Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma

Background: Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment. Methods: We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models. Results: Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo. Conclusion: Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients

Spawning of bluefin tuna in the black sea: historical evidence, environmental constraints and population plasticity

<div><p>The lucrative and highly migratory Atlantic bluefin tuna, <em>Thunnus thynnus</em> (Linnaeus 1758<em>;</em> Scombridae), used to be distributed widely throughout the north Atlantic Ocean, Mediterranean Sea and Black Sea. Its migrations have supported sustainable fisheries and impacted local cultures since antiquity, but its biogeographic range has contracted since the 1950s. Most recently, the species disappeared from the Black Sea in the late 1980s and has not yet recovered. Reasons for the Black Sea disappearance, and the species-wide range contraction, are unclear. However bluefin tuna formerly foraged and possibly spawned in the Black Sea. Loss of a locally-reproducing population would represent a decline in population richness, and an increase in species vulnerability to perturbations such as exploitation and environmental change. Here we identify the main genetic and phenotypic adaptations that the population must have (had) in order to reproduce successfully in the specific hydrographic (estuarine) conditions of the Black Sea. By comparing hydrographic conditions in spawning areas of the three species of bluefin tunas, and applying a mechanistic model of egg buoyancy and sinking rate, we show that reproduction in the Black Sea must have required specific adaptations of egg buoyancy, fertilisation and development for reproductive success. Such adaptations by local populations of marine fish species spawning in estuarine areas are common as is evident from a meta-analysis of egg buoyancy data from 16 species of fish. We conclude that these adaptations would have been necessary for successful local reproduction by bluefin tuna in the Black Sea, and that a locally-adapted reproducing population may have disappeared. Recovery of bluefin tuna in the Black Sea, either for spawning or foraging, will occur fastest if any remaining locally adapted individuals are allowed to survive, and by conservation and recovery of depleted Mediterranean populations which could through time re-establish local Black Sea spawning and foraging.</p> </div

The qualitative and quantitative distribution in phytoplankton and zooplankton of southern Black Sea of cape Sinop, Turkey in 1999-2000

In the present study, seasonality and composition of phytoplankton and zooplankton were comparatively studied at two stations (one inshore and one offshore) off Sinop, in southern Black Sea during January-May 1999 and March -October 2000. A total 76 genera including 149 species and varieties were identified, of which 46% were dinoflagellates and 34% were diatoms in phytoplankton. Abundance of the genera Emiliana (in January-May 1999), Pseudosolenia and Ceratium (in March-October 2000) were higher than that of the other genera in almost every sampling period. Increased dinoflagellate to diatom ratio reflects more fertile conditions in the southern Black Sea. Abundance and biomass of the total fodder zooplankton the highest values were recorded in February 1999; March 2000. Cladocera and Appendicularia abundance and biomass values were higher in 1999 than 2000. Noctiluca scintillans was the most abundant of zooplankton group with a share of 43% (maximum: 416,925 ind.m(-2) in May) in 1999. The second abundant group was Copepoda with 42% (172,981 ind.m(-2) in February).Copepods with 78% of abundance and 73% of biomass (maximum: 372,330 ind.m(-2) and 15,253 mg.m(-2) in March) were the dominant group in 2000. They were followed by the dinoflagellate Noctiluca scintillans with 4.8% (maximum: 24,500 ind.m(-2) in June)

Electroencephalography Abnormalities in Intensive Care Unit and Frequency of Non-Convulsive/Convulsive Status Epilepticus in Long Term Monitoring

13th European Congress on Epileptology -- AUG 26-30, 2018 -- Vienna, AUSTRIAWOS: 000451817900742

The Qualitative and Quantitative Distribution in Phytoplankton and Zooplankton of Southern Black Sea of Cape Sinop, Turkey in 1999-2000

n the present study, seasonality and composition of phytoplankton and zooplankton were comparatively studied at two stations (one inshore and one offshore) off Sinop, in southern Black Sea during January-May 1999 and March-October 2000. A total 76 genera including 149 species and varieties were identified, of which 46% were dinoflagellates and 34% were diatoms in phytoplankton. Abundance of the genera Emiliana (in January-May 1999), Pseudosolenia and Ceratium (in March-October 2000) were higher than that of the other genera in almost every sampling period. Increased dinoflagellate to diatom ratio reflects more fertile conditions in the southern Black Sea. Abundance and biomass of the total fodder zooplankton the highest values were recorded in February 1999; March 2000. Cladocera and Appendicularia abundance and biomass values were higher in 1999 than 2000. Noctiluca scintillans was the most abundant of zooplankton group with a share of 43% (maximum: 416,925 ind. m-2 in May) in 1999. The second abundant group was Copepoda with 42% (172,981 ind.m-2 in February). Copepods with 78% of abundance and 73% of biomass (maximum: 372,330 ind. m-2 and 15,253 mg.m-2 in March) were the dominant group in 2000. They were followed by the dinoflagellate Noctiluca scintillans with 4.8% (maximum: 24,500 ind.m-2 in June).JRC.G.4-Maritime affair

Cerebral Venous Sinus Thrombosis and Seizures; Retrospective Evaluation of Long-Term Follow-Up

13th European Congress on Epileptology -- AUG 26-30, 2018 -- Vienna, AUSTRIAWOS: 000451817900593