Real World Evidence asthma and COPD inhaled treatment therapy in Spain.

Background: This study aimed to describe the use of pressured metered dose inhalers (pMDI) and dry powder inhalers (DPI) in Spanish patients in terms of socio-demographic, clinical, and functional characteristics in patients with asthma or COPD on maintenance treatment with inhaled therapy. Methods: A retrospective, descriptive, national, multicentre, and observational study using a database with 1.8 million patients from hospitals and primary care centers as a secondary information source. Results: The sample included 24,102 subjects with asthma on maintenance therapy (26.0% with pMDI, 54.9% with DPI, and 19.0% with a combination of DPI + pMDI inhalers) and 12,858 subjects with COPD on maintenance therapy (26.1% with pMDI, 38.7% with DPI and 35.2% with a combination of pMDI + DPI inhalers, mostly extemporary triple therapy). In proportion, subjects ≥ 75 years old use more pMDI than DPI, while younger subjects (40-64 years old) use more DPI. An inhalation chamber was prescribed in 51.0% of asthma subjects and 47.2% of COPD subjects treated with pMDI. The use of an inhalation chamber increases with the degree of airflow limitation by disease and age. In subjects with comorbidities, pMDI inhaler use increased in those ≥75 years old for asthma and COPD subjects. Switching from pMDI to DPI and vice versa was relatively common: 25.5% of asthma subjects and 21.9% of COPD subjects treated with pMDI had switched from DPI in the previous year. On the contrary, 14.1% and 11.7% of asthma and COPD patients treated with DPI had switched from pMDI the last year. Conclusions: The use of pMDI or DPI can vary according to age, both in asthma and COPD. Switching from pMDI to DPI and vice versa is relatively common. Despite the availability of dual and triple therapy inhalers on the market, a considerable number of subjects were treated with multiple devices.

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy.

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

Anomer-Specific Recognition and Dynamics in a Fucose-Binding Lectin.

Sugar binding by a cell surface ∼29 kDa lectin (RSL) from the bacterium Ralstonia solanacearum was characterized by NMR spectroscopy. The complexes formed with four monosaccharides and four fucosides were studied. Complete resonance assignments and backbone dynamics were determined for RSL in the sugar-free form and when bound to l-fucose or d-mannose. RSL was found to interact with both the α- and the ß-anomer of l-fucose and the "fucose like" sugars d-arabinose and l-galactose. Peak splitting was observed for some resonances of the binding site residues. The assignment of the split signals to the α- or ß-anomer was confirmed by comparison with the spectra of RSL bound to methyl-α-l-fucoside or methyl-ß-l-fucoside. The backbone dynamics of RSL were sensitive to the presence of ligand, with the protein adopting a more compact structure upon binding to l-fucose. Taking advantage of tryptophan residues in the binding sites, we show that the indole resonance is an excellent reporter on ligand binding. Each sugar resulted in a distinct signature of chemical shift perturbations, suggesting that tryptophan signals are a sufficient probe of sugar binding.

Some cyclization reactions of 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one: preparation and computational analysis of non symmetrical zwitterionic biscyanines.

Regioselective nucleophilic addition of bisnucleophiles 1,2-benzenediamine, 2-amino-benzenethiol, and N-phenyl-1,2-benzenediamine to 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (1) at C6 followed by intramolecular cyclocondensation at the C7 carbonyl afforded highly coloured tetracenes 1,3-diphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-4-ium 4-methylbenzenesulfonate (12), 1,3-diphenyl-1H-[1,2,4]triazino[6,5-b]phenothiazine (14) and 1,3,11-triphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-11-ium 4-methylbenzenesulfonate (15), respectively. Neutralization of the latter with alkali gave the free base 1,3,11-triphenyl-1H-[1,2,4]triazino[5,6-b]phenazin-11-ium-6-ide (16). Furthermore, the benzotriazinone 1 reacts with dimethyl malonate to give 6-(methoxycarbonyl)-7-oxo-1,3-diphenyl-7H-benzofuro[5,6-e][1,2,4]triazin-1-ium-4-ide (17) in 74% yield, while with S(4)N(4) [5,6-c]-thiadiazolo-7-oxo-1,3-diphenyl-1,2,4-benzotriazine (22) was formed in 15% yield. The free bases 16 and 17 display negative solvatochromism, which supports charge separated ground states similar to those of zwitterionic biscyanines, and DFT calculations at the UB3LYP/6-31G(d) level afford ΔE(ST) values of -13.6 and -18.7 kcal mol(-1), respectively that strongly favour the singlet ground state. All ring systems described are new and fully characterized.