The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth

Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAFV600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 μM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma

The association of objectively measured physical activity and sedentary behavior with skeletal muscle strength and muscle power in older adults: a systematic review and meta-analysis

Background Engaging in physical activity (PA) and avoiding sedentary behavior (SB) are important for healthy ageing with benefits including the mitigation of disability and mortality. Whether benefits extend to key determinants of disability and mortality, namely muscle strength and muscle power, is unclear. Aims This systematic review aimed to describe the association of objective measures of PA and SB with measures of skeletal muscle strength and muscle power in community-dwelling older adults. Methods Six databases were searched from their inception to June 21st, 2020 for articles reporting associations between objectively measured PA and SB and upper body or lower body muscle strength or muscle power in community dwelling adults aged 60 years and older. An overview of associations was visualized by effect direction heat maps, standardized effect sizes were estimated with albatross plots and summarized in box plots. Articles reporting adjusted standardized regression coefficients (β) were included in meta-analyses. Results A total of 112 articles were included representing 43,796 individuals (range: 21 to 3726 per article) with a mean or median age from 61.0 to 88.0 years (mean 56.4 % female). Higher PA measures and lower SB were associated with better upper body muscle strength (hand grip strength), upper body muscle power (arm curl), lower body muscle strength, and lower body muscle power (chair stand test). Median standardized effect sizes were consistently larger for measures of PA and SB with lower compared to upper body muscle strength and muscle power. The meta-analyses of adjusted β coefficients confirmed the associations between total PA (TPA), moderate-to-vigorous PA (MVPA) and light PA (LPA) with hand grip strength (β = 0.041, β = 0.057, and β = 0.070, respectively, all p ≤ 0.001), and TPA and MVPA with chair stand test (β = 0.199 and β = 0.211, respectively, all p ≤ 0.001). Conclusions Higher PA and lower SB are associated with greater skeletal muscle strength and muscle power, particularly with the chair stand test

Deep-water circulation changes lead North Atlantic climate during deglaciation

Constraining the response time of the climate system to changes in North Atlantic Deep Water (NADW) formation is fundamental to improving climate and Atlantic Meridional Overturning Circulation predictability. Here we report a new synchronization of terrestrial, marine, and ice-core records, which allows the first quantitative determination of the response time of North Atlantic climate to changes in high-latitude NADW formation rate during the last deglaciation. Using a continuous record of deep water ventilation from the Nordic Seas, we identify a ∼400-year lead of changes in high-latitude NADW formation ahead of abrupt climate changes recorded in Greenland ice cores at the onset and end of the Younger Dryas stadial, which likely occurred in response to gradual changes in temperature- and wind-driven freshwater transport. We suggest that variations in Nordic Seas deep-water circulation are precursors to abrupt climate changes and that future model studies should address this phasing

Chronology in Late Antiquity: A lesson from the Palaestra

This article deals with the fundamental problem of working in Ostia : how to devise a respectable chronology for a city that was mostly cleared of soil in a few years, with the aid of railways and poor families, for the World Exhibition of 1942. In the absence of photographs and serious notes, we have little to fall back on. I offer a field methodology against despair, applied to the difficult case of the Palaestra. What we need to do is clean up large areas, establish phases between them, and undertake selective excavation of pottery-rich rubbish deposits. From the resultant Harris Matrix, a more nuanced history of Ostia can emerge, of late antique centuries, extending far beyond the « Hadrianic » fantasy of Mussolini. The scale of this exercise makes it possible to assess the reliability and relative utility of different dating methods. Most early methods now fail, but others remain. It seems that future chronology will depend on an uncomfortable cohabitation of old and new