Safety and pharmacokinetic study of the combination of trastuzumab emntansine and non-pegylated liposomal doxorubicin for the treatment of advanced HER2 positive breast cancer

Este estudio es un ensayo fase Ib, de un solo brazo, abierto (NCT02562378) en el que se incluyeron pacientes con cáncer de mama metastásico Her2 positivo que no habían recibido tratamiento previo con antraciclinas, y que además habían progresado a trastuzumab y taxanos. Tiene un diseño 3+3 de escalada de dosis seguido de una fase de expansión. Los pacientes recibieron un máximo de 6 ciclos de doxorrubicina liposomal no pegilada intravenosa a varios niveles de dosis (45, 50, and 60 mg/m2) en la parte de escalada de dosis y a 60 mg/m2 durante la fase de expansión, cada 3 semanas junto con T-DM1 a una dosis estándar. El objetivo principal fue establecer la máxima dosis tolerada y las toxicidades limitantes de dosis de esta combinación. Se incluyeron un total de 15 pacientes (12 pacientes durante la parte de escalada de dosis y tres pacientes más adicionales en la parte de expansión). Un paciente sufrió una toxicidad limitante de dosis a 60 mg/m2 (neutropenia grado 4 durante 13 días). La máxima dosis tolerada de doxorrubicina liposomal pegilada fue 60 mg/m2. No se reportó un deterioro clínicamente relevante de la función cardiaca. La tasa de respuesta global fue el 40.0% con una mediana de duración de la respuesta de 6.9 meses, la tasa de beneficio clínico fue del 66.7%, y la mediana de supervivencia libre de progresión fue de 7.2 meses (95%CI, 4.5–9.6). No se observó una influencia significativa de la doxorrubicina liposomal pegilada en la farmacocinética del T-DM1

Role of type I interferon in the bacillus Calmette-Guérin-induced expression of CXCL10 from human monocytes.

BACKGROUND: The proinflammatory chemokine CXCL10, in addition to its chemotactic properties, is also involved in the stimulation of natural killer and T-cell migration in Mycobacterium tuberculosis infection. In this study, our experiments were designed to determine the role of interferon (IFN)-alphabeta in the production of CXCL10 by human monocytes infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG). METHODS: The concentrations of CXCL10 in culture supernatants of monocytes infected with M. bovis BCG were determined by enzyme-linked immunosorbent assay. CXCL10 mRNA levels were determined by the reverse transcription-polymerase chain reaction method. RESULTS: We have shown the induction of CXCL10 following infection with M. bovis BCG in a dose-dependent and time-dependent manner. Importantly, the secretion of CXCL10 in response to M. bovis was increased by IFN-alpha. These results were further confirmed by the fact that the addition of an anti-IFN-alphabeta neutralizing antibody completely reversed the stimulatory effect, whereas an isotype-matched control antibody had no significant effect on CXCL10 secretion. It is important to note that no significant effect of type I IFN on CXCL8 production in M. bovis-infected monocytes was observed. This was consistent with the finding by the reverse transcription-polymerase chain reaction method that treatment with anti-IFN-alpha/beta antibodies potentially inhibited CXCL10 mRNA levels, whereas no significant effect was observed on CXCL8 mRNA. Moreover, in THP-1 monocytes and THP-1 macrophages, the addition of exogenous IFN-alpha stimulated CXCL10 secretion. CONCLUSIONS: Collectively, these results indicate that the type I IFN may play an important role to modulate the expression of CXCL10 in M. bovis BCG infection. Studies on M. bovis-induced chemokine secretion could provide important insight into the regulation of the immune response against tuberculosis

Advances in the design of a multi-strain homologous probiotic formula for cattle

Microorganisms colonizing different mucosas can exert diverse type of beneficial effects if they are included in probiotic formula. Then, the objective of this work was to complete the set of probiotic-related characteristics of different lactic acid bacteria strains previously isolated from different bovine mucosas to further include them in a probiotic product. The studies include some complementary assays related with their surface-adhesive characteristics (autoaggregation, biofilm formation, hydrophobicity, production of exopolisaccharides), production of inhibitory substances against pathogenic bacteria (hydrogen peroxide, bacteriocins). Also, the strains compatibility to go further in the design of a multi?strain probiotic formula to be used either to pregnant cows through the vaginal tract (for metritis prevention), later to the newborn calves (for diarrhea prevention), and to the mammary gland of the cows (for mastitis prevention). The formula will be integrated by strains from the three bovine tracts, being host? specific and able to promote the mucosal colonization and the beneficial effect in different ages and physiological states of bovines.Fil: Miranda, Maria Hortencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; ArgentinaFil: Nader, Maria Elena Fatima. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentin

Expression and Secretion of CXCL-8 and CXCL-10 From Mycobacterium Bovis BCG-Infected Human Epithelial Cells: Role of IL-4

CXC chemokine release can be modulated by Th2-derived cytokines. Interleukin(IL)-4 is one of the cytokines that are the hallmark of the Th-2 response, and plays an important role in human tuberculosis. In the current study, we investigated the effect of IL-4 on chemokine production by human epithelial cells infected with Mycobacterium bovis bacillus calmette-guérin (BCG). Gene expression of CXCL-8 and CXCL-10 was determined by the reverse transcription (RT)-polymerase chain reaction method. The levels of immunoreactive CXCL-8 and CXCL-10 were determined by enzyme-linked immunosorbent assay. We found that, although M. bovis BCG induced gene expression of CXCL-8 and CXCL-10 in M. bovis BCG-infected human epithelial cells, CXCL-8 mRNA level was significantly reduced by IL-4, whereas no significant effect of IL-4 was observed on CXCL10 mRNA level. In addition, IL-4 decreased CXCL-8 (in a graded and significant manner) but not CXCL-10 secretion. These results were further confirmed, since a significant reversion was obtained with a neutralizing antibody to human IL-4, whereas an isotype-matched control antibody had no significant effect on CXCL-8 secretion. Furthermore, we found a similar effect of IL-4 on M. bovis BCG-induced CXCL-8 and CXCL-10 secretion by using other human epithelial A549 cell line. Collectively, these data demonstrate that M. bovis BCG-infected human epithelial cells can have an active role in a local inflammatory immune response via the secretion of CXC chemokines which can be selectively regulated by Th2-derived cytokines

Neuroserpin: a serpin to think about

Proteinases and their inhibitors play important roles in neural development, homeostasis and disease. Neuroserpin is a member of the serine proteinase inhibitor (serpin) superfamily that is secreted from the growth cones of neurons and inhibits the enzyme tissue-type plasminogen activator (tPA). The temporal and spatial pattern of neuroserpin expression suggests a role in synaptogenesis and is most prominent in areas of the brain that participate in learning, memory and behaviour. Neuroserpin also provides neuronal protection in pathologies such as cerebral ischaemia and epilepsy by preventing excessive activity of tPA. Point mutations in neuroserpin cause aberrant conformational transitions and the formation of loop-sheet polymers that are retained within the endoplasmic reticulum of neurons, forming inclusion bodies that underlie an autosomal dominant dementia that we have called familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the role of neuroserpin and other proteinase inhibitors in brain development, function and disease

The stability and activity of human neuroserpin are modulated by a salt bridge that stabilises the reactive centre loop

Neuroserpin (NS) is an inhibitory protein belonging to the serpin family and involved in several pathologies, including the dementia Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), a genetic neurodegenerative disease caused by accumulation of NS polymers. Our Molecular Dynamics simulations revealed the formation of a persistent salt bridge between Glu289 on strand s2C and Arg362 on the Reactive Centre Loop (RCL), a region important for the inhibitory activity of NS. Here, we validated this structural feature by simulating the Glu289Ala mutant, where the salt bridge is not present. Further, MD predictions were tested in vitro by purifying recombinant Glu289Ala NS from E. coli. The thermal and chemical stability along with the polymerisation propensity of both Wild Type and Glu289Ala NS were characterised by circular dichroism, emission spectroscopy and non-denaturant gel electrophoresis, respectively. The activity of both variants against the main target protease, tissue-type plasminogen activator (tPA), was assessed by SDS-PAGE and chromogenic kinetic assay. Our results showed that deletion of the salt bridge leads to a moderate but clear reduction of the overall protein stability and activity

Situación

Se presenta un estudio sobre el efecto de la mediatización de las situaciones hídricas para poder delinear el futuro de las políticas ambientales relativas al servicio de agua potable, alcantarillado y abasto público.El poder de los medios de comunicación sobre la opinión pública los hace elegibles como instrumentos por excelencia de legitimación de las políticas públicas. En este sentido, las problemáticas hídricas han sido trastocadas por el poder mediático puesto que los niveles de disponibilidad, abasto, higiene y consumo relativos a la escasez de agua, corrupción e ineficiencia del servicio público, han sido transformados en los medios de comunicación en noticias, comentarios, reportajes o anuncios sesgados. Entre las políticas ambientales y las necesidades de los usuarios, los medios de comunicación cobran una relevancia especial. La mediatización de la naturaleza define la discusión pública relativa a inversiones, tarifas, sanciones o subsidios. El impacto de los noticieros de televisión, las emisiones informativas de radio y las primeras planas de los diarios incide directa y significativamente sobre la opinión y la acción pública. En la medida en que los medios de comunicación contextualizan, enmarcan e intensifican las imágenes de los hechos, acceden a la posibilidad de sesgar y manipular a sus audiencias y públicos. En este sentido es menester estudiar el efecto de la mediatización de las situaciones hídricas para poder delinear el futuro de las políticas ambientales relativas al servicio de agua potable, alcantarillado y abasto público.Unidad Académica Profesional Chimalhuacá