95 research outputs found
Intravitreal injection of proinsulin-loaded microspheres delays photoreceptor cell death and vision loss in the rd10 mouse model of retinitis pigmentosa
9 p.-6 fig.PURPOSE. The induction of proinsulin expression by transgenesis or intramuscular gene therapy has been shown previously to retard retinal degeneration in mouse and rat models of retinitis pigmentosa (RP), a group of inherited conditions that result in visual impairment. We investigated whether intraocular treatment with biodegradable poly (lactic-co-glycolic) acid microspheres (PLGA-MS) loaded with proinsulin has cellular and functional neuroprotective effects in the retinaMETHODS. Experiments were performed using the Pde6brd10 mouse model of RP.
Methionylated human recombinant proinsulin (hPI) was formulated in PLGA-MS, which
were administered by intravitreal injection on postnatal days (P) 14 to 15. Retinal
neuroprotection was assessed at P25 by electroretinography, and by evaluating outer nuclear layer (ONL) cellular preservation. The attenuation of photoreceptor cell death by hPI was determined by TUNEL assay in cultured P22 retinas, as well as Akt phosphorylation by immunoblottingRESULTS. We successfully formulated hPI PLGA-MS to deliver the active molecule for several weeks in vitro. The amplitude of b-cone and mixed b-waves in electroretinographic recording was significantly higher in eyes injected with hPI-PLGA-MS compared to control eyes.Treatment with hPI-PLGA-MS attenuated photoreceptor cell loss, as revealed by comparing ONL thickness and the number of cell rows in this layer in treated versus untreated retinas. Finally, hPI prevented photoreceptor cell death and increased AktThr308 phosphorylation in organotypic cultured retinas.CONCLUSIONS. Retinal degeneration in the rd10 mouse was slowed by a single intravitreal injection of hPI-PLGA-MS. Human recombinant proinsulin elicited a rapid and effective neuroprotective effect when administered in biodegradable microspheres, which may constitute a future potentially feasible delivery method for proinsulin-based treatment of RP.Supported by Grants from the Spanish Ministerio de Ciencia e
Innovacion (MICINN) and Spanish Ministerio de EconomĂa y
Competitividad (MINECO), SAF2010-21879 (EJdlR and PdlV),
SAF2013-41059-R (FdP and EJdlR), and technical personnel
support from CIBERDEM, ISCIII, Madrid, SpainPeer reviewe
OGG1 inhibition triggers synthetic lethality and enhances the effect of PARP inhibitor olaparib in BRCA1-deficient TNBC cells
Background: PARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types.
Methods: We hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478.
Results: Knocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction.
Discussion: These results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer
Photoactive assemblies of organic compounds and biomolecules: drug-protein supramolecular systems
[EN] The properties of singlet and triplet excited states are strongly medium-dependent.
Hence, these species constitute valuable tools as reporters to probe compartmentalised
microenvironments, including drug@protein supramolecular systems. In the present
review, the attention is focused on the photophysical properties of the probe drugs
(rather than those of the protein chromophores) using transport proteins (serum
albumins and 1-acid glycoproteins) as hosts. Specifically, fluorescence measurements
allow investigating the structural and dynamic properties of biomolecules or their
complexes. Thus, the emission quantum yields and the decay kinetics of the drug singlet
excited states provide key information to determine important parameters such as the
stoichiometry of the complex, the binding constant, the relative degrees of occupancy of
the different compartments, etc. Application of the FRET concept allows determining
donor-acceptor interchromophoric distances. In addition, anisotropy measurements can
be related to the orientation of the drug within the binding sites, where the degrees of
freedom for conformational relaxation are restricted. Transient absorption spectroscopy
is also a potentially powerful tool to investigate the binding of drugs to proteins, where
formation of encapsulated triplet excited states is favoured over other possible processes
leading to ionic species (i. e. radical ions), and their photophysical properties are
markedly sensitive to the microenvironment experienced within the protein binding
sites. Even under aerobic conditions, the triplet lifetimes of protein-complexed drugs are
remarkably long, which provides a broad dynamic range for identification of distinct
triplet populations or for chiral discrimination. Specific applications of the laser flash
photolysis technique include the determination of drug distribution among the bulk
solution and the protein binding sites, competition of two types of proteins to bind a
3
drug, occurrence of drug-drug interactions within protein binding sites, enzymatic-like
activity of the protein or determination of enantiomeric compositions.
The use of proteins as supramolecular hosts modifies the photoreactivity of
encapsulated substrates by providing protection against oxygen or other external
reagents, by imposing conformational restrictions in the binding pockets, or by
influencing the stereochemical outcome. In this review, a selected group of examples is
presented including decarboxylation, dehalogenation, nucleophilic addition,
dimerisation, oxidation, Norrish type II reaction, photo-Fries rearrangement and 6
electrocyclisationFinancial support from the Spanish Government (CTQ2010-14882, JCI-2011-09926, RyC-2007-00476), from the EU (PCIG12-GA-2012-334257), from the Universitat PolitĂšnica de ValĂšncia (SP20120757) and from the ConsellerĂa de EducaciĂł, Cultura i Esport (PROMETEOII/2013/005, GV/2013/051) is gratefully acknowledged.VayĂĄ PĂ©rez, I.; Lhiaubet-Vallet, VL.; JimĂ©nez Molero, MC.; Miranda Alonso, MĂ. (2014). Photoactive assemblies of organic compounds and biomolecules: drug-protein supramolecular systems. Chemical Society Reviews. 43:4102-4122. https://doi.org/10.1039/C3CS60413FS410241224
Rate and duration of hospitalisation for acute pulmonary embolism in the real-world clinical practice of different countries : Analysis from the RIETE registry
publishersversionPeer reviewe
Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years
publishersversionPeer reviewe
Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism
Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio
The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry
Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes
La RĂĄbida : Revista Colombina Iberoamericana. NĂșmero 70 - Año VII
16 pĂĄginasRuiz Marchena, A.: Patrimonio Espiritual.- Juan del Camino: DespuĂ©s del EmprĂ©stito.- Santa Verdad. Preguntas.- Diccionario de voces geogrĂĄficas españolas.- Homenaje a Nogales.- Marchena Colombo, JosĂ©: Acercamiento espiritual entre Cuba y España.- La "entente" con Portugal. Labor patriĂłtica de nuestro ministro en Lisboa (que es el onubense Antonio LĂłpez Muñoz).- Garrido PerellĂł, M.: BibliografĂa. Movimiento hispano-americano, Madrid 1917.- Causerie por les refuges belges de Pau
La RĂĄbida : Revista Colombina Iberoamericana. NĂșmero 73 - Año VII
16 pĂĄginas.Marchena Colombo, JosĂ©: 3 de Agosto.- Programa de las Fiestas.- Ruiz Marchena: Ecos americanos.- Iniciativa plausible. En homenaje al mĂ©rito y en interĂ©s propio. Rafael Calzada sobre la obra de JosĂ© LeĂłn SuĂĄrez.- Promesa Cumplida (el MarquĂ©s de Aracena -SĂĄnchez Dalp- compra muebles para la Colombina).- El "Centro de Cultura" en ParĂs (homenaje al pintor JosĂ© Villegas) e incluye el discurso de Luis Palomo, presidente del Centro.- Marchena Colombo: Donativo esplĂ©ndido y tributo justo (relaciĂłn de muebles donados por SĂĄnchez-Dalp y tributo por su generosidad).- Las Escuelas de la Esperanza.- Causeries por les refugies belges de Pau.- Cosas del puebluco (el Puerto inaugura la Avda. de La RĂĄbida y no invita a la Colombina).- Carta de JosĂ© de Diego a JosĂ© Marchena Colombo y comentario que Ă©ste realiza.- Movimiento americanista.- Noticias Colombinas.
La RĂĄbida : Revista Colombina Iberoamericana. NĂșmero 68 - Año VII
16 pĂĄginasRuiz Marchena A.: Pensemos en el porvenir. A nuestros productores e industriales.- JosĂ© MarĂa GonzĂĄlez "Columbia": Por la Independencia de Puerto Rico. JosĂ© de Diego, orientado y fortalecido.- El Comercio Hispano-Americano (tomado de "El Diario Español").- Lozano, JosĂ© MarĂa: Una administraciĂłn ejemplar (la del Ayuntamiento de Albacete).- A Sevilla (Manuel Siurot designado para representar a Huelva en los Juegos Florales de Sevilla).- Los exploradores españoles. Un libro de vindicaciĂłn, por un norteamericano (Ch. Lummis). La ediciĂłn ha sido posible gracias a Juan C. CebriĂĄn.- Marchena Colombo, JosĂ©: JoaquĂn Dicenta (necrolĂłgica).- Desde Puerto Rico (por el corresponsal).- Tenreiro, R.M.: Protectorado del niño delincuente.- HernĂĄndez PinzĂłn, JosĂ© L.: Labor americanista.- Javier FernĂĄndez Pesquero (marcha a Punta Arenas para dirigir una nueva publicaciĂłn).
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