Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia

BACKGROUND: Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings. METHODS: The eukaryotic initiation factor (eIF) 4E is a cap binding protein that stimulates ribosome recruitment to mRNA templates during the initiation phase of translation. Suppression of eIF4E is known to induce cell cycle arrest. Using a novel inducible and reversible transgenic mouse model that enables RNAi-mediated suppression of eIF4E in vivo, we assessed the consequences of temporal eIF4E suppression on CIA. RESULTS: Our results demonstrate that transient inhibition of eIF4E protects against cyclophosphamide-induced alopecia at the organismal level. At the cellular level, this protection is associated with an accumulation of cells in G1, reduced apoptotic indices, and was phenocopied using small molecule inhibitors targeting the process of translation initiation. CONCLUSIONS: Our data provide a rationale for exploring suppression of translation initiation as an approach to prevent or minimize cyclophosphamide-induced alopecia.1U01 CA168409 - NCI NIH HHS; P01 CA 87497 - NCI NIH HHS; P30 CA008748 - NCI NIH HHS; MOP-106530 - Canadian Institutes of Health Research; P01 CA013106 - NCI NIH HH

Upper Toarcian (Lower Jurassic) marine gastropods from the Cleveland Basin, England: systematics, palaeobiogeography and contribution to biotic recovery from the early Toarcian extinction event

Here we describe a new upper Toarcian (Lower Jurassic) marine gastropod fauna from rocks of the Cleveland Basin exposed on the North Yorkshire coast of England. The fossil assemblage consists of 16 species, of which three are new: Katosira ? bicarinata sp. nov., Turritelloidea stepheni sp. nov. and Striactaenonina elegans sp. nov. Four species are described in open nomenclature as Tricarilda ? sp., Jurilda sp., Cylindrobullina sp. and Cossmannina sp. The other species have previously been described: Coelodiscus minutus (Schübler in Zieten), Procerithium quadrilineatum (Römer), Pseudokatosira undulata (Benz in von Zieten), Palaeorissoina aff. acuminata (Gründel), Pietteia unicarinata (Hudleston), Globularia cf. canina (Hudleston), Striactaeonina cf. richterorum Schulbert & Nützel, Striactaenonina aff. tenuistriata (Hudleston) and Sulcoactaeon sedgvici (Phillips). Most of these species are the earliest records of their respective genera and show palaeobiogeographical connections with contemporary gastropod associations from other regions of Europe and South America. The taxonomic composition of the upper Toarcian Cleveland Basin gastropod assemblage differs substantially from the faunas of the upper Pliensbachian and lower Toarcian Tenuicostatum Zone, showing the strong effect of the early Toarcian mass extinction event on the marine gastropod communities in the basin. Only a few gastropod species are shared between the late Toarcian faunas and the much more diverse Aalenian gastropod faunas in the Cleveland Basin, suggesting that there was a facies control on gastropod occurrences at that time. This is also a potential explanation for the taxonomic differences between the late Toarcian gastropod faunas in the Cleveland Basin and those in France, and northern and southern Germany

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Nunataryuk field campaigns: understanding the origin and fate of terrestrial organic matter in the coastal waters of the Mackenzie Delta region

Climate warming and related drivers of soil thermal change in the Arctic are expected to modify the distribution and dynamics of carbon contained in perennially frozen grounds. Thawing of permafrost in the Mackenzie River watershed of northwestern Canada, coupled with increases in river discharge and coastal erosion, triggers the release of terrestrial organic matter (OMt) from the largest Arctic drainage basin in North America into the Arctic Ocean. While this process is ongoing and its rate is accelerating, the fate of the newly mobilized organic matter as it transits from the watershed through the delta and into the marine system remains poorly understood. In the framework of the European Horizon 2020 Nunataryuk programme, and as part of the Work Package 4 (WP4) Coastal Waters theme, four field expeditions were conducted in the Mackenzie Delta region and southern Beaufort Sea from April to September 2019. The temporal sampling design allowed the survey of ambient conditions in the coastal waters under full ice cover prior to the spring freshet, during ice breakup in summer, and anterior to the freeze-up period in fall. To capture the fluvial–marine transition zone, and with distinct challenges related to shallow waters and changing seasonal and meteorological conditions, the field sampling was conducted in close partnership with members of the communities of Aklavik, Inuvik and Tuktoyaktuk, using several platforms, namely helicopters, snowmobiles, and small boats. Water column profiles of physical and optical variables were measured in situ, while surface water, groundwater, and sediment samples were collected and preserved for the determination of the composition and sources of OMt, including particulate and dissolved organic carbon (POC and DOC), and colored dissolved organic matter (CDOM), as well as a suite of physical, chemical, and biological variables. Here we present an overview of the standardized datasets, including hydrographic profiles, remote sensing reflectance, temperature and salinity, particle absorption, nutrients, dissolved organic carbon, particulate organic carbon, particulate organic nitrogen, CDOM absorption, fluorescent dissolved organic matter intensity, suspended particulate matter, total particulate carbon, total particulate nitrogen, stable water isotopes, radon in water, bacterial abundance, and a string of phytoplankton pigments including total chlorophyll. Datasets and related metadata can be found in Juhls et al. (2021) (https://doi.org/10.1594/PANGAEA.937587).</p