SummaryBackgroundThe vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials.MethodsWe undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed).FindingsMajor vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14–1·66; p=0·0009) or diclofenac (1·41, 1·12–1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31–2·37; p=0·0001; diclofenac 1·70, 1·19–2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10–4·48; p=0·0253), but not major vascular events (1·44, 0·89–2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69–1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56–6·41; p=0·17), but not by naproxen (1·08, 0·48–2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17–2·81, p=0·0070; diclofenac 1·89, 1·16–3·09, p=0·0106; ibuprofen 3·97, 2·22–7·10, p<0·0001; and naproxen 4·22, 2·71–6·56, p<0·0001).InterpretationThe vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making.FundingUK Medical Research Council and British Heart Foundation.

The epithelial to mesenchymal transition (EMT) that occurs during embryonic development has begun to attract attention as a potential mechanism for tumor cell metastasis. Snail is a well-known Zn-finger transcription factor that promotes EMT by repressing E-cadherin expression. It is known that Snail is phosphorylated by GSK3b and degraded by b-TrCP-mediated ubiquitination. Here we described another protein kinase, CK1, whose phosphorylation of Snail is required for the subsequent GSK3b phosphorylation. Specific inhibition or depletion of CK1e inhibits the phosphorylation and degradation of Snail and promotes cell migration, suggesting a central role of CK1e in the EMT process. Furthermore, our study uncovered distinct roles and steps of Snail phosphorylation by CK1e and GSK3b. Taken together, we identified CK1e as a new component of the Snail-mediated EMT process, providing insight into the mechanism of human cancer metastasis.

The excellent cryogenic tensile properties of the CrMnFeCoNi alloy are generally caused by deformation twinning, which is difficult to achieve at room temperature because of insufficient stress for twinning. Here, we induced twinning at room temperature to improve the cryogenic tensile properties of the CrMnFeCoNi alloy. Considering grain size effects on the critical stress for twinning, twins were readily formed in the coarse microstructure by cold rolling without grain refinement by hot rolling. These twins were retained by partial recrystallization and played an important role in improving strength, allowing yield strengths approaching 1 GPa. The persistent elongation up to 46% as well as the tensile strength of 1.3 GPa are attributed to additional twinning in both recrystallized and non-recrystallization regions. Our results demonstrate that non-recrystallized grains, which are generally avoided in conventional alloys because of their deleterious effect on ductility, can be useful in achieving high-strength high-entropy alloys.

Although almost all primary colorectal lymphomas are of B-cell lineage in Western countries, primary colorectal T-cell lymphomas are not uncommon in the East. The aim of this study was to review the clinical characteristics and treatment outcomes of primary colorectal lymphomas, with special emphasis on the differences between T-cell and B-cell lymphomas. Ninety-five cases of primary colorectal lymphomas that satisfied Dawson's criteria were identified from the clinical databases of 13 university hospitals in Korea. The mean age at the time of presentation was 51.1 years and the male:female ratio was 64:31. The clinical information, including endoscopic and histological characteristics, was retrospectively analyzed. Of the primary colorectal lymphomas, 78 cases (82.1%) were of B-lineage and 17 cases (17.9%) were of T-cell lineage. Patients with T-cell lymphomas presented at a younger age than patients with B-cell lymphomas (42.8 vs 52.9 years, respectively; P = 0.016). The most common presenting symptom was abdominal pain (87.1%) for B-cell lymphomas, whereas hematochezia or night fever was more common for T-cell lymphomas (52.9% and 35.3%, respectively). The most common endoscopic type was fungating mass (54.0%) for B-cell lymphomas and ulcerative/ulcero-infiltrative lesions (80.0%) for T-cell lymphomas. Intussusception was more common in B-cell lymphomas than in T-cell lymphomas (30.8% vs 5.9%, respectively; P = 0.035), but perforation was more common in T-cell lymphomas than in B-cell lymphomas (23.5% vs 3.8%, respectively; P = 0.005). The prognosis was significantly worse for T-cell lymphomas than for B-cell lymphomas (P = 0.002). Primary colorectal T-cell lymphomas are characterized by multifocal ulcerative lesions in relatively young patients, a high rate of hematochezia, fever, or perforation, and a poor prognosis even for cases of localized disease.

A B S T R A C TThe ratcheting behaviour of Inconel 718 was investigated at 649 • C under uniaxial cyclic loading. Stress-control tests have been conducted at various combinations of stress amplitude and mean stress. The ratcheting strain at failure increases with increasing mean stress for a given stress amplitude and with decreasing stress amplitude for a given mean stress. Fatigue lives were correlated using three mean stress models: the Goodman equation, the Smith-Watson-Topper (SWT) parameter and the Walker parameter. It has been shown that the Goodman equation and the SWT parameter do not correlate life data, while the Walker parameter yields acceptable correlation. The SWT parameter was modified to incorporate the ratcheting effect. The new parameter is found to yield correlation similar to that of the Walker parameter.Keywords Goodman equation; mean stress effect; ratcheting strain; SWT parameter; uniaxial fatigue; Walker parameter. N O M E N C L A T U R Eσ a = stress amplitude σ m = mean stress σ eq a = equivalent stress amplitude σ max = maximum stress R = stress ratio (R = σ min /σ max ) ε r = ratcheting strain N = number of cycles N f = number of cycles to failure σ f = fatigue strength coefficient b = fatigue strength exponent γ = Walker exponent I N T R O D U C T I O NMany engineering components are subjected to cyclic loading in which the fatigue process takes place under stress-control conditions. Fatigue cycles may not be fully reversed. In these circumstances, the mean stress effect has to be taken into account in fatigue life prediction. A phenomenon that occurs in the presence of mean stress in the low-cycle fatigue regime is ratcheting, which results from the accumulation of plastic strain. Ratcheting causes fatigue damage of the material and shortens the life of engineering components significantly, unless a shakedown state is reached in the early stage of life. Naturally, this important phenomenon has received the attention of many researchers, and numerous studies have been carried out on the deformation aspect of the phenomenon. The Armstrong-Frederick nonlinear kinematic hardening rule 1 is widely used in ratcheting analysis. The decomposed model by Chaboche 2 and the multilinear model by Ohno and Wang 3 belong to this category. These models have been successful for predicting uniaxial ratcheting, but they tend to overpredict ratcheting under multiaxial loading. Despite many modified models suggested 4,5 to resolve the shortcomings, the prediction of ratcheting strain under multiaxial loading still remains a challenging problem. Not only that, there are many other variables influencing ratcheting behaviour which need to be further investigated. For all these and other reasons, the 1076