A Variant in a MicroRNA complementary site in the 3' UTR of the KIT oncogene increases risk of acral melanoma.

MicroRNAs (miRNAs) are small ∼22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3' untranslated region (3' UTRs) of target gene messenger RNAs (mRNA). Recently, mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships, contribute to oncogenesis and serve as biomarkers for cancer risk. KIT, an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis, has recently been shown to be upregulated in some melanomas, and is also a target of the miRNA miR-221. Here, we describe a genetic variant in the 3' UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of acral melanoma. This KIT variant results in a mismatch in the seed region of a miR-221 complementary site and reporter data suggests that this mismatch can result in increased expression of the KIT oncogene. Consistent with the hypothesis that this is a functional variant, KIT mRNA and protein levels are both increased in the majority of samples harboring the KIT variant. This work identifies a novel genetic marker for increased heritable risk of melanoma

Expression and Targeting of the Apoptosis Inhibitor, Survivin, in Human Melanoma

The newly described apoptosis inhibitor survivin is expressed in many human cancers and appears to play a critical part in both apoptosis regulation and cell cycle progression. Its potential role in malignant melanoma is unknown. In a panel of 30 malignant melanomas, survivin was strongly expressed in all cases (15 of 15) of metastatic malignant melanomas and 13 of 15 cases of invasive malignant melanomas by immunohistochemistry. In invasive malignant melanomas, survivin was also expressed in the in-situ component of the lesion. Survivin expression was found in all cases (11 of 11) of nevi, but not in melanocytes in sections of normal skin. The apoptosis inhibitor bcl-2 was expressed in 26 of 30 cases, but generally at lower levels than that of infiltrating lymphocytes. The mitotic index, as assessed by MIB-1 staining, was consistently higher in metastatic than invasive malignant melanomas. Assessment of apoptotic index by in situ end-labeling revealed extremely low rates of apoptosis in most malignant melanomas. Survivin expression by western blotting was detected in four human metastatic malignant melanoma cell lines but not in cultured normal human melanocytes. Transfection of both YUSAC-2 and LOX malignant melanoma cells with green fluorescence protein-conjugated survivin anti-sense or green fluorescence protein-conjugated survivin dominant negative mutant (Cys85Ala) resulted in increased apoptosis in the absence of other genotoxic stimuli. Two-color flow cytometry confirmed that YUSAC-2 cells transfected with survivin anti-sense expressed less endogenous survivin and exhibited an increased fraction of cells with sub-G1 DNA content. These data demonstrate that apoptosis inhibition by survivin may participate in the onset and progression of malignant melanomas, and suggest that therapeutic targeting of survivin may be beneficial in patients with recurrent or metastatic disease

Circadian periodicity in acetate non-utilizing mutants

Circadian periodicity in acetate non-utilizing mutant

“…el ruido de lo roto…”. Un estudio sobre OID de Juan Pampín

OID is an homage to Darío Santillán and Maximiliano Kosteki by Argentinian composer Juan Pampin (b. 1967). The piece, scored for piano, live electronics, and video consists of a set of variations on the introduction of the piano version of the Argentinian National Anthem, which, according to the composer, ciphers the Argentinian catastrophic destiny.Not ignoring the composer’s ideas on his piece, we propose that OID offers a singular –musical– perspective of post-2001Argentina. This means that the music is not (just) the testimony of a ‘disaster’, but it also opens a crack which allows for the emergency of a new perspective, an emancipatory power to aid us in rethinking the present and the future.To go through this aesthetic political operation, we analyze Pampin’s piece by looking for moments where compositional technique and aesthetic discourse intersect. To do this, we follow Theodor Adorno’s critique of Gustav Mahler, which gives us clues to understand the destructive-constructive process that of this work. It is not about reconciling our broken national identity, but to embrace this fracture, its deformity, and to amplify it, thus providing a way to allow the defeated to speak up.La obra OID para piano, electrónica en tiempo real y video del compositor argentino Juan Pampin (n. 1967) es un homenaje a Darío Santillán y Maximiliano Kosteki. Consiste en una serie de elaboraciones sobre la introducción de la versión para piano del Himno Nacional Argentino, que, de acuerdo al compositor, contiene la cifra del destino catastrófico argentino.Sin dejar de lado los dichos del compositor, proponemos que la obra de Pampin es una lectura singular de la Argentina post-2001, en el plano musical. Esto significa que esta música no testimonia (solo) una ‘catástrofe’, sino que también abre una hendija para la emergencia de una nueva perspectiva, una potencia emancipatoria para repensar el presente y el porvenir.Para abordar esta operación estético-política apelamos a la lectura adorniana de la obra de Gustav Mahler en la medida que sugiere pistas para comprender el trabajo destructivo-constructivo de la composición. Es a partir de estas herramientas que exploramos un análisis de algunos momentos de la pieza en los que se imbrica la técnica con la apuesta estética que aquí se reconstruye. No se trata de reconciliar la identidad nacional partida, sino de abrazar esa fractura, su deformidad y amplificarla para así habilitar un punto de fuga que dé voz a los vencidos

Interpretación musical y anacronismo: impurezas del tiempo en los modos de interpretación

In this paper, we aim to problematize the relationship between musical performance and music history taking as a point of departure the different modes of performance as categorized by Hermann Danuser: the “traditional mode”, the “actualizing mode” and the “historical-reconstructive mode”, the last one is also known as “historically informed performance (HIP)” since its “resurgence” in the 1960’s and 1970’s. Thus, we intend to show, by way of analyzing some recordings, the potential of musical performance in revealing the anachronistic character of musical works, i.e.: to bring to the surface the heterogeneous tem-poralities that conform the musical work, the “prophetic” of past music and what “survives” from these works in contemporary music.El objetivo de este trabajo es problematizar la relación entre interpretación musical e historia de la música a partir de los modos de interpretación, según la sistematización de Hermann Danuser. Se trata de los mo-dos «tradicional», «actualizador» e «histórico-reconstructivo», este último en su resurgimiento fue renom-brado como «históricamente informado». A través de algunas propuestas teóricas de Didi-Huberman, Bloch y Adorno, realizamos una lectura a contrapelo de la «interpretación históricamente informada» para tensionarla con el «modo actualizador». Así, mostramos con algunos ejemplos cómo la interpretación musical tiene el potencial de revelar el carácter anacrónico de las obras musicales; es decir, cómo puede traer a la superficie las temporalidades heterogéneas que trabajan al interior de ellas, lo «profético» inscrip-to en la música del pasado y lo que de esas obras «sobrevive» en la música del presente

Historical Imagination, Form and Aesthetic Experience in Sound Installations

En este trabajo se indaga sobre el problema de la forma en un tipo específico de instalaciones sonoras y su implicancia política. Se considera que una concepción historizada de la imaginación permite desgarrar el continuum destemporalizado e indeterminado de esos dispositivos artísticos y reconstruir las relaciones materiales allí cifradas. Para esto se propone articular el análisis empírico de algunas instalaciones sonoras con un recorrido teórico. En este último se discute la lectura de Jacques Rancière sobre políticas estéticas para centrar el debate sobre el arte sublime lyotardiano y la tensión con la propuesta adorniana. El arte sublime, para François Lyotard, es aquel que posibilita el desborde de la razón por la experiencia sensible y se caracteriza por ser “pura diferencia”, una “materia inmaterial” indeterminada –en música esto se encuentra en el timbre. Se sostiene, sin embargo, que los experimentos de Pierre Schaeffer indican que en la contemporaneidad no es posible una experiencia tal. La propuesta del artículo es que se puede recuperar el pensamiento formal en las instalaciones sonoras como la síntesis que opera la razón de los fragmentos producidos por la imaginación historizada que penetra al interior de aquello “indeterminado”.Este artigo visa refletir sobre o problema da forma dentro de um tipo específico de instalações sonoras e a sua implicação política. Considera-se que uma concepção historicizada da imaginação permite romper o continuum destemporalizado e indeterminado daqueles dispositivos artísticos e reconstruir as relações materiais ali cifradas. Nesse sentido propomos articular a análise empírica de algumas instalações sonoras a partir de um enquadramento teórico baseado na proposta de Jacques Rancière sobre políticas estéticas, focando no debate lyotardiano sobre a arte sublime e na tensão com a proposta adorniana. A arte sublime, segundo François Lyotard, é aquela que torna possível o transbordar da razão pela experiência sensível, caracterizado-se por ser “pura diferença”, uma “matéria imaterial” indeterminada, que na música se encontra no timbre. Porém as propostas de Pierre Schaeffer indicam que na contemporaneidade não é possível tal experiência. Este artigo propõe que é possível recuperar o pensamento formal em instalações sonoras enquanto síntese que opera sobre a razão dos fragmentos produzidos pela imaginação da consciência historicizada que penetra ao interior do “indeterminado”.This paper reflects on the problem of form and its political implications in some specific kind of sound installations. It is argued that a historized conception of imagination allows us to tear through the detemporalized continuum of such artistic devices thus grasping the material relationships ciphered in them. In order to do that an articulation between the empirical analysis of some sound installations and a theoretical journey is proposed. At first, Jacques Rancière’s thesis on politics of aesthetics are discussed, especially his contraposition between François Lyotard’s aesthetics of the sublime and Theodor Adorno’s stance on art as critique. Sublime art is, for Lyotard, one that allows reason to be exceeded by sensitive experience and is characterized as being “pure difference”, an indeterminate “immaterial matter” –which, in music, can be found in timbre. It is argued, however, that Pierre Schaeffer’s experiments indicate that today such an experience is not possible. This article posits that formal thought can be found in sound installations as the synthesis that reason elaborates from the fragments produced by a historical imagination, which can penetrate the “indeterminate”

Innervation and Second Technology in Vilanos by Luciano Azzigotti

En este trabajo nos proponemos pensar la obra Vilanos, para dos flautas amplificadas, del compositor argentino Luciano Azzigotti, volviendo sobre los conceptos benjaminianos de “inervación” y “segunda técnica”. La apuesta consiste en poner en juego estas categorías, las cuales han sido vastamente retomadas para pensar el cine, y transponerlas a la reflexión sobre música, para acercarnos, desde una perspectiva poco explorada, a un problema central de la Nueva Música: el uso de medios técnicos electrónicos. Consideramos que en la obra de Azzigotti el modo particular de amplificación - un pequeño micrófono de condensador colocado adentro de cada una de las flautas y un compresor en la amplificación-, tienen un papel decisivo, tanto en la construcción de la pieza, cuanto en su recepción. Podemos escuchar en detalle todos los sonidos de las llaves, las articulaciones más sutiles de los intérpretes en la embocadura, e incluso acoples que se producen debido a la preparación de la flauta. De este modo, las singularidades de la pieza apelan a un modo específico de interacción entre el cuerpo del intérprete y el instrumento musical, volviendo sobre reflexiones en torno a Marx y la relación entre la tecnología y lo humano. Con estos elementos se procura, no solo decir algo sobre Vilanos, sino en avanzar en una propuesta de reflexión que pueda captar algunas implicancias políticas y filosóficas de los usos de la técnica en las obras musicales, un aspecto central en la composición de Nueva Música en la actualidad.In this paper we aim to analyse Vilanos for two amplified flutes in C, by Argentinian composer Luciano Azzigotti, through Walter Benjamin’s concepts of “innervation” and “second technology”. We attempt to rethink these categories, which have been extensively applied to cinema, and transpose them into the reflection on music, in order to approach, from an scarcely explored perspective, a central problem of New Music: the use of electronic media. We posit that in Azzigotti’s work the particular way the instruments are amplified -i.e.: through a condenser microphone inserted inside each flute- has a decisive role in the construction of the piece and in it’s reception. We can hear with utmost detail all key clicks, subtle changes in embochure and even feedback sounds produced due to the flute preparation. Thus the singularities of the piece direct our attention to a specific modus of interaction between the performer’s body and the musical instrument, demanding us to reconsider Marx’s ideas about the relationship between humans and technology. Hence what we intend is, not only to say something about Vilanos, but to contribute in providing tools to reflect on political and aesthetical implications of technology in New Music today.Asociación Argentina de MusicologíaFacultad de ArtesInstituto Nacional de Musicología "Carlos Vega

Future perspectives in melanoma research: meeting report from the “Melanoma Bridge”, Napoli, December 5th-8th 2013

The fourth “Melanoma Bridge Meeting” took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent research in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, like BRAF and MEK inhibitors, as well as other signaling pathways inhibitors, are being tested in metastatic melanoma either as monotherapy or in combination, and have yielded promising results. Improved survival rates have also been observed with immune therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in melanoma as well. This meeting’s specific focus was on advances in targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. Significant consideration was given to issues surrounding the development of novel therapeutic targets as further study of patterns of resistance to both immunologic and targeted drugs are paramount to future drug development to guide existing and future therapies. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma