Munckdamm4565

PURPOSE Most spinal metastases are detected late, and thus, the impact of treatment on the health-related quality of life (HRQOL) is an important consideration. This study investigated the HRQOL following surgery for spinal metastases. METHODS A prospective study of patients operated for symptomatic spinal metastases, at a single tertiary referral spine centre (2011-2013). Data were collected pre-operatively and up to 2 years following surgery (if alive). The HRQOL assessment was performed using recognised systems including the Frankel score (neurological status), EQ-5D, and the Oswestry Disability Index. RESULTS A total of 199 patients were studied (median age 65 years, 43% (86) F; 57% (113) M). The Frankel score improved significantly after surgery in 69 patients (35%), worsened in 17 (8%), with 20/39 patients regaining the ability to walk (51%). All the HRQOL scores improved significantly following surgery. The complication rate was 27% and median survival 270 days, and 44 patients (22%) survived at 2 years. CONCLUSIONS This large prospective study showed that surgical treatment for spinal metastases significantly improved the HRQOL.The high-resolution X-ray crystal structures of the adducts formed between the "half sandwich"-type Ru(II) coordination compound [RuII(1,4,7-trithiacyclononane)(ethane-1,2-diamine)Cl]+ and two proteins, namely hen egg-white lysozyme and proteinase K, are presented. The structures unveil that upon reaction with both enzymes the Ru(II) compound is coordinated by solvent-exposed aspartate residues after releasing the chloride ligand (Asp101 in lysozyme, Asp200 and Asp260 in proteinase K), while retaining the two chelating ligands. The adduct with Asp101 residue at the catalytic cleft of lysozyme is accompanied by residue-specific conformational changes to accommodate the Ru(II) fragment, whereas the complexes bound at the two calcium-binding sites of proteinase K revealed minimal structural perturbation of the enzyme. To the best of our knowledge, proteinase K is used here for the first time as a model system of protein metalation and these are the first X-ray crystal structures of protein adducts of a Ru(II) coordination compound that maintains its coordination sphere almost intact upon binding. Selleck Zidesamtinib Our data demonstrate the role of ligands in stabilizing the protein adducts via hydrophobic/aromatic or hydrogen-bonding interactions, as well as their underlying role in the selection of specific sites on the electrostatic potential surface of the enzymes.We have made a systematic combined quantum mechanical and molecular mechanical (QM/MM) investigation of possible structures of the N2 bound state of nitrogenase. We assume that N2 is immediately protonated to a N2H2 state, thereby avoiding the problem of determining the position of the protons in the cluster. We have systematically studied both end-on and side-on structures, as well as both HNNH and NNH2 states. Our results indicate that the binding of N2H2 is determined more by interactions and steric clashes with the surrounding protein than by the intrinsic preferences of the ligand and the cluster. The best binding mode with both the TPSS and B3LYP density-functional theory methods has trans-HNNH terminally bound to Fe2. It is stabilised by stacking of the substrate with His-195 and Ser-278. However, several other structures come rather close in energy (within 3-35 kJ/mol) at least in some calculations The corresponding cis-HNNH structure terminally bound to Fe2 is second best with B3LYP. A structure with HNNH2 terminally bound to Fe6 is second most stable with TPSS (where the third proton is transferred to the substrate from the homocitrate ligand). Structures with trans-HNNH, bound to Fe4 or Fe6, or cis-HNNH bound to Fe6 are also rather stable. Finally, with the TPSS functional, a structure with cis-HNNH side-on binding to the Fe3-Fe4-Fe5-Fe7 face of the cluster is also rather low in energy, but all side-on structures are strongly disfavoured by the B3LYP method.PURPOSE Progress in radiation therapy of head and neck squamous cell carcinomas (HNSCCs) is logically linked to the development of molecular predictors that would help to enhance individually tailored treatment. MicroRNA (miRNA) expression profiles in tumors have repeatedly been tested to optimize the molecular diagnostics of HNSCC. In addition to tumor tissues, miRNAs are stably present in body fluids, including saliva, and can thus be collected non-invasively. The aim of our current study was to evaluate whether salivary miRNAs have potential as response predictors in HNSCC patients treated with intensity modulated radiation therapy (IMRT). METHODS In total 48 HNSCC patients treated by definitive IMRT were enrolled in our prospective study. To identify predictive salivary miRNAs, we used small RNA sequencing in 14 saliva samples of HNSCC patients and qRT-PCR validation of selected miRNA candidates in an independent set of 34 patients. RESULTS We found that salivary miR-15a-5p and miR-15b-5p exhibited differential levels between patients with and without complete remission (p = 0.025 and p = 0.028, respectively). Subsequent Kaplan-Meier analysis confirmed that patients with higher levels of miR-15a-5p reached a significantly longer locoregional progression-free survival (LPFS) than those with low levels (p = 0.024). Finally, multivariate Cox regression analysis revealed that miR-15a-5p may serve as an independent predictive biomarker of LPFS in HNSCC patients treated with IMRT (HR 0.104; 95% CI 0.004-0.911; p = 0.04). CONCLUSIONS We conclude that salivary miR-15a-5p may represent a potential biomarker for individualized treatment decision-making in HNSCC patients.Background Concurrent opioid and benzodiazepine use ("double-threat") and opioid, benzodiazepine, and muscle relaxant use ("triple-threat") are linked to increased adverse events compared to opioid use alone. Objectives To assess prevalence of double-threat and triple-threat in the US and to measure association between double- and triple-threat and emergency department visits. Setting Nationally representative, 2-year health database of the United States. Method A retrospective cohort study was conducted using the national medical expenditure panel survey. Two-year prevalence of combination use was measured. Association between 2013-2014 double- and triple-threat exposure and emergency department visit compared to non-users, opioid-users, and all other exposure combinations assessed using logistic regression. Main outcome measures Survey-weighted prevalence of triple-threat and double-threat in 2013 and 2014 was measured. The outcome variable of at least one emergency department visit in a study year was utilized for the logistic regression.