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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.

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.

Colon cancer is a deadly disease affecting millions of people worldwide. Current treatment challenges include management of disease burden as well as improvements in detection and targeting of tumor cells. To identify disease state-specific surface antigen signatures, we combined fluorescent cell barcoding with high-throughput flow cytometric profiling of primary and metastatic colon cancer lines (SW480, SW620, and HCT116). Our multiplexed technique offers improvements over conventional methods by permitting the simultaneous and rapid screening of cancer cells with reduced effort and cost. The method uses a protein-level analysis with commercially available antibodies on live cells with intact epitopes to detect potential tumor-specific targets that can be further investigated for their clinical utility. Multiplexed antibody arrays can easily be applied to other tumor types or pathologies for discovery-based approaches to target identification.

The Rb/p16Ink⁴a and p53/p19Arf tumor suppressor pathways have been linked to diverse cancer-relevant processes, including those governing the cellular responses to telomere dysfunction. In this study, we sought to provide direct genetic evidence of a role for the Ink4a/Arf tumor suppressor gene, encoding both p16Ink⁴a and p19Arf, in modulating the cellular and tissue phenotypes associated with telomere dysfunction by using the mTerc Ink4a/Arf mouse model. In contrast to the rescue associated with p53 deficiency, Ink4a/Arf deficiency did not attenuate the degenerative phenotypes elicited by telomere dysfunction in the late-generation mTerc-/- mice. Furthermore, in contrast to accelerated cancer onset and increased epithelial cancers of late-generation mTerc-/- p53 mutant mice, late-generation mTerc-/- Ink4a/Arf mutant mice experienced a delayed tumor onset and maintained the lymphoma and sarcoma spectrum. Consistent with the negligible role of Ink4a/Arf in the telomere checkpoint response in vivo, late-generation mTerc-/- Ink4a/Arf-/- tissues show activated p53, and derivative tumor cell lines sustain frequent loss of p53 function, whereas all early generation mTerc Ink4a/Arf-/- tumor cell lines remain intact for p53. In addition, the late-generation mTerc-/- Ink4a/Arf-/- tumors showed activation of the alternative lengthening of telomere mechanism, underscoring the need for adaptation to the presence of telomere dysfunction in the absence of p16Ink⁴a and p19Arf. These observations highlight the importance of genetic context in dictating whether telomere dysfunction promotes or suppresses age-related degenerative conditions as well as the rate of initiation and type of spontaneous cancers.

Ataxia-telangiectasia (A-T) results from the loss of ataxia-telangiectasia mutated ( Atm ) function and is characterized by accelerated telomere loss, genomic instability, progressive neurological degeneration, premature ageing and increased neoplasia incidence 1 . Here we evaluate the functional interaction of Atm and telomeres in vivo . We examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and the telomerase RNA component ( Terc ) 2 , 3 , 4 . These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multi-organ system compromise, accelerated ageing and premature death. We show that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of A-T pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves.

Germline mutations in LKB1 (also known as STK11 ) are associated with Peutz–Jeghers syndrome (PJS), a disorder with predisposition to gastrointestinal polyposis and cancer 1 . PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential 2 . Here we show that Lkb1 +/- mice develop intestinal polyps identical to those seen in individuals affected with PJS. Consistent with this in vivo tumour suppressor function, Lkb1 deficiency prevents culture-induced senescence without loss of Ink4a / Arf or p53 . Despite compromised mortality, Lkb1 -/- mouse embryonic fibroblasts show resistance to transformation by activated Ha- Ras either alone or with immortalizing oncogenes. This phenotype is in agreement with the paucity of mutations in Ras seen in PJS polyps 3 , 4 and suggests that loss of Lkb1 function as an early neoplastic event renders cells resistant to subsequent oncogene-induced transformation. In addition, the Lkb1 transcriptome shows modulation of factors linked to angiogenesis, extracellular matrix remodelling, cell adhesion and inhibition of Ras transformation. Together, our data rationalize several features of PJS polyposis—notably its peculiar histopathological presentation and limited malignant potential—and place Lkb1 in a distinct class of tumour suppressors.

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.

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.