct FoxO targets and revealed that FoxO regulation of these targets in vivo is highly context-specific, even in the same cell type. Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.
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