ALK Inhibitors, a Pharmaceutical Perspective

In 2007, the ALK tyrosine kinase was described as a potential therapeutic target for a subset of non-small-cell lung cancer patients. Clinical proof of concept, culminating in the recent approval by the Food and Drug Administration of the Pfizer drug crizotinib followed in record time. The drug was approved together with a companion diagnostic for detection of patients eligible for therapy. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in a rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may additionally occur through ALK-independent mechanisms, which still need to be elucidated in detail. Here we discuss the factors that led to such a rapid approval of a targeted agent, and we describe the second-generation compounds currently in development

De la fragmentación de las audiencias a las comunidades transmedia

La tecnología digital amplifica de manera exponencial el ecosistema mediático a la vez que posibilita la expansión (y reelaboración) de los universos narrativos y sus sentidos, en los cuales cada intervención lo es en el marco de experiencias conversacionales moldeadas por diferentes interfaces comunicacionales. Las historias de las personas y las personas de las historias se (re) construyen a través de los diferentes medios y plataformas de manera colaborativa, generando una disrupción en las nociones de planificación, guionado, pautado, etc. a la vez que el propio concepto de autoría aparece disputado, pues las diferentes intervenciones implican también resignificaciones desde diferentes conciencias, identidades, voluntades y sensibilidades que se articulan y conjugan. La linealidad en la producción, distribución y consumo de mensajes se pliega sobre sí misma y reconfigura un universo social en expansión, una experiencia colectiva que parte desde un punto central (como una piedra en un charco) generando ondas de intervenciones que (re) dibujan los bordes difusos de las historias; frecuencias capaces de alterar no solamente el espejo inicial, sino que avanzan hacia las profundidades, hacen vibrar la humedad del aire, generan sinuosidades en el polvo de la tierra y en las hierbas y resuenan en el interior de las mentes de los participantes y sus historias para ser convertidas en nuevos puntos de partida de una red fractal de significados. El desarrollo tecnomediático como momento del capitalismo configura una hipersegmentación de mercado, donde se desarrollan perfiles de consumo casi a nivel personal con la apelación a la participación activa en el mismo, cuestión que -paradójicamente- genera los dispositivos que permiten comunitarizar esas particularidades e integrarlas en narraciones conversacionales expansivas. ¿Es posible construir con la lógica transmedia pedagogías del encuentro? ¿Habilitan las técnicas y dispositivos transmedia a generar instancias dialógicas que contribuyan a procesos comunitarios y organizacionales? ¿Qué solidaridades y densidades vinculares construyen estas experiencias? Estas son algunas de las preguntas que en tiempos de convergencia tecnológica, cultural y mediática nos hacemos y que a la luz de dos experiencias diversas de procesos comunicacionales colectivos, serán motivo de reflexión en esta ponencia.Fil: Ardini, Claudia. Universidad Nacional de Córdoba. Facultad de Ciencias de la Comunicación; Argentina.Fil: Ciolli, María Elena. Universidad Nacional de Córdoba. Facultad de Ciencias de la Comunicación; Argentina.Fil: Mirad, Heraldo Nahúm. Universidad Nacional de Córdoba. Facultad de Ciencias de la Comunicación; Argentina.Otras Comunicación y Medio

The 67-kDa laminin receptor originated from a ribosomal protein that acquired a dual function during evolution.

The 67-kDa laminin receptor (67LR) is a nonintegrin cell surface receptor that mediates high-affinity interactions between cells and laminin. Overexpression of this protein in tumor cells has been related to tumor invasion and metastasis. Thus far, only a full-length gene encoding a 37-kDa precursor protein (37LRP) has been isolated. The finding that the cDNA for the 37LRP is virtually identical to a cDNA encoding the ribosomal protein p40 has suggested that 37LRP is actually a component of the translational machinery, with no laminin-binding activity. On the other hand, a peptide of 20 amino acids deduced from the sequence of 37LR/p40 was shown to exhibit high laminin-binding activity. The evolutionary relationship between 23 sequences of 37LRP/p40 proteins was analyzed. This phylogenetic analysis indicated that all of the protein sequences derive from orthologous genes and that the 37LRP is indeed a ribosomal protein that acquired the novel function of laminin receptor during evolution. The evolutionary analysis of the sequence identified as the laminin-binding site in the human protein suggested that the acquisition of the laminin-binding capability is linked to the palindromic sequence LMWWML, which appeared during evolution concomitantly with laminin

Sensitivity to Entrectinib Associated with a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib

p53-dependent downregulation of metastasis-associated laminin receptor

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild-type p53 (wt p53) ovarian carcinoma cell line and in a cisplatin-resistant subline with mutated p53. We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct. Cotransfection experiments showed that the promoter is downregulated by both wt and mutated p53. Deletion analysis of the first intron localized an enhancer activity in the first 5' 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53. Cotransfection, mutagenesis and gel-shift experiments identified a functional AP-2 cis-acting element in this intron region that is repressed by increased levels of both wt and mutated p53. Coimmunoprecipitation studies revealed AP-2 in physical association in vivo with both wt and mutated p53, indicating for the first time that interaction of p53 with AP-2 is involved in the repression mechanism and in the regulation of genes involved in cancer growth and progression

Influence of Australian Black Summer smoke in Antarctic aerosol collected on board during the R/V Laura Bassi first campaign in the Ross Sea

Biomass burning has been recognized as the largest source of primary fine carbonaceous particles, influencing the climate system and the Earth’s solar balance. During the 2019-2020 Australian bushfire season, and particularly from December to January, a lot of wildfires impacted the South-East of Australia, affecting local air quality. The huge amount of emitted smoke influenced stratospheric temperature over Antarctica and stratospheric aerosol optical properties (Damany-Pearce et al., 2022; Tencé et al., 2022). Long-range atmospheric transport to Antarctica and South America was also hypothesized. Levoglucosan is an anhydrosugar widely recognized as a key tracer of biomass combustion, because it can be only produced by the combustion of cellulose. Polycyclic aromatic hydrocarbons (PAHs) are organic compounds typically produced during combustion processes and are known to be present in wildfire smoke. In this work, levoglucosan and PAHs, together with other complementary sugars, were determined in aerosol samples collected during the XXXV Italian Expedition in Antarctica on board the R/V Laura Bassi from 6th January to 16th February 2020, at the end of the so-called Australian Black Summer. Total suspended particles (TSP) with a diameter >1 mm were collected on a circular quartz fiber filter (Filtros Anoia S.A. Filter-Lab, Barcelona, Spain) using a TE 5000 High-Volume Air Sampler (Tisch Environmental Inc., Cleves, OH, USA). The sampling system was connected to a wind control system, to avoid contamination from the ship. For this reason, the sampling lasted between 2 and 7 days and was carried out mainly in the coastal area of the Ross Sea. The results clearly indicate a contribution of Australian wildfires on Antarctic aerosol composition, by comparison with the detected levels of the same compounds during previous sampling campaigns in the Ross Sea area (Barbaro et al., 2016; Zangrando et al., 2016). Back trajectories indicate a local source of aerosol, confirming the hypothesis of long-term persistence of smoke over the globe, with a long-lasting influence on general air quality. Together with biomass burning tracers, a marine biogenic component was also identified using other chemical tracers, such as monosaccharides. Barbaro, E., Zangrando, R., Kirchgeorg, T., Bazzano, A., Illuminati, S., Annibaldi, A., Rella, S., Truzzi, C., Grotti, M., Ceccarini, A., Malitesta, C., Scarponi, G., Gambaro, A., 2016. An integrated study of the chemical composition of Antarctic aerosol to investigate natural and anthropogenic sources. Environmental Chemistry 13(5), 867-876. https://doi.org/10.1071/EN16056. Damany-Pearce, L., Johnson, B., Wells, A., Osborne, M., Allan, J., Belcher, C., Jones, A., Haywood, J., 2022. Australian wildfires cause the largest stratospheric warming since Pinatubo and extends the lifetime of the Antarctic ozone hole. Scientific Reports 12, Article number: 12665. https://doi.org/10.1038/s41598-022-15794-3. Tencé, F., Jumelet, J., Bekki, S., Khaykin, S., Sarkissian, A., Keckhut, P., 2022. Australian Black Summer Smoke Observed by Lidar at the French Antarctic Station Dumont d’Urville. Journal of Geophysical Research: Atmospheres 127(4), Article number: e2021JD035349. https://doi.org/10.1029/2021JD035349. Zangrando, R., Barbaro, E., Vecchiato, M., Kehrwald, N.M., Barbante, C., Gambaro, A., 2016. Levoglucosan and phenols in Antarctic marine, coastal and plateau aerosols. Science of The Total Environment 544, 606-616. https://doi.org/10.1016/j.scitotenv.2015.11.166