Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent

BACKGROUND: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. METHODS: This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours

Loss of Melanopsin-Expressing Ganglion Cell Subtypes and Dendritic Degeneration in the Aging Human Retina

In mammals, melanopsin-expressing retinal ganglion cells (mRGCs) are, among other things, involved in several non-image-forming visual functions, including light entrainment of circadian rhythms. Considering the profound impact of aging on visual function and ophthalmic diseases, here we evaluate changes in mRGCs throughout the life span in humans. In 24 post-mortem retinas from anonymous human donors aged 10–81 years, we assessed the distribution, number and morphology of mRGCs by immunostaining vertical retinal sections and whole-mount retinas with antibodies against melanopsin. Human retinas showed melanopsin immunoreactivity in the cell body, axon and dendrites of a subset of ganglion cells at all ages tested. Nearly half of the mRGCs (51%) were located within the ganglion cell layer (GCL), and stratified in the outer (M1, 12%) or inner (M2, 16%) margin of the inner plexiform layer (IPL) or in both plexuses (M3, 23%). M1 and M2 cells conformed fairly irregular mosaics, while M3 cell distribution was slightly more regular. The rest of the mRGCs were more regularly arranged in the inner nuclear layer (INL) and stratified in the outer margin of the IPL (M1d, 49%). The quantity of each cell type decrease after age 70, when the total number of mRGCs was 31% lower than in donors aged 30–50 years. Moreover, in retinas with an age greater than 50 years, mRGCs evidenced a decrease in the dendritic area that was both progressive and age-dependent, as well as fewer branch points and terminal neurite tips per cell and a smaller Sholl area. After 70 years of age, the distribution profile of the mRGCs was closer to a random pattern than was observed in younger retinas. We conclude that advanced age is associated with a loss in density and dendritic arborization of the mRGCs in human retinas, possibly accounting for the more frequent occurrence of circadian rhythm disorders in elderly persons.This research was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO-FEDER BFU2015-67139-R), Instituto de Salud Carlos III (RETICS-FEDER RD16/0008/0016) and Generalitat Valenciana (PROMETEO/2016/158)

A Review and Characterization of Progressive Visual Analytics

Progressive Visual Analytics (PVA) has gained increasing attention over the past years. It brings the user into the loop during otherwise long-running and non-transparent computations by producing intermediate partial results. These partial results can be shown to the user for early and continuous interaction with the emerging end result even while it is still being computed. Yet as clear-cut as this fundamental idea seems, the existing body of literature puts forth various interpretations and instantiations that have created a research domain of competing terms, various definitions, as well as long lists of practical requirements and design guidelines spread across different scientific communities. This makes it more and more difficult to get a succinct understanding of PVA’s principal concepts, let alone an overview of this increasingly diverging field. The review and discussion of PVA presented in this paper address these issues and provide (1) a literature collection on this topic, (2) a conceptual characterization of PVA, as well as (3) a consolidated set of practical recommendations for implementing and using PVA-based visual analytics solutions

Profiling the Stromal and Vascular Heterogeneity in Patient-derived Xenograft Models of Head and Neck Cancer: Impact on Therapeutic Response

Head and neck squamous cell carcinomas (HNSCC) represent a group of epithelial neoplasms that exhibit considerable heterogeneity in clinical behavior. Here, we examined the stromal and vascular heterogeneity in a panel of patient-derived xenograft (PDX) models of HNSCC and the impact on therapeutic response. Tumor sections from established tumors were stained for p16 (surrogate for human papillomavirus (HPV) infection), stromal (Masson’s trichrome) and vascular (CD31) markers. All PDX models retained the HPV/p16 status of the original patient tumor. Immunohistochemical evaluation revealed the presence of multiple vessel phenotypes (tumor, stromal or mixed) in the PDX panel. Vascular phenotypes identified in the PDX models were validated in a tissue microarray of human HNSCC. Treatment with a microtubule targeted vascular disrupting agent (VDA) resulted in a heterogeneous antivascular and antitumor response in PDX models. The PDX with the tumor vessel phenotype that exhibited higher CD31+ vessel counts and leaky vasculature on magnetic resonance imaging (MRI) was sensitive to VDA treatment while the PDX with the stromal vessel phenotype was resistant to therapy. Collectively, our results demonstrate the phenotypic and functional vascular heterogeneity in HNSCC and highlight the impact of this heterogeneity on response to antivascular therapy in PDX models of HNSC

Estado del conocimiento de los Anthribidae (Insecta: Coleoptera: Curculionoidea) de Colombia con clave a los géneros

Anthribidae is a small family of beetles known as fungus weevils, for which the state of knowledge for Colombian species has never been synthesized. Anthribids are scarce in Colombian biological collections and are usually only identified at the family level. We updated the list of species of fungus weevils recorded from Colombia. There are 37 species of anthribids recorded for the country, placed into 14 genera, 10 tribes, and 2 subfamilies. Three additional genera have been observed in the country based on records from the online platform iNaturalist. Verification of these records and species-level identifications require the revision of national biological collections. We discuss the biodiversity of Colombian fungus weevils compared to neighboring countries and provide a key to identify the genera present in Colombia. The species Domoptolis championi Jordan, 1906 is recorded for Colombia for the first time.Anthribidae es una familia pequeña de coleópteros conocidos como gorgojos de los hongos, cuyo conocimiento en Colombia nunca ha sido sintetizado. En las colecciones biológicas colombianas los antríbidos son escasos y por lo general solo están identificados a nivel de familia. Actualizamos el listado de especies de gorgojos de los hongos registrados en Colombia. Existen 37 especies de antríbidos registrados para el país, agrupadas en 14 géneros, 10 tribus y 2 subfamilias. Tres géneros adicionales han sido observados en el país a partir de registros disponibles en la plataforma iNaturalist. La verificación de estos registros requiere la revisión de colecciones biológicas nacionales. Discutimos la biodiversidad de gorgojos de los hongos colombianos comparada con países vecinos y proveemos una clave para identificar los géneros presentes en Colombia. La especie Domoptolis championi Jordan, 1906 se registra para Colombia por primera vez

Antivascular and antitumor properties of the tubulin-binding chalcone TUB091

We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)- 2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-tostraight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.M-DC thanks the Fondo Social Europeo (FSE) and the JAE Predoc Programme for a predoctoral fellowship. This work has received the Ramón Madroñero award for young researchers (to M-DC and OB) in the XVII call www.impactjournals.com/oncotarget 17 Oncotarget sponsored by the Spanish Society of Medicinal Chemistry (SEQT). This project has been supported by the Spanish Ministerio de Economia y Competitividad (SAF2012- 39760-C02-01 to M-JC, M-JP-P, SV and E-MP; and BIO2013-42984-R to JFD), Comunidad de Madrid (BIPEDD2; ref. P2010/BMD-2457 to M-JC and J-FD), the Swiss National Science Foundation (310030B_138659 and 31003A_166608; to MOS). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery” and COST action CM1470.Peer reviewe

Seguimiento de la ejecución de viviendas unifamiliares

En este proyecto final de grado de la modalidad B2 del practicum se explican los trabajos realizados durante 6 meses en la empresa SUANT.S.R.L., ubicada en Santa Cruz de la Sierra, Bolivia. Primeramente, el trabajo realizado se centro en el seguimiento de ejecución de una obra, pero más adelante, se ha ido ampliando en diferentes tareas tanto del mismo edificio como de otros. Mayormente, he podido trabajar en seguimiento de ejecución de obra, pero también en seguimiento del proyecto, mediciones, presupuesto, planificación, organización y modelación 3D. El trabajo se caracteriza por haber sido un practicum realizado en un país sudamericano tal como Bolivia, en el que hay una notable falta de organización y normativa en general, sobre todo en cuanto a la seguridad y salud de los trabajadores. Por lo que, personalmente ha sido posible reflexionar estos temas de la construcción e intentar ayudar en lo posible. En conclusión, este trabajo final de grado es un trabajo extenso y completo en el que se tratan diversos temas de la construcción y desde un punto de vista diferente, por el hecho de haberlo realizado en Bolivia