Cyclooxygenase-2 Expression in Bladder Cancer and Patient Prognosis: Results from a Large Clinical Cohort and Meta-Analysis

Aberrant overexpression of cyclooxygenase-2 (COX2) is observed in urothelial carcinoma of the bladder (UCB). Studies evaluating COX2 as a prognostic marker in UCB report contradictory results. We determined the prognostic potential of COX2 expression in UCB and quantitatively summarize the results with those of the literature through a meta-analysis. Newly diagnosed UCB patients recruited between 1998–2001 in 18 Spanish hospitals were prospectively included in the study and followed-up (median, 70.7 months). Diagnostic slides were reviewed and uniformly classified by expert pathologists. Clinical data was retrieved from hospital charts. Tissue microarrays containing non-muscle invasive (n = 557) and muscle invasive (n = 216) tumours were analyzed by immunohistochemistry using quantitative image analysis. Expression was evaluated in Cox regression models to assess the risk of recurrence, progression and disease-specific mortality. Meta-hazard ratios were estimated using our results and those from 11 additional evaluable studies. COX2 expression was observed in 38% (211/557) of non-muscle invasive and 63% (137/216) of muscle invasive tumors. Expression was associated with advanced pathological stage and grade (p<0.0001). In the univariable analyses, COX2 expression - as a categorical variable - was not associated with any of the outcomes analyzed. As a continuous variable, a weak association with recurrence in non-muscle invasive tumors was observed (p-value = 0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes. The meta-analysis confirmed these results. We did not find evidence that COX2 expression is an independent prognostic marker of recurrence, progression or survival in patients with UCB.The work was partially supported by the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministry of Science and Innovation, Spain (G03/174, 00/0745, PI051436, PI061614 and G03/174); Red Temática de Investigación Cooperativa en Cáncer- RD06/0020-RTICC; Consolider ONCOBIO; EU-FP6-STREP-37739-DRoP-ToP; EU-FP7-HEALTH-F2-2008-201663-UROMOL; EU-FP7-HEALTH-F2-2008-201333-DECanBio; USA-NIH-RO1-CA089715; and a PhD fellowship awarded to MJC from the ‘‘la Caixa’’ foundation, Spain, and a postdoctoral fellowship awarded to AFSA from the Fundación Científica de la AEC

Creep of binary Fe-Al alloys with ultrafine lamellar microstructures

On the Al-rich side of the Fe-Al binary system, the eutectoid decomposition of Fe5Al8 into B2-ordered FeAl and triclinic FeAl2 in the composition range of 55–65 at.% Al produces an ultrafine lamellar microstructure. The compression creep behavior of such two-phase intermetallic materials was investigated in the temperature range 600–800 °C under constant stress. In addition to the fully lamellar Fe-61Al alloy, Fe-58Al and Fe-62Al that included, pro-eutectoid FeAl and FeAl2, respectively, were characterized in terms of their microstructure and creep response. For all microstructures, the strain rate as a function of time and strain exhibits a distinct minimum instead of a steady state creep regime. Microstructure instability, primarily in the vicinity of colony boundaries, is identified as the main reason for the increase in strain rate beyond the minimum. In contrast, lamellar coarsening is shown to be only a secondary factor influencing creep response for the conditions investigated. In comparison to single phase FeAl, the fully lamellar FeAl-FeAl2 shows enhanced creep resistance while the presence of either pro-eutectoid phase leads to a relative deterioration of the creep resistance

Creep of binary Fe-Al alloys with ultrafine lamellar microstructures

On the Al-rich side of the Fe-Al binary system, the eutectoid decomposition of Fe5Al8 into B2-ordered FeAl and triclinic FeAl2 in the composition range of 55–65 at.% Al produces an ultrafine lamellar microstructure. The compression creep behavior of such two-phase intermetallic materials was investigated in the temperature range 600–800 °C under constant stress. In addition to the fully lamellar Fe-61Al alloy, Fe-58Al and Fe-62Al that included, pro-eutectoid FeAl and FeAl2, respectively, were characterized in terms of their microstructure and creep response. For all microstructures, the strain rate as a function of time and strain exhibits a distinct minimum instead of a steady state creep regime. Microstructure instability, primarily in the vicinity of colony boundaries, is identified as the main reason for the increase in strain rate beyond the minimum. In contrast, lamellar coarsening is shown to be only a secondary factor influencing creep response for the conditions investigated. In comparison to single phase FeAl, the fully lamellar FeAl-FeAl2 shows enhanced creep resistance while the presence of either pro-eutectoid phase leads to a relative deterioration of the creep resistance

Special Issue of Journal of Data and Information Science on ISSI2019 Conference-Part I

n/

IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways.

Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu ) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism

A significant improvement in the superconducting properties of MgB2 by co-doping with graphene and nano-SiC

The effects of graphene (G) and nanosilicon carbide (SiC) co-doping on the superconducting properties of MgB2 were studied using bulk samples. SiC remains one of the best dopants which can significantly improve the high field performance, while graphene is emerging as a new dopant for MgB2, which can improve the zero field critical current density (Jc). The superconducting properties characterized by Jc, the intergrain connectivity, and the critical fields were significantly improved by the use of both SiC and graphene as dopants

Understanding activity trends in electrochemical water oxidation to form hydrogen peroxide

Electrochemical production of hydrogen peroxide (H2O2) from water oxidation could provide a very attractive route to locally produce a chemically valuable product from an abundant resource. Herein using density functional theory calculations, we predict trends in activity for water oxidation towards H2O2 evolution on four different metal oxides, i.e., WO3, SnO2, TiO2 and BiVO4. The density functional theory predicted trend for H2O2 evolution is further confirmed by our experimental measurements. Moreover, we identify that BiVO4 has the best H2O2 generation amount of those oxides and can achieve a Faraday efficiency of about 98% for H2O2 production

Structural characterization of the interaction of α-synuclein nascent chains with the ribosomal surface and trigger factor

The ribosome is increasingly becoming recognized as a key hub for integrating quality control processes associated with protein biosynthesis and cotranslational folding (CTF). The molecular mechanisms by which these processes take place, however, remain largely unknown, in particular in the case of intrinsically disordered proteins (IDPs). To address this question, we studied at a residue-specific level the structure and dynamics of ribosome-nascent chain complexes (RNCs) of α-synuclein (αSyn), an IDP associated with Parkinson’s disease (PD). Using solution-state nuclear magnetic resonance (NMR) spectroscopy and coarse-grained molecular dynamics (MD) simulations, we find that, although the nascent chain (NC) has a highly disordered conformation, its N-terminal region shows resonance broadening consistent with interactions involving specific regions of the ribosome surface. We also investigated the effects of the ribosome-associated molecular chaperone trigger factor (TF) on αSyn structure and dynamics using resonance broadening to define a footprint of the TF–RNC interactions. We have used these data to construct structural models that suggest specific ways by which emerging NCs can interact with the biosynthesis and quality control machinery

Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases

Background: To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy. Methods: The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue -specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence. Findings: PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects. Interpretation: This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoim-mune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects.De två första författarna delar förstaförfattarskapet.De tre sista författarna delar sistaförfattarskapet.</p