MiR-429 is linked to metastasis and poor prognosis in renal cell carcinoma by affecting epithelial-mesenchymal transition

Tumor Biology - MicroRNAs (miRNAs) have been proven to be important oncogenes and tumor suppressors in wide range of cancers, including renal cell carcinoma (RCC). In our study, we evaluated...     

Consistent blind protein structure generation from NMR chemical shift data

Protein NMR chemical shifts are highly sensitive to local structure. A robust protocol is described that exploits this relation for de novo protein structure generation, using as input experimental parameters the (13)C(alpha), (13)C(beta), (13)C', (15)N, (1)H(alpha) and (1)H(N) NMR chemical shifts. These shifts are generally available at the early stage of the traditional NMR structure determination process, before the collection and analysis of structural restraints. The chemical shift based structure determination protocol uses an empirically optimized procedure to select protein fragments from the Protein Data Bank, in conjunction with the standard ROSETTA Monte Carlo assembly and relaxation methods. Evaluation of 16 proteins, varying in size from 56 to 129 residues, yielded full-atom models that have 0.7-1.8 A root mean square deviations for the backbone atoms relative to the experimentally determined x-ray or NMR structures. The strategy also has been successfully applied in a blind manner to nine protein targets with molecular masses up to 15.4 kDa, whose conventional NMR structure determination was conducted in parallel by the Northeast Structural Genomics Consortium. This protocol potentially provides a new direction for high-throughput NMR structure determination.     

Comparison of Different Treatment Modalities Outcomes in Clinically Node-positive Bladder Cancer: Analysis of a Population-based Cancer Registry

IntroductionPatients with clinically node-positive bladder cancer were historically considered to have uniformly poor prognosis and were frequently treated with palliative chemotherapy (CHT) only. Although retrospective data show that long-term survival with combined treatment (surgery + CHT) is possible in one-third of these patients, consensus on a treatment algorithm is still lacking. The aim of the study is to compare the efficacy of different treatment modalities based on data from a population-based cancer registry.Patients and MethodsThe study comprises 661 patients identified from the Czech National Cancer Registry (1996-2015) with cTanyN1-3M0 bladder cancer; 195 were treated with CHT alone, 234 underwent radical cystectomy alone (RC), and 232 received a combination of RC and perioperative CHT (RC + CHT). Multivariate Cox proportional hazard regression analyses were used to evaluate the effectiveness of various treatments.ResultsThe 5-year OS for CHT alone, RC alone, and RC + CHT were 21.7% (95% confidence interval [CI], 15.4%-28.0%), 12.1% (95% CI, 7.4%-16.7%), and 25.4% (95% CI, 18.9%-31.9%), respectively (P < .001). The median survivals were 17, 10, and 23 months, respectively. In multivariate analysis, age > 60 years (hazard ratio, 1.29; 95% CI, 1.06-1.56; P = .011) and clinical stage cT3-4 (hazard ratio, 1.39; 95% CI, 1.12-1.71; P = .002) were negative predictors of survival. When compared with CHT, RC + CHT reduced the risk of overall mortality by 21% (P = .044).ConclusionApproximately one-quarter of clinically node-positive patients may achieve long-term survival with combined treatment integrating RC and perioperative CHT. The overall survival of patients is significantly improved with a multimodal approach in comparison to CHT alone.     

Designing Nutritionally Adequate and Climate-Friendly Diets for Omnivorous,Pescatarian, Vegetarian and Vegan Adolescents in Sweden Using Linear Optimization

Low-carbon diets can counteract climate change and promote health if they are nutritionally adequate, affordable and culturally acceptable. This study aimed at developing sustainable diets and to compare these with the EAT-Lancet diet. The Swedish national dietary survey Riksmaten Adolescents 2016–2017 was used as the baseline. Diets were optimized using linear programming for four dietary patterns: omnivores, pescatarians, vegetarians and vegans. The deviation from the baseline Riksmaten diet was minimized for all optimized diets while fulfilling nutrient and climate footprint constraints. Constraining the diet-related carbon dioxide equivalents of omnivores to 1.57 kg/day resulted in a diet associated with a reduction of meat, dairy products, and processed foods and an increase in potatoes, pulses, eggs and seafood. Climate-friendly, nutritionally adequate diets for pescatarians, vegetarians and vegans contained fewer foods and included considerable amounts of fortified dairy and meat substitutes. The optimized diets did not align very well with the food-group pattern of the EAT-Lancet diet. These findings suggest how to design future diets that are climate-friendly, nutritionally adequate, affordable, and culturally acceptable for Swedish adolescents with different dietary patterns. The discrepancies with the EAT diet indicate that the cultural dietary context is likely to play an important role in characterizing sustainable diets for specific populations.     

Main partitioning criteria for the characterization of the health status in the freshwater mussel Anodonta cygnea from spontaneously polluted area in Western Ukraine

The aim of this study was to appreciate the consequences of spontaneous human activity for freshwater mollusks in the generally ecologically sustainable area in Western Ukraine. For this, bivalve mollusk, Anodonta cygnea, at three sites, with mixed agricultural and municipal activities (A), close to a municipal water inlet (F) and the cooling pond of a nuclear power plant (N), were studied in spring, summer, and autumn. The set of parameters included the characteristics of oxidative stress (activity of catalase (CAT), levels of protein carbonyls (PC)), levels of reduced and oxidized glutathione (GSH, GSSG, respectively), activities of lactate dehydrogenase (LD), cholinesterase (ChE), ethoxyresorufin‐O‐deethylase (EROD), glutathione S‐transferase (GST) in the digestive gland, and concentrations of vitellogenin‐like proteins (Vtg‐LP) in gonads and also morphological indices. Although the discriminant functional analysis confirmed the general seasonal regularities for studied groups, it allowed to discriminate between sites (P < 0.05). At site A, oxidative stress; high levels of LD, EROD, and GST; and low levels of ChE and condition factor were reflected. This demonstrated the sensitivity of mussels to constant effect of mixed pollution. At site N, oxidative injury was shown that might be explained by the constantly high temperature. At site F, abrupt elevations of Vtg‐LP and EROD levels in autumn were probably related to an emergency situation on the nearby dump. So, both chronic and temporal environmental effects were reflected by a set of markers in mollusk. The classification and regression tree (CART) algorithm selected GSH and PC in the digestive gland and Vtg‐LP as partitioning criteria for the characterization of mussel health status. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation

In many types of cancer, the expression of the immunoregulatory protein B7-H3 has been associated with poor prognosis. Previously, we observed a link between B7-H3 and tumor cell migration and invasion, and in present study, we have investigated the role of B7-H3 in chemoresistance in breast cancer. We observed that silencing of B7-H3, via stable short hairpin RNA or transient short interfering RNA transfection, increased the sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Overexpression of B7-H3 made the cancer cells more resistant to the drug. Next, we investigated the mechanisms behind B7-H3-mediated paclitaxel resistance and found that the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells along with the expression of its direct downstream targets Mcl-1 and survivin. The phosphorylation of Janus kinase 2 (Jak2), an upstream molecule of Stat3, was also significantly decreased. In contrast, reexpression of B7-H3 in B7-H3 knockdown and low B7-H3 expressing cells increased the phosphorylation of Jak2 and Stat3. In vivo animal experiments showed that B7-H3 knockdown tumors displayed a slower growth rate than the control xenografts. Importantly, paclitaxel treatment showed a strong antitumor activity in the mice with B7-H3 knockdown tumors, but only a marginal effect in the control group. Taken together, our data show that in breast cancer cells, B7-H3 induces paclitaxel resistance, at least partially by interfering with Jak2/Stat3 pathway. These results provide novel insight into the function of B7-H3 and encourage the design and testing of approaches targeting this protein and its partners.     

Magnetic resonance imaging and computed tomography developments in imaging of venous thromboembolism

Venous thromboembolism (VTE) is a disease that causes high morbidity and mortality in the population. At present the first-line imaging test for a suspected pulmonary embolism (PE) is computed tomography (CT) pulmonary angiography, and ultrasonography is widely used for the diagnosis of deep-vein thrombosis (DVT). Although these modalities are proven to be safe and accurate, unresolved issues remain, such as whether CT scanning in patients with a suspected PE should be extended to the legs. Another issue is the diagnosis of recurrent DVT. Magnetic resonance imaging (MRI) offers a number of advantages in the imaging of VTE. Recent developments of scanning protocols with shorter acquisition times, sometimes complemented by navigator gating or making use of endogenous contrast, offer new perspectives for the use of MRI. This review provides an overview of state of the art MRI techniques for the diagnosis of PE and DVT. Furthermore, the use of new contrast agents such as fibrin labeling to detect thrombi are addressed.     

Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation

Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515_2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02–4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515_2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel–Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups.