Permafrost thaw causes large carbon loss in boreal peatlands while changes to peat quality are limited.

Rapid, ongoing permafrost thaw of peatlands in the discontinuous permafrost zone is exposing a globally significant store of soil carbon (C) to microbial processes. Mineralization and release of this peat C to the atmosphere as greenhouse gases is a potentially important feedback to climate change. Here we investigated the effects of permafrost thaw on peat C at a peatland complex in western Canada. We collected 15 complete peat cores (between 2.7 and 4.5 m deep) along four chronosequences, from elevated permafrost peat plateaus to saturated thermokarst bogs that thawed up to 600 years ago. The peat cores were analysed for peat C storage and peat quality, as indicated by decomposition proxies (FTIR and C/N ratios) and potential decomposability using a 200-day aerobic laboratory incubation. Our results suggest net C loss following thaw, with average total peat C stocks decreasing by ~19.3 ± 7.2 kg C m-2 over <600 years (~13% loss). Average post-thaw accumulation of new peat at the surface over the same period was ~13.1 ± 2.5 kg C m-2 . We estimate ~19% (±5.8%) of deep peat (>40 cm below surface) C is lost following thaw (average 26 ± 7.9 kg C m-2 over <600 years). Our FTIR analysis shows peat below the thaw transition in thermokarst bogs is slightly more decomposed than peat of a similar type and age in permafrost plateaus, but we found no significant changes to the quality or lability of deeper peat across the chronosequences. Our incubation results also showed no increase in C mineralization of deep peat across the chronosequences. While these limited changes in peat quality in deeper peat following permafrost thaw highlight uncertainty in the exact mechanisms and processes for C loss, our analysis of peat C stocks shows large C losses following permafrost thaw in peatlands in western Canada.

Climate-driven spatial and temporal patterns in peatland pool biogeochemistry.

Peatland pools are freshwater bodies that are highly dynamic aquatic ecosystems because of their small size and their development in organic-rich sediments. However, our ability to understand and predict their contribution to both local and global biogeochemical cycles under rapidly occurring environmental change is limited because the spatiotemporal drivers of their biogeochemical patterns and processes are poorly understood. We used (1) pool biogeochemical data from 20 peatlands in eastern Canada, the United Kingdom, and southern Patagonia and (2) multi-year data from an undisturbed peatland of eastern Canada, to determine how climate and terrain features drive the production, delivering and processing of carbon (C), nitrogen (N), and phosphorus (P) in peatland pools. Across sites, climate (24%) and terrain (13%) explained distinct portions of the variation in pool biogeochemistry, with climate driving spatial differences in pool dissolved organic C (DOC) concentration and aromaticity. Within the multi-year dataset, DOC, carbon dioxide (CO2 ), total N concentrations, and DOC aromaticity were highest in the shallowest pools and at the end of the growing seasons, and increased gradually from 2016 to 2021 in relation to a combination of increases in summer precipitation, mean air temperature for the previous fall, and number of extreme summer heat days. Given the contrasting effects of terrain and climate, broad-scale terrain characteristics may offer a baseline for the prediction of small-scale pool biogeochemistry, while broad-scale climate gradients and relatively small year-to-year variations in local climate induce a noticeable response in pool biogeochemistry. These findings emphasize the reactivity of peatland pools to both local and global environmental change and highlight their potential to act as widely distributed climate sentinels within historically relatively stable peatland ecosystems.

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

PURPOSE: 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. METHODS: We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou-Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment. RESULTS: MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination. CONCLUSION: The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood-brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.

Widespread global peatland establishment and persistence over the last 130,000 y.

Glacial-interglacial variations in CO2 and methane in polar ice cores have been attributed, in part, to changes in global wetland extent, but the wetland distribution before the Last Glacial Maximum (LGM, 21 ka to 18 ka) remains virtually unknown. We present a study of global peatland extent and carbon (C) stocks through the last glacial cycle (130 ka to present) using a newly compiled database of 1,063 detailed stratigraphic records of peat deposits buried by mineral sediments, as well as a global peatland model. Quantitative agreement between modeling and observations shows extensive peat accumulation before the LGM in northern latitudes (>40°N), particularly during warmer periods including the last interglacial (130 ka to 116 ka, MIS 5e) and the interstadial (57 ka to 29 ka, MIS 3). During cooling periods of glacial advance and permafrost formation, the burial of northern peatlands by glaciers and mineral sediments decreased active peatland extent, thickness, and modeled C stocks by 70 to 90% from warmer times. Tropical peatland extent and C stocks show little temporal variation throughout the study period. While the increased burial of northern peats was correlated with cooling periods, the burial of tropical peat was predominately driven by changes in sea level and regional hydrology. Peat burial by mineral sediments represents a mechanism for long-term terrestrial C storage in the Earth system. These results show that northern peatlands accumulate significant C stocks during warmer times, indicating their potential for C sequestration during the warming Anthropocene.

Connexin43 intercellular communication drives the early differentiation of human bone marrow stromal cells into osteoblasts.

Although it has been demonstrated that human bone marrow stromal cells (hBMSCs) express the ubiquitous connexin43 (Cx43) and form functional gap junctions, their role in the early differentiation of hBMSCs into osteoblasts remains poorly documented. Using in vitro assays, we show that Cx43 expression and gap junctional intercellular communication (GJIC) are increased during the differentiation of hBMSCs into osteoblasts, both at the protein and mRNA levels. Two independent procedures to reduce GJIC, a pharmacological approach with GJIC inhibitors (18α-glycyrrhetinic acid and Gap27 peptide) and a molecular approach using small interfering RNA against Cx43, demonstrated that the presence of Cx43 and functional junctional channels are essential to the ability of hBMSCs to differentiate into osteoblasts in vitro. In addition, a reduced GJIC decreases the expression of Runx2, the major transcription factor implicated in the control of osteoblast commitment and early differentiation of hBMSCs into osteoblasts, suggesting that GJIC mediated by Cx43 is implicated in this process. Together our results demonstrate that GJIC mediated by the Cx43 channels plays a central role throughout the differentiation of hBMSC into osteoblasts, from the early stages to the process of mineralization.

Carbon accumulation of tropical peatlands over millennia: a modeling approach.

Tropical peatlands cover an estimated 440,000 km2 (~10% of global peatland area) and are significant in the global carbon cycle by storing about 40-90 Gt C in peat. Over the past several decades, tropical peatlands have experienced high rates of deforestation and conversion, which is often associated with lowering the water table and peat burning, releasing large amounts of carbon stored in peat to the atmosphere. We present the first model of long-term carbon accumulation in tropical peatlands by modifying the Holocene Peat Model (HPM), which has been successfully applied to northern temperate peatlands. Tropical HPM (HPMTrop) is a one-dimensional, nonlinear, dynamic model with a monthly time step that simulates peat mass remaining in annual peat cohorts over millennia as a balance between monthly vegetation inputs (litter) and monthly decomposition. Key model parameters were based on published data on vegetation characteristics, including net primary production partitioned into leaves, wood, and roots; and initial litter decomposition rates. HPMTrop outputs are generally consistent with field observations from Indonesia. Simulated long-term carbon accumulation rates for 11,000-year-old inland, and 5000-year-old coastal peatlands were about 0.3 and 0.59 Mg C ha(-1) yr(-1), and the resulting peat carbon stocks at the end of the 11,000-year and 5000-year simulations were 3300 and 2900 Mg C ha(-1), respectively. The simulated carbon loss caused by coastal peat swamp forest conversion into oil palm plantation with periodic burning was 1400 Mg C ha(-1) over 100 years, which is equivalent to ~2900 years of C accumulation in a hectare of coastal peatlands.

Loss of connexin43 expression in Ewing's sarcoma cells favors the development of the primary tumor and the associated bone osteolysis.

Ewing's sarcoma (ES) is a primary bone tumor characterized by a chromosomic translocation between the EWS gene and a member of the ETS gene family, mainly FLI1, which leads to an aberrant transcription factor EWS-FLI1 that promotes tumorigenicity. Gap junctions are intercellular channels composed of transmembrane proteins (connexin: Cx), that allow direct intercellular communication between adjacent cells. Numerous studies have shown that tumorigenesis may be associated with a loss of gap junctional intercellular communication (GJIC). Loss of Cx43 expression was observed at the protein and mRNA levels in ES cell lines compared to those measured in human mesenchymal stem cells. A673 ES cells stably transfected with an shRNA targeting EWS-FLI1 showed an increase in Cx43 expression (at the mRNA, protein and transcriptional levels) and GJIC. In an osteolytic murine model of ES, the overexpression of Cx43 in ES cells dramatically reduced tumor growth, leading to a significant increase in animal survival. In vitro assays showed that Cx43 overexpression increases the p27 level with an associated marked decrease of Rb phosphorylation, consistent with the observed blockade of the cell cycle in G0/G1 phase. In addition, the bone microarchitectural parameters, assessed by micro-CT analysis, showed an increased bone volume when Cx43 expression was enhanced. Histological analysis demonstrated that the overexpression of Cx43 in ES tumor cells inhibits osteoclast activity and therefore bone resorption. Our study demonstrated that the loss of Cx43 expression in ES cells plays a crucial role in the development of the primary tumor and the associated bone osteolysis.

The vitamin K-dependent anticoagulant factor, protein S, inhibits multiple VEGF-A-induced angiogenesis events in a Mer- and SHP2-dependent manner.

Protein S is a vitamin K-dependent glycoprotein, which, besides its anticoagulant function, acts as an agonist for the tyrosine kinase receptors Tyro3, Axl, and Mer. The endothelium expresses Tyro3, Axl, and Mer and produces protein S. The interaction of protein S with endothelial cells and particularly its effects on angiogenesis have not yet been analyzed. Here we show that human protein S, at circulating concentrations, inhibited vascular endothelial growth factor (VEGF) receptor 2-dependent vascularization of Matrigel plugs in vivo and the capacity of endothelial cells to form capillary-like networks in vitro as well as VEGF-A-induced endothelial migration and proliferation. Furthermore, protein S inhibited VEGF-A-induced endothelial VEGFR2 phosphorylation and activation of mitogen-activated kinase-Erk1/2 and Akt. Protein S activated the tyrosine phosphatase SHP2, and the SHP2 inhibitor NSC 87877 reversed the observed inhibition of VEGF-A-induced endothelial proliferation. Using siRNA directed against Tyro3, Axl, and Mer, we demonstrate that protein S-mediated SHP2 activation and inhibition of VEGF-A-stimulated proliferation were mediated by Mer. Our report provides the first evidence for the existence of a protein S/Mer/SHP2 axis, which inhibits VEGFR2 signaling, regulates endothelial function, and points to a role for protein S as an endogenous angiogenesis inhibitor.

Cancer-specific epigenome identifies oncogenic hijacking by nuclear factor I family proteins for medulloblastoma progression.

Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.

From scaling up to sustainability in HIV: potential lessons for moving forward.

BACKGROUND: In 30 years of experience in responding to the HIV epidemic, critical decisions and program characteristics for successful scale-up have been studied. Now leaders face a new challenge: sustaining large-scale HIV prevention programs. Implementers, funders, and the communities served need to assess what strategies and practices of scaling up are also relevant for sustaining delivery at scale. METHODS: We reviewed white and gray literature to identify domains central to scaling-up programs and reviewed HIV case studies to identify how these domains might relate to sustaining delivery at scale. RESULTS: We found 10 domains identified as important for successfully scaling up programs that have potential relevance for sustaining delivery at scale: fiscal support; political support; community involvement, integration, buy-in, and depth; partnerships; balancing flexibility/adaptability and standardization; supportive policy, regulatory, and legal environment; building and sustaining strong organizational capacity; transferring ownership; decentralization; and ongoing focus on sustainability. We identified one additional potential domain important for programs sustaining delivery at scale: emphasizing equity. CONCLUSIONS: Today, the public and private sector are examining their ability to generate value for populations. All stakeholders are aiming to stem the tide of the HIV epidemic. Implementers need a framework to guide the evolution of their strategies and management practices. Greater research is needed to refine the domains for policy and program implementers working to sustain HIV program delivery at scale.

Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma.

BACKGROUND: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of ß-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. METHODS: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between ß-blockers and ionising radiations. Gene expression profiles of ß-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. FINDINGS: Low concentrations of ß-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of ß-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. INTERPRETATION: These data provide the evidence of the efficacy of ß-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. FUNDING: This study was funded by institutional grants and charities.

The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors.

Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.

Recent climate change has driven divergent hydrological shifts in high-latitude peatlands.

High-latitude peatlands are changing rapidly in response to climate change, including permafrost thaw. Here, we reconstruct hydrological conditions since the seventeenth century using testate amoeba data from 103 high-latitude peat archives. We show that 54% of the peatlands have been drying and 32% have been wetting over this period, illustrating the complex ecohydrological dynamics of high latitude peatlands and their highly uncertain responses to a warming climate.

Global CO2 fertilization of Sphagnum peat mosses via suppression of photorespiration during the twentieth century.

Natural peatlands contribute significantly to global carbon sequestration and storage of biomass, most of which derives from Sphagnum peat mosses. Atmospheric CO2 levels have increased dramatically during the twentieth century, from 280 to > 400 ppm, which has affected plant carbon dynamics. Net carbon assimilation is strongly reduced by photorespiration, a process that depends on the CO2 to O2 ratio. Here we investigate the response of the photorespiration to photosynthesis ratio in Sphagnum mosses to recent CO2 increases by comparing deuterium isotopomers of historical and contemporary Sphagnum tissues collected from 36 peat cores from five continents. Rising CO2 levels generally suppressed photorespiration relative to photosynthesis but the magnitude of suppression depended on the current water table depth. By estimating the changes in water table depth, temperature, and precipitation during the twentieth century, we excluded potential effects of these climate parameters on the observed isotopomer responses. Further, we showed that the photorespiration to photosynthesis ratio varied between Sphagnum subgenera, indicating differences in their photosynthetic capacity. The global suppression of photorespiration in Sphagnum suggests an increased net primary production potential in response to the ongoing rise in atmospheric CO2, in particular for mire structures with intermediate water table depths.

Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors.

Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as osteosarcoma and Ewing's sarcoma or secondary bone tumors such as bone metastases from prostate carcinoma. Gap junctions are specialized plasma membrane structures consisting of transmembrane channels that directly link the cytoplasm of adjacent cells, thereby enabling the direct exchange of small signaling molecules between cells. Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function. Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is thus a main mechanism for tumor cells to communicate with other tumor cells and their surrounding microenvironment to survive and proliferate. If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells. If so, connexin expression would facilitate secondary tumor dissemination. This paper discusses evidence that suggests that connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.

ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of ßTrCP.

The Hedgehog (Hh) pathway is essential for embryonic development and tissue homeostasis. Aberrant Hh signaling may occur in a wide range of human cancers, such as medulloblastoma, the most common brain malignancy in childhood. Here, we identify endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptive antitumor immune responses, as a previously unknown player in the Hh signaling pathway. We demonstrate that ERAP1 binds the deubiquitylase enzyme USP47, displaces the USP47-associated ßTrCP, the substrate-receptor subunit of the SCFßTrCP ubiquitin ligase, and promotes ßTrCP degradation. These events result in the modulation of Gli transcription factors, the final effectors of the Hh pathway, and the enhancement of Hh activity. Remarkably, genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo. Our findings unveil an unexpected role for ERAP1 in cancer and indicate ERAP1 as a promising therapeutic target for Hh-driven tumors.

Drainage and fertilization effects on nutrient availability in an ombrotrophic peatland.

Nutrient availability is an important control on the vegetation distribution, productivity and functioning of peatland ecosystems and we examined spatial and temporal patterns of nutrient availability through ion exchange at Mer Bleue bog, southeast Ontario, Canada. We installed ion exchange probes at 5-15cm for 4weeks and determined nutrient sorption at undisturbed sites as well as those affected by nitrogen (N), phosphorus (P), potassium (K) fertilization and drainage. Under undisturbed conditions, the bog had very small amount of available nutrients, especially N (ammonium>nitrate) and P, and exhibited small variations in nutrient availability during the growing season (May to October). The increase in NPK availability upon fertilization was short-lived over the season and the stoichiometry of available NPK captured by the probes was mismatched with the vegetation. The increase in nutrient availability with drainage was confounded by substantial changes in vegetation. We compare these results with data from other Canadian bogs and fens to provide baseline data on nutrient availability in peatlands.

Environmental controls of C, N and P biogeochemistry in peatland pools.

Pools are common in northern peatlands but studies have seldom focused on their nutrient biogeochemistry, especially in relation to their morphological characteristics and through seasons. We determined the environmental characteristics controlling carbon (C), nitrogen (N) and phosphorus (P) biogeochemistry in pools and assessed their evolution over the course of the 2016 growing season in a subboreal ombrotrophic peatland of eastern Canada. We showed that water chemistry variations in 62 pools were significantly explained by depth (81.9%) and the surrounding vegetation type (14.8%), but not by pool area or shape. Shallow pools had larger dissolved organic carbon (DOC) and total nitrogen (TN) concentrations and lower pH than deep pools, while pools surrounded by coniferous trees had more recalcitrant DOC than pools where vegetation was dominated by mosses. The influence of depth on pool biogeochemistry was confirmed by the seasonal survey of pools of different sizes with 47.1% of the variation in pool water chemistry over time significantly explained. Of this, 67.3% was explained by the interaction between time and pool size and 32.7% by pool size alone. P concentrations were small in all pools all summer long and combined with high N:P ratios, are indicative of P-limitation. Our results show that pool biogeochemistry is influenced by internal processes and highlight the spatial and temporal heterogeneity of nutrient biogeochemistry in ombrotrophic peatlands.

Distribution of lead and mercury in Ontario peatlands.

While considerable attention has been given to the measurement of mercury (Hg) and lead (Pb) concentrations and accumulation in detailed peat cores in central Canada, the geographic distribution and density of sampling are generally limited. Here, we use the Ontario Peatland Inventory to examine broad patterns of Hg and Pb concentration with depth, based on 338 peat cores (containing >1500 analyzed samples) from 127 bogs, fens and swamps located in southeastern, northeastern and northwestern sections of Ontario. Overall, Hg concentrations averaged 0.05 µg g-1 and that of Pb averaged 10.8 µg g-1. Maximum values in the top 50 cm of the profiles are 0.08 µg g-1 and 26.2 µg g-1 for Hg and Pb, respectively. The ratio between these values (surface) and the values from below 100 cm (background), where peat likely accumulated before 1850 and industrial activities were limited, are 2.3 and 6.6 for Hg and Pb, respectively. The highest surface:background concentration ratios are generally found in the westernmost part of the province and in the southeast for Hg and around areas that are more heavily populated for Pb. Our results show that a vast amount of Hg and Pb are stored in Ontarian peatlands, although the spatial distribution of these stores varies. The rapid decomposition of peat in a changing climate could release these pollutants to the atmosphere.

TGF-ß Signaling in Bone Remodeling and Osteosarcoma Progression.

Osteosarcomas are the most prevalent malignant primary bone tumors in children. Despite intensive efforts to improve both chemotherapeutics and surgical management, 40% of all osteosarcoma patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma remains poor; less than 30% of patients who present metastases will survive five years after initial diagnosis. Treating metastatic osteosarcoma thus remains a challenge. One of the main characteristics of osteosarcomas is their ability to deregulate bone remodelling. The invasion of bone tissue by tumor cells indeed affects the balance between bone resorption and bone formation. This deregulation induces the release of cytokines or growth factors initially trapped in the bone matrix, such as transforming growth factor-ß (TGF-ß), which in turn promote tumor progression. Over the past years, there has been considerable interest in the TGF-ß pathway within the cancer research community. This review discusses the involvement of the TGF-ß signalling pathway in osteosarcoma development and in their metastatic progression.