Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma.

Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor's own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions.

Effects of conducting and blocking ions on the structure and stability of the potassium channel KcsA.

This article reports on the interaction of conducting (K(+)) and blocking (Na(+)) monovalent metal ions with detergent-solubilized and lipid-reconstituted forms of the K(+) channel KcsA. Monitoring of the protein intrinsic fluorescence reveals that the two ions bind competitively to KcsA with distinct affinities (dissociation constants for the KcsA.K(+) and KcsA.Na(+) complexes of approximately 8 and 190 mm, respectively) and induce different conformations of the ion-bound protein. The differences in binding affinity as well as the higher K(+) concentration bathing the intracellular mouth of the channel, through which the cations gain access to the protein binding sites, should favor that only KcsA.K(+) complexes are formed under physiological-like conditions. Nevertheless, despite such prediction, it was also found that concentrations of Na(+) well below its dissociation constant and even in the presence of higher K(+) concentrations, cause a remarkable decrease in the protein thermal stability and facilitate thermal dissociation into subunits of the tetrameric KcsA, as concluded from the temperature dependence of the protein infrared spectra and from gel electrophoresis, respectively. These latter observations cannot be explained based on the occupancy of the binding sites from above and suggest that there must be additional ion binding sites, whose occupancy could not be detected by fluorescence and in which the affinity for Na(+) must be higher or at least similar to that of K(+). Moreover, cation binding as reported by means of fluorescence does not suffice to explain the large differences in free energy of stabilization involved in the formation of the KcsA.Na(+) and KcsA.K(+) complexes, which for the most part should arise from synergistic effects of the ion-mediated intersubunit interactions.

Clustering and coupled gating modulate the activity in KcsA, a potassium channel model.

Different patterns of channel activity have been detected by patch clamping excised membrane patches from reconstituted giant liposomes containing purified KcsA, a potassium channel from prokaryotes. The more frequent pattern has a characteristic low channel opening probability and exhibits many other features reported for KcsA reconstituted into planar lipid bilayers, including a moderate voltage dependence, blockade by Na(+), and a strict dependence on acidic pH for channel opening. The predominant gating event in this low channel opening probability pattern corresponds to the positive coupling of two KcsA channels. However, other activity patterns have been detected as well, which are characterized by a high channel opening probability (HOP patterns), positive coupling of mostly five concerted channels, and profound changes in other KcsA features, including a different voltage dependence, channel opening at neutral pH, and lack of Na(+) blockade. The above functional diversity occurs correlatively to the heterogeneous supramolecular assembly of KcsA into clusters. Clustering of KcsA depends on protein concentration and occurs both in detergent solution and more markedly in reconstituted membranes, including giant liposomes, where some of the clusters are large enough (up to micrometer size) to be observed by confocal microscopy. As in the allosteric conformational spread responses observed in receptor clustering (Bray, D. and Duke, T. (2004) Annu. Rev. Biophys. Biomol. Struct. 33, 53-73) our tenet is that physical clustering of KcsA channels is behind the observed multiple coupled gating and diverse functional responses.

Receptores de estrógeno y progesterona en cáncer de mama: asociación con variables clinicopatológicas / Estrogen and progesterone receptors in breast cancer: association with clinicopathological variables

La expresión de receptores de estrógeno (RE) y de progesterona (RP) constituyen una variable de valor pronóstico en el cáncer de mama, donde la respuesta a la terapia endocrina ser  más favorable en tumores con estos receptores positivos. El objetivo del presente trabajo fue determinar la expresión de RE y de RP y su asociación con las variables pronósticas: edad, presencia de ganglios linfáticos axilares con metástasis, tamaño del tumor, grado histológico, grado nuclear, estadio clínico, tiempo libre de enfermedad y sobrevida. Se estudiaron 53 pacientes con carcinoma de mama, con edades comprendidas entre 29 y 77 años, diagnósticadas en el Instituto Oncológico "Dr. Miguel P‚rez Carreño" que no habían recibido quimioterapia. Los cortes de biopsias se analizaron por inmunohistoquímica, utilizando el método de estreptavidina-biotina-peroxidasa. En los resultados obtenidos se observó un 22,6 por ciento de expresión de RE y un 18,8 por ciento de RP con una asociación significativa entre ambos receptores (p< 0,005). Se evidenció relación significativa entre los RE y la edad de las pacientes (p<0,005), el porcentaje de negativos fue mayor en los pacientes hasta los 50 años y el porcentaje de positivos mayor en el grupo de más de 50 años. Las pacientes con RE y RP positivos presentaron mayor tiempo libre de enfermedad y mayor sobrevida aunque sin significación estadística. No se observó asociación significativa entre el estatus de los receptores de estrogeno y progesterona con las demás variables en estudio