A highly distorted ultraelastic chemically complex Elinvar alloy.

The development of high-performance ultraelastic metals with superb strength, a large elastic strain limit and temperature-insensitive elastic modulus (Elinvar effect) are important for various industrial applications, from actuators and medical devices to high-precision instruments1,2. The elastic strain limit of bulk crystalline metals is usually less than 1 per cent, owing to dislocation easy gliding. Shape memory alloys3-including gum metals4,5 and strain glass alloys6,7-may attain an elastic strain limit up to several per cent, although this is the result of pseudo-elasticity and is accompanied by large energy dissipation3. Recently, chemically complex alloys, such as 'high-entropy' alloys8, have attracted tremendous research interest owing to their promising properties9-15. In this work we report on a chemically complex alloy with a large atomic size misfit usually unaffordable in conventional alloys. The alloy exhibits a high elastic strain limit (approximately 2 per cent) and a very low internal friction (less than 2 × 10-4) at room temperature. More interestingly, this alloy exhibits an extraordinary Elinvar effect, maintaining near-constant elastic modulus between room temperature and 627 degrees Celsius (900 kelvin), which is, to our knowledge, unmatched by the existing alloys hitherto reported.

[Clinical value of inflammatory biomarkers in predicting prognosis of patients with ureteral urothelial carcinoma].

OBJECTIVE: To evaluate the clinical value of inflammation-related markers in predicting the prognosis of patients with ureteral urothelial carcinoma. METHODS: 200 patients with ureteral urothelial carcinoma were randomly divided into two groups by split sample validation: modeling group and validation group. Paraffin embedded pathological specimens of the patients were reviewed. Immunohistochemical method was used to detect tumor-infiltrating neutrophil (TIN) (CD66b+), tumor-associated macrophage (TAM) (CD163+), lymphocyte (CD+, CD4+, CD8+) counts, peripheral blood neutrophil / lymphocyte ratio (NLR) and tumor tissue neutrophil/monocyte ratio (NMR). According to the results of pathological staging, the patients were divided into non-muscle-invasive and muscle-invasive ureteral urothelial carcinoma group. The resolution of the models was evaluated, and the prognostic nomogram models including only peripheral blood parameters and all parameters were established to compare the accuracy of the two models in predicting the prognosis of patients with urothelial carcinoma of the ureter. RESULTS: The median follow-up time was 36 months, the progression-free survival was 40 months, and 42 cases (21.0%) showed tumor progression within 3 years. Tumor size, pathological stage and pathological grade were all single-factor variables predicting the first recurrence of ureteral urothelial carcinoma three years after operation. Tumor size, pathological stage, pathological grade, TIN, TAM, NLR and NMR were multi-factor variables predicting the first recurrence three years after operation. Among 104 cases of non-muscle-invasive ureteral urothelial carcinoma, 10 cases (9.6%) recurred for the first time 3 years after operation, 96 cases (33.3%) of muscle invasive ureteral urothelial carcinoma, and the diffe-rence between the two groups was statistically significant (χ2=15.53, P < 0.05). The predictive nomogram model of progression free survival was established. The concordance index of progression free survi-val was 0.722 (95%CI: 0.70-0.78) in non-muscle-invasion group, and 0.725 (95%CI: 0.71-0.79) in muscle-invasion group, which was in good agreement with the observed 3-year survival rate. The results of discrimination test showed that the concordance index of the whole parameter prediction model of ureteral urothelial carcinoma was 0.726, which was higher than that of peripheral blood parameters (consistency index 0.672). The immune microenvironment of ureteral urothelial carcinoma improved the prediction accuracy of the model. CONCLUSION: The prognosis prediction model based on immune inflammation-related markers was established as a perfection and supplement for the existing pathological grading and staging system, providing a basis for accurate individualized treatment of patients with urete-ral urothelial carcinoma. The prognosis prediction model based on the relevant indicators of peripheral blood samples is established, which is easy to obtain specimens, and the detection method is simple and economical, which is more conducive to clinical application.

Randomized trial of oral versus enteral feeding for patients with postoperative pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Whether continued oral feeding may have a negative impact on healing of postoperative pancreatic fistula (POPF) is unclear. The aim was to test the hypothesis that oral feeding is non-inferior to enteral feeding in closure of POPF after pancreatoduodenectomy, and to clarify the effects of oral feeding on the duration and grade of POPF. METHODS: This multicentre, non-inferiority randomized trial of oral or enteral feeding of patients with POPF after pancreatoduodenectomy recruited patients between August 2013 and September 2016. The primary efficacy outcome was the 30-day fistula closure rate. The prespecified non-inferiority margin was 15 per cent. Other efficacy outcomes included grade of fistula, and hospital stay and costs. RESULTS: A total of 114 patients were included, and received oral (57) or enteral (57) feeding. The two groups were balanced in baseline characteristics and no patient was lost to follow-up. In intention-to-treat analysis, oral feeding was non-inferior to enteral feeding in terms of 30-day fistula closure rate (88 versus 89 per cent respectively; difference -1·8 per cent, lower limit of 95 per cent c.i. -14·4 per cent; P = 0·020 for non-inferiority). Compared with enteral feeding, oral feeding significantly reduced hospital costs and duration of stay. No significant differences were noted in the number of patients whose POPF evolved into grade B/C, or other outcomes. CONCLUSION: Oral feeding in patients with POPF after pancreatoduodenectomy did not increase the duration or grade of POPF, and was associated with reduced duration of stay and hospital costs. Registration number: NCT01755260 (http://www.clinicaltrials.gov).

miR-520h is crucial for DAPK2 regulation and breast cancer progression.

This corrects the article DOI: 10.1038/onc.2015.168.

miR-520h is crucial for DAPK2 regulation and breast cancer progression.

MicroRNAs (miRNAs) are small RNAs that suppress gene expression by their interaction with 3'untranslated region of specific target mRNAs. Although the dysregulation of miRNAs has been identified in human cancer, only a few of these miRNAs have been functionally documented in breast cancer. Thus, defining the important miRNA and functional target involved in chemoresistance is an urgent need for human breast cancer treatment. In this study, we, for the first time, identified a key role of miRNA 520h (miR-520h) in drug resistance. Through protecting cells from paclitaxel-induced apoptosis, expression of miR-520h promoted the drug resistance of human breast cancer cells. Bioinformatics prediction, compensatory mutation and functional validation further confirmed the essential role of miR-520h-suppressed Death-associated protein kinase 2 (DAPK2) expression, as restoring DAPK2 abolished miR-520h-promoted drug resistance, and knockdown of DAPK2 mitigated cell death caused by the depletion of miR-520h. Furthermore, we observed that higher level of miR-520h is associated with poor prognosis and lymph node metastasis in human breast cancer patients. These results show that miR-520h is not only an independent prognostic factor, but is also a potential functional target for future applications in cancer therapeutics.

Increased risk of glomerulonephritis and chronic kidney disease in relation to the severity of psoriasis, concomitant medication, and comorbidity: a nationwide population-based cohort study.

BACKGROUND: Few studies have examined the association between psoriasis and glomerulonephritis (GN) as well as chronic kidney disease (CKD). OBJECTIVES: To determine the risk of CKD in patients with psoriasis and evaluate the impact of the severity of psoriasis, comorbidities and concomitant drugs on the risk of GN and CKD in patients with psoriasis. METHODS: We identified 4344 patients with psoriasis for the study cohort and randomly selected 13,032 subjects as a control cohort. Each subject was individually followed for up for 5 years to identify those who subsequently developed GN and CKD. RESULTS: After adjustment for traditional CKD risk factors, psoriasis was found to be independently associated with an increased risk of CKD during the follow-up period [hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.14-1.44]. The increased incidence of GN in patients with psoriasis (HR 1.50, 95% CI 1.24-1.81) may contribute to the positive association between psoriasis and CKD. Patients with mild and severe psoriasis had an increased risk of CKD and GN compared with the control cohort; the risk increased with severity. Patients with psoriasis and arthritis exhibited a higher risk of CKD than patients without arthritis (HR 1.62 vs. 1.26). Among drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) have the strongest association with CKD in patients with psoriasis (adjusted odds ratio 1.69, 95% CI 1.14-2.49). CONCLUSIONS: Psoriasis was associated with a higher risk of developing CKD and GN. High severity, psoriatic arthritis involvement and concomitant NSAIDs use further increased the risk of CKD in patients with psoriasis.

MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol.

Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.

The effect of etanercept on anti-cyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the changes in anti-cyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) following etanercept treatment in patients with rheumatoid arthritis. METHODS: The study included 90 patients with rheumatoid arthritis who failed treatment with disease modifying antirheumatic drugs (DMARDs). All patients were allowed to continue treatment with DMARDs; 52 of them received etanercept as a twice weekly 25 mg subcutaneous injection for three months, and the others did not. Serum samples were collected at baseline and one month intervals during the treatment course. The serum levels of anti-CCP and RF were tested by enzyme linked immunosorbent assay and nephelometry, respectively. RESULTS: At baseline, 45 of the 52 etanercept treated patients (86.5%) and 32 of the 38 controls (84.2%) were positive for anti-CCP. Tests for RF were positive in 78.9% and 84.2% of patients with or without etanercept treatment, respectively. The serum levels of anti-CCP and RF decreased significantly after a three month etanercept treatment (p = 0.007 and p = 0.006, respectively). The average decrease from baseline calculated for each individual patient in the etanercept treated group was 31.3% for anti-CCP and 36% for RF. The variation in anti-CCP was positively correlated with the variation in disease activity, swollen and tender joint counts, RF, and C reactive protein. CONCLUSIONS: Etanercept combined with DMARDs leads to a much greater decrease than DMARDs alone in the serum levels of anti-CCP and RF in rheumatoid arthritis, compatible with a reduction in clinical disease activity.

Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in ankylosing spondylitis: MMP-3 is a reproducibly sensitive and specific biomarker of disease activity.

OBJECTIVE: To submit serum levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) to statistical analyses to test their exact degrees of clinical usefulness as biomarkers for detecting high disease activity in ankylosing spondylitis (AS), comparing them with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). METHODS: Serum levels of MMP-1, -3, -9 and TIMP-1 and -2 were measured in 42 AS patients and 20 healthy controls. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) provided the gold standard for measuring disease activity. Patients with BASDAI > or =4 were regarded as having high disease activity. The results were compared with results for a separate cohort of 41 AS patients. RESULTS: Only MMP-3 levels were significantly higher in AS patients than in healthy controls (P<0.001). Within AS patients, MMP-3 levels were also higher in patients with high disease activity compared with those with low disease activity, and correlated significantly with BASDAI (r = 0.366, P = 0.017) and functional indices (r = 0.344, P = 0.026). The correlation with BASDAI was stable in a 1-yr follow-up (r = 0.464, P = 0.095) and reproducible with two different enzyme-linked immunosorbent assays. For detecting high disease activity, the sensitivity and specificity of MMP-3 level was 69.2 and 68.8% respectively. Most importantly, using receiver operating characteristic plots to analyse the two cohorts, MMP-3 was more accurate than ESR and CRP in detecting AS patients with high disease activity (P = 0.01 and P = 0.009, respectively). CONCLUSION: Using several analytical approaches that have never been reported previously, we showed that MMP-3 is a more useful biomarker than ESR and CRP to detect high disease activity in AS.

Mononeuropathy multiplex and chylothorax as earlier manifestations of pulmonary tuberculosis.

Mononeuropathy multiplex (MNM) and chylothorax are rare clinical disorders. The concurrence of these two disorders with Mycobacterium tuberculosis infection has not been reported. We herein report a patient who was initially diagnosed with fever of unknown origin and MNM, and then developed chylothorax. Pulmonary tuberculosis was proved 1 month after chylothorax appeared. With low-dose prednisolone 15 mg day(-1) and anti-tuberculosis drugs, all these disorders completely resolved 1 year later.

The pH dependence of CD2 domain 1 self-association and 15N chemical exchange broadening is correlated with the anomalous pKa of Glu41.

We have previously shown using (15)N nuclear relaxation measurements that the concentration-dependent rotational correlation time and chemical exchange broadening for selected resonances of rat CD2 domain 1 (CD2d1) are consistent with a model of low-affinity self-association of the protein molecules. The exchange broadening data, which at high protein concentrations highlight selected nuclei in the major C'-C-F-G beta-sheet face of the immunoglobulin fold, implicate a surface reminiscent of the major lattice contact within crystals of the intact CD2 ectodomain. In a separate study, we have also demonstrated that the beta-strand C' surface-exposed residue Glu41 possesses an anomalously elevated acidity constant (pK(a) = 6.7 at a protein concentration of 1.2 mM). Mutagenesis studies showed that the close contact of residue Glu41 with Glu29 (beta-strand C) is the primary cause of the high pK(a). However, the measured pK(a) of Glu41 also shows a weak dependence on protein concentration, implicating Glu41 in the mechanism of CD2d1 self-association. In the study presented here, we demonstrate a correlation of the pH dependence of the chemical shift and (15)N nuclear relaxation parameters measured for wild-type and mutant forms of CD2d1 with pH and the protonation state of Glu41. Self-association of CD2d1 molecules is promoted whenever the side chain charge of residue 41 is neutralized. These observations are consistent with a model for CD2d1 self-association that corresponds to the crystal structure lattice contact where the interatomic distances are consistent with Glu41 being in the protonated state. This study reinforces the conclusion that residue-specific chemical exchange broadening of protein resonances can arise from weak self-association phenomena. In addition, the electrostatic profile of rat CD2 interfacial residues parallels that of the homologous human CD2 in a manner that suggests a rationalization of similar exchange broadening observations.

The solution structure of PapGII from uropathogenic Escherichia coli and its recognition of glycolipid receptors.

Uropathogenic Escherichia coli (UPEC) is the primary cause of symptomatic urinary tract infection. The P-pili, a bacterial surface organelle, mediates the bacterial host--cell adhesion. The PapG adhesin has generated much interest in recent years, not only because of its clinical value, i.e. in the prevention of microbial adherence, but also because of its ability to promote virulence. Using multidimensional nuclear magnetic resonance (NMR) and deuteration we have determined the solution structure of the adhesin domain from PapGII (PapGII-198). The novel structure of PapGII-198 is composed of a large elongated jellyroll motif. Despite an automated search of the structural database failing to reveal any similar proteins, PapGII adhesin shares some structural similarities with FimH. Furthermore, interpretation of NMR-titration data has enabled us to identify the putative binding site for the globoseries of oligosaccharides. This work provides insight into UPEC pathogenesis as well as aiding the development of preventative therapies and the guidance of future mutagenesis programmes.

Determination of pK(a) values of carboxyl groups in the N-terminal domain of rat CD2: anomalous pK(a) of a glutamate on the ligand-binding surface.

The ligand-binding surface of the T-lymphocyte glycoprotein CD2 has an unusually high proportion of charged residues, and ionic interactions are thought to play a significant role in defining the ligand specificity and binding affinity of CD2 with the structurally homologous ligands CD48 (in rodents) and CD58 (in humans). The determination of the electrostatic properties of these proteins can therefore contribute to our understanding of structure-activity relationships for these adhesion complexes that underpin T-cell adhesion to antigen-presenting cells. In this study, we investigated the pH titration behavior of the carboxyl groups of the N-terminal domain of rat CD2 (CD2d1) using the chemical shifts of backbone amide nitrogen-15 ((15)N) and proton NMR resonances, and carboxyl carbon-13 ((13)C) signals. The analysis revealed the presence of a glutamate (Glu41) on the binding surface of rat CD2 with an unusually elevated acidity constant (pK(a) = 6.73) for CD2d1 samples at 1.2 mM concentration. pH titration of CD2d1 at low protein concentration (0.1 mM) resulted in a slight decrease of the measured pK(a) of Glu41 to 6.36. The ionization of Glu41 exhibited reciprocal interactions with a second glutamate (Glu29) in a neighboring location, with both residues demonstrating characteristic biphasic titration behavior of the carboxyl (13)C resonances. Measurements at pH 5.5 of the two-bond deuterium isotope shift for the (13)C carboxyl resonances for Glu41 and Glu29 [(2)DeltaC(delta)(O(epsilon)D) = 0.2 and 0.1 ppm, respectively] were consistent with the assignment of the anomalous pK(a) to Glu41, under the strong influence of Glu29. The characterization of single site mutations of CD2d1 residues Glu41 and Glu29 to glutamine confirmed the anomalous pK(a) for Glu41, and indicated that electrostatic interaction with the Glu29 side chain is a significant contributing influence for this behavior in the wild-type protein. The implications of these observations are discussed with respect to recent structural and functional analyses of the interaction of rat CD2 with CD48. In particular, CD2 Glu41 must be a candidate residue to explain the previously reported strong pH dependence of binding of these two proteins in vitro.

NMR exchange broadening arising from specific low affinity protein self-association: analysis of nitrogen-15 nuclear relaxation for rat CD2 domain 1.

Nuclear spin relaxation monitored by heteronuclear NMR provides a useful method to probe the overall and internal molecular motion for biological macromolecules over a variety of time scales. Nitrogen-15 NMR relaxation parameters have been recorded for the N-terminal domain of the rat T-cell antigen CD2 (CD2d1) in a dilution series from 1.20 mM to 40 microM (pH 6.0, 25 degrees C). The data have been analysed within the framework of the model-free formalism of Lipari and Szabo to understand the molecular origin of severely enhanced transverse relaxation rates found for certain residues. These data revealed a strong dependence of the derived molecular correlation time tau c upon the CD2d1 protein concentration. Moreover, a number of amide NH resonances exhibited exchange broadening and chemical shifts both strongly dependent on protein concentration. These amide groups cluster on the major beta-sheet surface of CD2d1 that coincides with a major lattice contact in the X-ray structure of the intact ectodomain of rat CD2. The complete set of relaxation data fit well to an equilibrium monomer-dimer exchange model, yielding estimates of exchange rate constants (kON = 5000 M-1 s-1; kOFF = 7 s-1) and a dissociation constant (KD approximately 3-6 mM) that is consistent with the difficulty in detecting the weak interactions for this molecule by alternative biophysical methods. The self-association of CD2d1 is essentially invariant to changes in buffer composition and ionic strength and the associated relaxation phenomena cannot be explained as a result of neglecting anisotropic rotational diffusion in the analysis. These observations highlight the necessity to consider low affinity protein self-association interactions as a source of residue specific exchange phenomena in NMR spectra of macromolecular biomolecules, before the assignment of more elaborate intramolecular conformational mechanisms.