Sunitinib in the treatment of gastrointestinal stromal tumor: patient selection and perspectives

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. In advanced setting and after progression to imatinib, the multi-targeted receptor tyrosine kinase inhibitor sunitinib has clearly demonstrated a clinical benefit in terms of response rate and progression-free survival with an acceptable toxicity profile. The recommended schedule for sunitinib administration is 50 mg per day 4 weeks ON and 2 weeks OFF; however, potential alternative schedules are also reviewed in the present article. Several biomarkers have been explored to better select candidates for sunitinib therapy, such as the value of early changes in standardized uptake value assessed by positron emission tomography with F-18-fluorodeoxyglucose, circulating biomarkers, clinical biomarkers such as the appearance of arterial hypertension during treatment that correlates with better outcomes, and the GIST genotype. GISTs with KIT mutations at exon 9 and the so-called wild-type GISTs seem to better respond to sunitinib. Nonetheless, further investigation is required to confirm these findings as well as to understand the mechanisms of sunitinib resistance such as the development of new KIT mutations or conformational changes in KIT receptor

From Boltzmann to Zipf through Shannon and Jaynes

The word-frequency distribution provides the fundamental building blocks that generate discourse in natural language. It is well known, from empirical evidence, that the word-frequency distribution of almost any text is described by Zipf's law, at least approximately. Following Stephens and Bialek (2010), we interpret the frequency of any word as arising from the interaction potentials between its constituent letters. Indeed, Jaynes' maximum-entropy principle, with the constrains given by every empirical two-letter marginal distribution, leads to a Boltzmann distribution for word probabilities, with an energy-like function given by the sum of the all-to-all pairwise (two-letter) potentials. The so-called improved iterative-scaling algorithm allows us finding the potentials from the empirical two-letter marginals. We considerably extend Stephens and Bialek's results, applying this formalism to words with length of up to six letters from the English subset of the recently created Standardized Project Gutenberg Corpus. We find that the model is able to reproduce Zipf's law, but with some limitations: the general Zipf's power-law regime is obtained, but the probability of individual words shows considerable scattering. In this way, a pure statistical-physics framework is used to describe the probabilities of words. As a by-product, we find that both the empirical two-letter marginal distributions and the interaction-potential distributions follow well-defined statistical laws

Interaction effects and energy barrier distribution on the magnetic relaxation of nanocrystalline hexagonal ferrites

The static and dynamic magnetic properties of nanocrystalline BaFe10.4Co0.8Ti0.8O19 M-type doped barium ferrite were studied in detail to clarify the effect of interactions on the magnetic relaxation of an assembly of small particles. The logarithmic approximation was unable to account for the magnetic relaxation of the sample. Interaction effects were analyzed from the low-field susceptibility, DM plots and the time dependence of thermoremanence, indicating that demagnetizing interactions led to an enhancement of both the relaxation rate at low temperatures and the amount of the lowest energy barriers. It is thus suggested that care should be taken when analyzing thermoremanent data at low temperature, in order not to confuse these experimental findings with the signature of macroscopic quantum tunneling

Prevención de la ansiedad: técnica y recursos para la autogestión

Este proyecto centra su estudio en la ansiedad, considerada un trastorno de salud mental que puede presentarse de diversas formas. Las causas son diversas, ya que depende muchas veces no solo de la parte biológica y hereditaria sino del estilo de vida que lleven a cabo las personas. Por tanto, en una primera parte se profundiza en los principales conceptos y estudios sobre el tema. Además, de conocer los datos estadísticos de la Unidad de Salud Mental de Canarias, corroborando el alto índice de ansiedad que está sufriendo la población desde los/as más jóvenes hasta los adultos/as. De esta manera, se detecta la necesidad de dotar de herramientas a la población actual, principalmente, después de la pandemia que han aumentado los datos relacionados con la ansiedad. Hasta el momento, este tema es tabú, por tanto, esta intervención se centra en diseñar un circuito de talleres transversales ya que van dirigido a cualquier edad, son flexibles porque se pueden adaptar y está centrado en el entrenamiento de personas mediante el uso de herramientas prácticas que les ayuden a gestionar o prevenir este tipo de trastorno.This project focuses its study on anxiety, considered a mental health disorder that can present itself in various forms. The causes are diverse, since it often depends not only on the biological and hereditary part but also on the lifestyle that people lead. Therefore, in the first part, the main concepts and studies on the subject are discussed in depth. In addition, the statistical data of the Mental Health Unit of the Canary Islands, corroborating the high rate of anxiety that is suffering the population from the youngest to the adults. In this way, it is detected the need to provide tools to the current population, mainly after the pandemic that have increased the data related to anxiety. So far, this topic is taboo, therefore, this intervention focuses on designing a circuit of cross-cutting workshops as they are aimed for any age, are flexible because they can be adapted and is focused on training people through the use of practical tools to help them manage or prevent this type of disorder

Particle growing mechanisms in Ag-ZrO2 and Au-ZrO2 granular films obtained by pulsed laser deposition

Thin films consisting of Ag and Au nanoparticles embedded in amorphous ZrO2 matrix were grown by pulsed laser deposition in a wide range of metal volume concentrations in the dielectric regime (0.08<x(Ag)<0.28 and 0.08<x(Au)<0.52). High resolution transmission electron microscopy (TEM) showed regular distribution of spherical Au and Ag nanoparticles having very sharp interfaces with the amorphous matrix. Mean particle size determined from X-ray diffraction agreed with direct TEM observation. The silver mean diameter increases more abruptly with metal volume content than that corresponding to gold particles prepared under the same conditions. Two mechanisms of particle growing are observed: nucleation and particle coalescence, their relative significance being different in both granular systems, which yields very different values of the percolation threshold (xc(Ag)~0.28 and xc(Au)~0.52).Comment: 6 figure

Targeted Therapies in Sarcomas: Challenging the Challenge

Sarcomas are a heterogeneous group of mesenchymal malignancies that very often lead to death. Nowadays, chemotherapy is the only available treatment for most sarcomas but there are few active drugs and clinical results still remain very poor. Thus, there is an imperious need to find new therapeutic alternatives in order to improve sarcoma patient's outcome. During the last years, there have been described a number of new molecular pathways that have allowed us to know more about cancer biology and tumorigenesis. Sarcomas are one of the tumors in which more advances have been made. Identification of specific chromosomal translocations, some important pathways characterization such as mTOR pathway or the insulin-like growth factor pathway, the stunning development in angiogenesis knowledge, and brand new agents like viruses have lead to the development of new therapeutic options with promising results. This paper makes an exhaustive review of preclinical and clinical evidence of the most recent targeted therapies in sarcomas and provides a future view of treatments that may lead to improve prognosis of patients affected with this disease

Caveolin-1 in sarcomas: friend or foe?

Sarcomas represent a heterogeneous group of tumors with a complex and difficult reproducible classification. Their pathogenesis is poorly understood and there are few effective treatment options for advanced disease. Caveolin-1 is a multifunctional scaffolding protein with multiple binding partners that regulates multiple cancer-associated processes including cellular transformation, tumor growth, cell death and survival, multidrug resistance, angiogenesis, cell migration and metastasis. However, ambiguous roles have been ascribed to caveolin-1 in signal transduction and cancer, including sarcomas. In particular, evidence indicating that caveolin-1 function is cell context dependent has been repeatedly reported. Caveolin-1 appears to act as a tumor suppressor protein at early stages of cancer progression. In contrast, a growing body of evidence indicates that caveolin-1 is up-regulated in several multidrug-resistant and metastatic cancer cell lines and human tumor specimens. This review is focused on the role of caveolin-1 in several soft tissue and bone sarcomas and discusses the use of this protein as a potential diagnostic and prognostic marker and as a therapeutic target

Optimization of the therapeutic approach to patients with sarcoma: Delphi Consensus

Delphi consensus; Sarcoma treatment; Panel of expertsConsenso Delphi; Tratamiento del sarcoma; Panel de expertosConsens Delphi; Tractament del sarcoma; Panell d'expertsSoft tissue sarcomas (STS) constitute a heterogeneous group of rare solid tumors associated with significant morbidity and mortality. The evaluation and treatment of STS require a multidisciplinary team with extensive experience in the management of these types of tumors. National and international clinical practice guidelines for STS do not always provide answers to a great many situations that specialists have to contend with in their everyday practice. This consensus provides a series of specific recommendations based on available scientific evidence and the experience of a group of experts to assist in decision-making by all the specialists involved in the management of STS

Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Already natural low levels of pro-apoptotic proteins BIM and PUMA in tolerant cell lines were insufficient to inhibit Bcl-xL as this anti-apoptotic protein showed a slow decay curve after Dinaciclib-induced protein synthesis disruption. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS

Crucial Role of the Co Cations on the Destabilization of the Ferrimagnetic Alignment in Co-Ferrite Nanoparticles with Tunable Structural Defects

The key role of the structural defects on the magnetic properties of cobalt ferrite nanoparticles (NPs) is investigated by complementary local probes: element- and site-specific X-ray magnetic circular dichroism (XMCD) combined with high-resolution transmission electron microscopy of individual NPs. A series of monodisperse samples of 8 nm NPs with a tunable amount of structural defects were prepared by thermal decomposition of Fe(III) and Co(II) acetylacetonates in the presence of a variable concentration of 1,2-hexadecanediol. The particles show a partial inverse spinel structure, and their stoichiometry and cation distribution are comparable along the series. Element-specific XMCD hysteresis loops at all the cationic sites show a decrease in squareness and an increase in both the closure field and the high-field susceptibility as the NPs become more structurally defective, suggesting the progressive loss of the collinear ferrimagnetism. However, the Co2+ cations in octahedral sites are significantly more affected by the structural defects than the rest of the cations. This is because structural defects cause local distortions of the crystal field acting on the orbital component of the cations, yielding effective local anisotropy axes that cause a prevalent Co2+ spin canting through the spin–orbit coupling, owing to the relatively large value of the partially unquenched moment of these cations, as found by XMCD. All in all, our results emphasize the crucial role of the Co2+ cations on the destabilization of the collinear ferrimagnetism with the inclusion of structural defects in cobalt ferrite NPs