Synthesis and H+, Cu2+, and Zn2+ Coordination Behavior of a Bis(fluorophoric) Bibrachial Lariat Aza-Crown

The synthesis, protonation behavior, and Cu2+ and Zn2+ coordination chemistry of the novel bibrachial aza lariat ether (naphthalen-1-ylmethyl)[2-(20-{2-[(naphthalen-1-ylmethyl)amino]ethyl}-3,6,9,17,20,23,29,30-octaazatricyclo[23.3.1.1*11,15*]triaconta-1(29),11(30),12,14,25,27-hexaen-6-yl)ethyl]amine (L) are discussed. The macrocycle, which has two aminoethyl naphthyl moieties symmetrically appended to a 2:2 azapyridinophane structure, displays, in the pH range 2−11, six protonation steps that correspond to the protonation of the secondary amino groups. Steady-state fluorescence measurements show emissions due to the monomer and to the excimer formed between the two naphthalene fragments of the macrocycle. The time-resolved fluorescence data, obtained by the time-correlated single photon counting technique, show that a significant percentage of excimer is preformed as ground-state dimers. The ligand L forms with the metal ions Cu2+ and Zn2+ mono- and dinuclear complexes in aqueous solution. The influence of metal coordination in the fluorescence emission of L is analyzed. The acid−base, coordination capabilities, and emissive behavior of L are compared with those presented by its synthetic precursor L1, which has a tripodal tris(2-aminoethyl)amine structure functionalized at one of its terminal amino groups with a naphthyl moiet

Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results

Background: Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The “Tratamiento de Tumores Digestivos” group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years. Methods: Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks). Results: In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%). Conclusions: the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term

DOR/Tp53inp2 and Tp53inp1 Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription

Human DOR/TP53INP2 displays a unique bifunctional role as a modulator of autophagy and gene transcription. However, the domains or regions of DOR that participate in those functions have not been identified. Here we have performed structure/function analyses of DOR guided by identification of conserved regions in the DOR gene family by phylogenetic reconstructions. We show that DOR is present in metazoan species. Invertebrates harbor only one gene, DOR/Tp53inp2, and in the common ancestor of vertebrates Tp53inp1 may have arisen by gene duplication. In keeping with these data, we show that human TP53INP1 regulates autophagy and that different DOR/TP53INP2 and TP53INP1 proteins display transcriptional activity. The use of molecular evolutionary information has been instrumental to determine the regions that participate in DOR functions. DOR and TP53INP1 proteins share two highly conserved regions (region 1, aa residues 28–42; region 2, 66–112 in human DOR). Mutation of conserved hydrophobic residues in region 1 of DOR (that are part of a nuclear export signal, NES) reduces transcriptional activity, and blocks nuclear exit and autophagic activity under autophagy-activated conditions. We also identify a functional and conserved LC3-interacting motif (LIR) in region 1 of DOR and TP53INP1 proteins. Mutation of conserved acidic residues in region 2 of DOR reduces transcriptional activity, impairs nuclear exit in response to autophagy activation, and disrupts autophagy. Taken together, our data reveal DOR and TP53INP1 as dual regulators of transcription and autophagy, and identify two conserved regions in the DOR family that concentrate multiple functions crucial for autophagy and transcription

Specific and highly efficient condensation of GC and IC DNA by polyaza pyridinophane derivatives

Two bis-polyaza pyridinophane derivatives and their monomeric reference compounds revealed strong interactions with ds-DNA and RNA. The bis-derivatives show a specific condensation of GC- and IC-DNA, which is almost two orders of magnitude more efficient than the well-known condensation agent spermine. The type of condensed DNA was identified as psi-DNA, characterized by the exceptionally strong CD signals. At variance to the almost silent AT(U) polynucleotides, these strong CD signals allow the determination of GC-condensates at nanomolar nucleobase concentrations. Detailed thermodynamic characterisation by ITC reveals significant differences between the DNA binding of the bis- derivative compounds (enthalpy driven) and that of spermine and of their monomeric counterparts (entropy driven). Atomic force microscopy confirmed GC-DNA compaction by the bis-derivatives and the formation of toroid- and rod-like structures responsible for the psi-type pattern in the CD spectra

Role of age and comorbidities in mortality of patients with infective endocarditis.

The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups: A total of 3120 patients with IE (1327  There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in th