A simple approach for describing metal-supported cyclohexaphenylene dehydrogenation: Hybrid classical/DFT metadynamics simulations

The mechanisms for the dehydrogenation reaction of cyclohexaphenylene at a copper surface are investigated with the help of density functional theory and metadynamics. Our results represent a showcase for an approach that describes the surface using many-body classical potentials and molecule-surface interactions with a van der Waals model. Starting from the experimental observation that dispersion-assisted mechanisms are at least as important as catalytic processes for the description of the reaction, we fully describe the former, we identify intermediate states and estimate the free energy barriers that characterize the reactio

Painful oral aphthous-like lesions in patient with kidney cancer after target therapy and bisphosphonate administration: a case report of adverse drug reaction.

Aim. Tyrosine kinase inhibitors (TKIs) targeting tu- mor angiogenesis and mammalian target of rapamycin inhibitors (mTOR) are indicated for the management of several cancer types, as for renal cell carcinoma (RCC). Oral ulcerations are reported as common adverse drug reactions of mTOR inhibitors and are currently classified as mTOR inhibitor associated stomatitis (mIAS). Interestingly, these lesions appear as aphthous-like stoma- titis rather than the mucositis seen with chemotherapy agent. Case report. A 49 years old male patient underwent to the left radical nephrectomy in May 2014 for clear RCC. From July to October 2014 he was treated with Pazopanib, a tyrosine kinase inhibitor. In December 2014 the patient started the treatment with Zoledronic acid and Everolimus, an amino-bisphosphonates and an mTOR inhibitor, respectively. Everolimus administration was suspended on the 1st of January 2015 and resumed on the 4th of February. In February 2015, the patient referred to our department for acute pain of mouth floor and tongue; the onset of these symptoms was subse- quent to mTOR therapy. This pain compromised his oral functions (chewing, swallowing, phonetic) and quality of life. Intraoral examination showed aphthous-like lesions on both borders of the tongue and on the right side of the mouth floor. Local antiseptic (0.2% chlorhexidine rinse, twice daily for 1 week), 0.050 g clobetasol propionate cream (twice a day for 4 week, and one times a day for the following 4 weeks) and a wound-healing promoter (Mucosamin Spray®, twice a day for 2 weeks) were administered. Since the oncologist decided to not discontinue the target therapy, the patient continued local therapy until the end of the treatment with everolimus. After two weeks from the first visit, a complete healing of the oral mucosa was observed and the patient complained no pain. Conclusion. This case report confirms the recent view that target therapy with everolimus may induce the onset of aphthous-like stomatitis as adverse drug reaction. Therefore, diagnostic algorithms for stomatitis should include a careful drug history, emphasizing the focus also on oral adverse effects the new target cancer therapies

Biochemical and structural characterization of a novel arginine kinase from the spider <i>Polybetes pythagoricus</i>

Energy buffering systems are key for homeostasis during variations in energy supply. Spiders are the most important predators for insects and therefore key in terrestrial ecosystems. From biomedical interest, spiders are important for their venoms and as a source of potent allergens, such as arginine kinase (AK, EC 2.7.3.3). AK is an enzyme crucial for energy metabolism, keeping the pool of phosphagens in invertebrates, and also an allergen for humans. In this work, we studied AK from the Argentininan spider Polybetes pythagoricus (PpAK), from its complementary DNA to the crystal structure. The PpAK cDNA from muscle was cloned, and it is comprised of 1068 nucleotides that encode a 384-amino acids protein, similar to other invertebrate AKs. The apparent Michaelis-Menten kinetic constant (Km) was 1.7 mM with a kcat of 75 s-1. Two crystal structures are presented, the apoPvAK and PpAK bound to arginine, both in the open conformation with the active site lid (residues 310-320) completely disordered. The guanidino group binding site in the apo structure appears to be organized to accept the arginine substrate. Finally, these results contribute to knowledge of mechanistic details of the function of arginine kinase.Instituto de Investigaciones Bioquímicas de La Plat

MicroRNA-21 Expression as a Prognostic Biomarker in Oral Cancer: Systematic Review and Meta-Analysis

Oral carcinoma represents one of the main carcinomas of the head and neck region, with a 5-year survival rate of less than 50%. Smoking and tobacco use are recognized risk factors. Prognostic survival biomarkers can be a valid tool for assessing a patient’s life expectancy and directing therapy towards specific targets. Among the biomarkers, the alteration of miR-21 expression in tumor tissues is increasingly reported as a valid prognostic biomarker of survival for oral cancer. The purpose of this meta-analysis was, therefore, to investigate and summarize the results in the literature concerning the potential prognostic expression of tissue miR-21 in patients with OSCC. Methods: The systematic review was conducted following the PRISMA guidelines using electronic databases, such as PubMed, Scopus, and the Cochrane Central Register of Controlled Trials, with the use of combinations of keywords, such as miR-21 AND oral cancer, microRNA AND oral cancer, and miR-21. The meta-analysis was performed using the RevMan 5.41 software. Results: At the end of the article-selection process, 10 studies were included in the meta-analysis, and the result for the main outcome was a pooled HR per overall survival (OS) of 1.29 (1.16–1.44) between high and low expression of miR-21. Conclusions: The data in the literature and the results emerging from the systematic review indicate that miR-21 can provide a prognostic indication in oral cancer

Biochemical and structural characterization of a novel arginine kinase from the spider <i>Polybetes pythagoricus</i>

Energy buffering systems are key for homeostasis during variations in energy supply. Spiders are the most important predators for insects and therefore key in terrestrial ecosystems. From biomedical interest, spiders are important for their venoms and as a source of potent allergens, such as arginine kinase (AK, EC 2.7.3.3). AK is an enzyme crucial for energy metabolism, keeping the pool of phosphagens in invertebrates, and also an allergen for humans. In this work, we studied AK from the Argentininan spider Polybetes pythagoricus (PpAK), from its complementary DNA to the crystal structure. The PpAK cDNA from muscle was cloned, and it is comprised of 1068 nucleotides that encode a 384-amino acids protein, similar to other invertebrate AKs. The apparent Michaelis-Menten kinetic constant (Km) was 1.7 mM with a kcat of 75 s-1. Two crystal structures are presented, the apoPvAK and PpAK bound to arginine, both in the open conformation with the active site lid (residues 310-320) completely disordered. The guanidino group binding site in the apo structure appears to be organized to accept the arginine substrate. Finally, these results contribute to knowledge of mechanistic details of the function of arginine kinase.Instituto de Investigaciones Bioquímicas de La Plat

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy

INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. OBJECTIVES This study aimed to assess the genetic background of HCM in a cohort of Polish patients. PATIENTS AND METHODS Twenty–nine Polish patients were analyzed by a next–generation sequencing panel including 404 cardiovascular genes. RESULTS Pathogenic variants were found in 41% of the patients, with ultra–rare MYBPC3 c.2541C&gt;G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C&gt;T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3

The Prognostic Role of miR-31 in Head and Neck Squamous Cell Carcinoma: Systematic Review and Meta-Analysis with Trial Sequential Analysis

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with high recurrence, metastasis, and poor treatment outcome. Prognostic survival biomarkers can be a valid tool for assessing a patient’s life expectancy and directing therapy toward specific targets. Recent studies have reported microRNA (miR) might play a critical role in regulating different types of cancer. The main miR used as a diagnostic and prognostic biomarker and reported in the scientific literature for HNSCC is miR-21. Other miRs have been investigated to a lesser extent (miR-99a, miR-99b, miR-100, miR-143, miR-155, miR-7, miR-424, miR-183), but among these, the one that has attracted major interest is the miR-31. Methods: The systematic review was conducted following the PRISMA guidelines using electronic databases, such as PubMed, Scopus, and the Cochrane Central Register of Controlled Trials, with the use of combinations of keywords, such as miR-31 AND HNSCC, microRNA AND HNSCC, and miR-31. The meta-analysis was performed using the RevMan 5.41 software (Cochrane Collaboration, Copenhagen, Denmark). Results: This search produced 721 records, which, after the elimination of duplicates and the application of the inclusion and exclusion criteria, led to 4 articles. The meta-analysis was conducted by applying fixed-effects models, given the low rate of heterogeneity (I2 = 40%). The results of the meta-analysis report an aggregate hazard ratio (HR) for the overall survival (OS), between the highest and lowest miR-31 expression, of 1.59, with the relative intervals of confidence (1.22 2.07). Heterogeneity was evaluated through Chi2 = 5.04 df = 3 (p = 0.17) and the Higgins index I2 = 40; testing for the overall effect was Z = 3.44 (p = 0.00006). The forest plot shows us a worsening HR value of OS, in relation to the elevated expression of miR-31. Conclusions: In conclusion, the data resulting from the current meta-analysis suggest that miR-31 is associated with the prognosis of patients with HNSCC and that elevated miR-31 expression could predict a poor prognosis in patients with this type of neoplasm

Numerical Stability and Accuracy of Temporally Coupled Multi-Physics Modules in Wind Turbine CAE Tools

In this paper we examine the stability and accuracy of numerical algorithms for coupling time-dependent multi-physics modules relevant to computer-aided engineering (CAE) of wind turbines. This work is motivated by an in-progress major revision of FAST, the National Renewable Energy Laboratory's (NREL's) premier aero-elastic CAE simulation tool. We employ two simple examples as test systems, while algorithm descriptions are kept general. Coupled-system governing equations are framed in monolithic and partitioned representations as differential-algebraic equations. Explicit and implicit loose partition coupling is examined. In explicit coupling, partitions are advanced in time from known information. In implicit coupling, there is dependence on other-partition data at the next time step; coupling is accomplished through a predictor-corrector (PC) approach. Numerical time integration of coupled ordinary-differential equations (ODEs) is accomplished with one of three, fourth-order fixed-time-increment methods: Runge-Kutta (RK), Adams-Bashforth (AB), and Adams-Bashforth-Moulton (ABM). Through numerical experiments it is shown that explicit coupling can be dramatically less stable and less accurate than simulations performed with the monolithic system. However, PC implicit coupling restored stability and fourth-order accuracy for ABM; only second-order accuracy was achieved with RK integration. For systems without constraints, explicit time integration with AB and explicit loose coupling exhibited desired accuracy and stability