Heterobimetallic propargyl gold complexes with p-bound copper or silver with enhanced anticancer activity

Several propargyl functionalised substrates with different heteroatoms (N, O or S) have been used for the preparation of propargyl gold(i) phosphine complexes. The complexes were prepared in high yields either by reaction of the substrate with [Au(acac)PPh3] or by reaction of [AuCl(PPh3)] with potassium hydroxide and the substrate in methanol. Several of the complexes have been characterised by X-ray diffraction showing the presence of secondary bonds such as p-stacking and aurophilic interactions. The reaction of the propargyl gold(i) phosphine complexes with [Cu(NO3)(PPh3)2] or [Ag(OTf)(PPh3)2] afforded heterobimetallic complexes with p-coordination of {Cu(PPh3)2} or {Ag(PPh3)2} to the alkyne bond. When the substituent of the propargyl unit contained more strongly coordinating pyridine moieties, [(PyCH2)2NCH2CCAuPPh3], coordination of the heterometal to the pyridine units occurred, displacing the phosphine groups and giving rise to a dimeric structure. The antiproliferative activity of the complexes against cisplatin resistant lung cancer cell line A549 was determined by MTT assay. The mononuclear gold complexes showed excellent activities with IC50 values < 14 µM. Coordination of copper of silver to the alkynyl fragment resulted in a significant increase in activity suggesting a synergistic effect between the two metal centres

Synthesis and antiproliferative study of phosphorescent multimetallic Re(I)/Au(I) complexes containing fused imidazo[4, 5-f]-1, 10-phenanthroline core

Five heterobimetallic Re-I/Au-I and a tri-metallic Re-I/Au-I/Re-I species following the formulas fac-ReCl (CO)(3)(NNCAuR)](0/+) and (fac-ReCl (CO)(3)(NNC)])(2)Au](+), where R is an iodide (1), phenylacetylene (2), dodecanethiol (3), 2, 3, 4, 6-tetra-O-acetyl-1-thio-beta-D-glucopyranose (4) and JohnPhos (5) and NNC is the fused imidazo4, 5-f]-1, 10-phenanthroline heterotopic ligand, were synthesised and fully characterised by a variety of spectroscopic and analytical techniques. The resultant complexes are luminescent in the orange region, revealing classical metal-to-ligand charge transfer ((MLCT)-M-3) ((Re (d pi) -> (NNC)(pi*)) emission in aerated DMSO solution. The red shifted emission observed on going from 3 to 4 suggests that the electronic properties of the gold ancillary ligand are implicated in the emissive properties. Antiproliferative activity in tumour cell lines, lung (A549) and cervix (HeLa) cells revealed that only complex 4 containing a 2, 3, 4, 6-tetra-O-acetyl-1-thio-beta-D-glucopyranose as gold ancillary ligand possesses certain cytotoxicity in both cell lines

Evaluación de las técnicas de diagnóstico de la enfermedad de Marek

El diagnóstico de las enfermedades tumorales en avicultura es complejo y las consecuencias económicas deun diagnóstico incorrecto son muy graves. Esta revisión está dirigida a los profesionales en el campo avícolacon el fin de clarificar conceptos básicos para el diagnóstico diferencial de las enfermedades neoplásicas. Enparticular se ha prestado mayor atención a la enfermedad de Marek (MD) y al diagnóstico diferencial entreMD y los tumores inducidos por retrovirus. El trabajo incluye la descripción de los diferentes agentes causalesde enfermedades neoplásicas en avicultura; los diferentes métodos para el diagnóstico diferencial y para eldiagnóstico precoz de MD; así como recomendaciones sobre la toma de muestras y métodos de conservaciónadecuados para cada método diagnóstico

The next generation of fibroblast-based vaccine development

Chicken embryo fibroblasts (CEF) and diploid cells have a long history in vaccine production since their isolation in the 1960s at the Wistar Institute (WI-38 cells) as well as the Medical Research Council (MRC-5 cells). The cells quickly became adopted for a number of vaccines: varicella zoster (VZV), MMR, yellow fever, polio, hepatitis A, rotavirus, rabies, Marek\u27s disease, and dengue virus. Most of these vaccine processes were developed with classical media supplemented with Fetal Bovine Serum (FBS). The Hayflick limit of diploid cells restricted their adaptation to a serum-free process. While some of the vaccines such as polio and rabies have been transitioned to Vero cells, several vaccines continue to be manufactured with CEF and human diploid cells. Currently, FBS from Australia and New Zealand are utilized for the highest level of patient safety for human vaccines. However, this supply of serum is challenged by two factors: growth of existing vaccines to improve global access and the development of new gene therapies that require FBS. In order to reduce dependency on serum, we initiated a medium development program. Using metabolite analysis and DOE, we have developed a serum-reduced growth medium and a serum-free virus production medium for MRC-5 and other fibroblast cells. With a serum reduction of 90-100%, the growth medium can support direct recovery from thaw and adaptation-free expansion, resulting in performance that is comparable to classical medium with 10% serum. We confirmed virus production with VZV and vesicular stomatitis virus in MRC-5 cells as well as Marek’s disease virus in CEFs and demonstrate a higher specific productivity. By switching to a low serum process, vaccine manufacturers can reduce production and purification costs, and increase product consistency and safety

Differential attenuation of Marek's disease virus-induced tumours and late-Marek's disease virus-induced immunosuppression

Marek's disease virus (MDV) is a herpesvirus that induces lymphoma and a variety of non-neoplastic syndromes in chickens. Furthermore, very virulent plus (vv+) MDVs induce a form of immunosuppression (late-MDV-IS) that might involve both neoplastic and non-neoplastic mechanisms. The objective of this study was to evaluate whether the attenuation of MDV-induced tumours and late-MDV-IS occurs simultaneously or can be dissociated. The immunosuppressive ability of three viruses derived from vv+ MDV strain 686 (wild-type 686, the somewhat attenuated molecular clone 686-BAC, and the nononcogenic molecular clone lacking the two copies of the oncogene meq 686-BACΔMEQ) was evaluated. Late-MDV-IS was evaluated indirectly by assessing the negative effect of MDV strains on the protection conferred by infectious laryngotracheitis (ILT) vaccines. Our results showed that the ability to induce late-MDV-IS was attenuated before the ability to induce tumours. Strain 686 induced both tumours and late-MDV-IS, 686-BAC induced tumours but did not induce late-MDV-IS and 686-BACΔMEQ did not induce either tumours or late-MDV-IS. Further comparison of strains 686 and 686-BAC revealed that strain 686 reduced the humoral immune responses to ILTV (1132 vs 2167) more severely, showed higher levels of meq transcripts (2.1E+09 vs 4.98E+8) and higher expression of MDV microRNAs (mdv1-miR-M4-5p and mdv1-miR-M2-3p) in the spleen, and further reduced the percentage of CD45+-MHC-I+splenocytes (13 vs32 %) compared to molecular clone 686-BAC. This study suggests that the immunosuppressive ability of MDV might follow a continuous spectrum and only the most virulent MDVs can overcome a certain threshold level and induce clinical MDV-IS in the ILT model

Silver-based terpyridine complexes as antitumor agents

Silver complexes bearing substituted terpyridine or tetra-2-pyridinylpyrazine ligands have been prepared and structurally characterised. The study of the anticancer properties of silver complexes with this type of ligands is scarce, despite the possibilities of combining the properties of the metal and the ability of the ligands for DNA binding. Here, the antiproliferative activity, stability, CT-DNA binding and mechanism of cell death of these types of derivatives are studied. High cytotoxicity against different tumour cells was observed, and, more important, a great selectivity index has been detected between tumour cells and healthy Lymphocytes T for some of these compounds. The CT-DNA interaction study has shown that these derivatives are be able to interact with CT-DNA via moderate intercalation. Furthermore, cell death studies indicate that these derivatives promote the apoptosis via mitochondrial pathway

Deformidades congénitas del desarrollo facial: Labio fisurado y paladar hendido

Las fisuras labio palatinas son los defectos congénitos orofaciales más frecuentes en la población. Su prevalencia varía en función del sexo y la zona geográfica. Estas malformaciones derivan de alteraciones embriológicas en los procesos de fusión de los primordios faciales durante la cuarta y la doceava semanas de gestación. El desarrollo del labio y del paladar está regulado por una gran variedad de genes y moléculas, y es considerado uno de los procesos más complejos de la embriogénesis. Su etiología no presenta una base sólida, pero el patrón de herencia multifactorial es el más extendido actualmente. Este describe el desarrollo de las fisuras labio palatinas como el resultado de la combinación de una serie de factores ambientales y genéticos. El conocimiento de la base genética de esta patología es incompleto, sin embargo, gracias al avance de la genómica, se han identificado diversos genes implicados como IRF6, WNT, MSX1 y BMP, entre muchos otros. El desarrollo de una clasificación simple, capaz de ser aceptada universalmente, sigue siendo uno de los problemas derivados de su diversidad fenotípica. La clasificación de Kernahan y Stark, junto con la representación gráfica de la fisura en “Y”, es el método más extendido. El diagnóstico prenatal de estas hendiduras se realiza en el cribado ecográfico de malformaciones a las veinte semanas de gestación, si bien puede complementarse con el uso de la resonancia magnética fetal de secuencias ultrarrápidas. El cuadro clínico derivado del fracaso del cierre labial y palatino conlleva problemas de alimentación, mayor riesgo de infecciones del tracto respiratorio y oído medio, desarrollo de problemas fonoarticulares e hipoacusia, y alteraciones psicosociales. El tratamiento debe ser multidisciplinario e integral para intentar cubrir todas las necesidades del paciente. Las intervenciones quirúrgicas básicas a las que será sometido son la queilorrafia o cirugía de reparación del cierre labial y la palatoplastia o cirugía de reparación del cierre palatino. Estas serán combinadas con otros procedimientos como la alveoloplastia, la cirugía ortognática y el tratamiento de la insuficiencia velofaríngea y de las secuelas quirúrgicas.<br /

Evaluation of factors influencing the development of late Marek`s disease virus-induced immunosuppression: virus pathotype and host sex

Marek’s disease virus (MDV) is a herpesvirus that induces lymphoma and immunosuppression in chickens. MDV-induced immunosuppression (MDV-IS) is complex and can be divided into two phases: early-MDV-IS associated with cytolytic infection in the lymphoid organs in chickens lacking maternal antibodies against MDV (MAbs) and late-MDV-IS that appears later in the pathogenesis and occurs even in chickens bearing MAbs. We have recently developed a model to reproduce late-MDV-IS under laboratory conditions. This model evaluates late-MDV-IS indirectly by assessing the effect of MDV infection on the efficacy of infectious laryngotracheitis (ILT) vaccines against challenge with ILT virus. In the present study, we have used this model to investigate the role of two factors (MDV pathotype and host sex) on the development of late-MDV-IS. Five MDV strains representing three different pathotypes: virulent (vMDV; 617A, GA), very virulent (vvMDV; Md5), and very virulent plus (vv+MDV; 648A, 686), were evaluated. Only vv+ strains were able to induce late-MDV-IS. An immunosuppression rank (IS-rank) was established based on the ability of MDV to reduce the efficacy of chicken embryo origin vaccine (values go from 0 to 100, with 100 being the highest immunosuppressive ability). The IS-rank of the evaluated MDV strains ranged from 5.97 (GA) to 20.8 (617A) in the vMDV strains, 5.97 to 16.24 in the vvMDV strain Md5, and 39.08 to 68.2 in the vv+ strains 648A and 686. In this study both male and female chickens were equally susceptible to MDV-IS by vv+MDV 686. Our findings suggest that late-MDV-IS is a unique feature of vv+ strains

El mestre competent. Què hauria de posseir i què hauria de transmetre de les diverses àrees curriculars?

Aquest article respon a què és el que entenen els mestres de les diverses àrees curriculars com a mestre competent i quins mecanismes activen per a formar-lo.