Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors.

BACKGROUND: Ataxia telangiectasia mutated (ATM) kinase orchestrates DNA double strand break (DSB) repair; ATM inhibitors may therefore enhance the therapeutic effect of DSB-inducing treatments such as radiotherapy (RT). M3541 is an orally administered selective inhibitor of ATM. METHODS: This phase I dose-escalation study evaluated the maximum-tolerated dose (MTD), recommended phase II dose(s) (RP2D), safety, pharmacokinetics (PK) and antitumor activity of M3541 in combination with fractionated palliative RT in patients with solid tumors. Fifteen patients received palliative RT (30 Gy in 10 fractions) and escalating doses of M3541 (50-300 mg administered on RT fraction days) guided by a Bayesian 2-parameter logistic regression model with overdose control. RESULTS: Doses of M3541 up to 300 mg/fraction day were well tolerated. One patient (200 mg group) experienced two dose-limiting toxicities (urinary tract infection, febrile neutropenia) that resolved with antibiotics. All patients reported ≥ 1 treatment-emergent adverse event (TEAE) but none led to treatment discontinuation. No grade ≥ 4 TEAEs were reported and there was no indication of a dose effect for any TEAE. Three patients (20.0%; 95% confidence interval 4.3-48.1) had confirmed complete or partial response. M3541 total plasma levels did not increase with dose following single or repeated dosing. No relationship was observed between dose and changes in the ratio of phosphorylated to total ATM or in immune cell counts. CONCLUSIONS: The MTD and RP2D could not be established as the study closed early due to the absence of a dose-response relationship and non-optimal PK profile. No further clinical development of M3541 was pursued. (Trial registration number ClinicalTrials.gov NCT03225105. Registration date July 21, 2017).

Effects of autologous, cross-linked erythrocytes on isolated hypoperfused rabbit heart dynamics.

The present study was aimed at assessing the effects of either red blood cells (RBC) or RBC cross-linked with the bifunctional dimethyl suberimidate reagent (C-RBC) on contractile force (CFo), heart rate (HR) and coronary flow (CF) of the isolated rabbit heart hypoperfused with RBC suspensions under 30 mm Hg constant pressure. RBC or C-RBC caused a rapid and marked reduction of CF, CFo and HR. In RBC-treated hearts, however, reperfusion with Tyrode solution partially restored the initial myocardial parameters, while in C-RBC-treated hearts a rapid impairment of diastolic relaxation with a subsequent, steady and increasing heart contracture was observed. Histological analysis showed that in C-RBC-perfused hearts either capillaries or precapillary arterioles were occluded by C-RBC in spite of extensive washings with Tyrode solution. These findings indicate that C-RBC impair coronary circulation markedly and irreversibly.

Cuidado humanizado: Reto para el profesional de enfermería / Humanized Care: A Challenge for the Nursing Professional

Objetivo: El objetivo general de la investigación fue analizar el cuidado humanizado: Reto para el profesional de enfermería. Método: Se desarrolló desde un enfoque cuantitativo con una metodología descriptiva con diseño no experimental, la cual se apoya en el análisis documental­bibliográfico. Se organizó un proceso investigativo en donde la población de estudio, se basó primordialmente en documentos escritos como tesis, revistas arbitradas y artículos científicos. Resultados: Se planteó la idea de desconstruir el significado de humanizar y reconstruir el concepto de cuidad desde la humanización. En conclusión: Sin duda alguna el profesional de enfermería se enfrenta a grandes retos en la gestión de cuidado humanizado, en un mundo globalizado y en donde se están desarrollando tecnologías que buscan desplazar la acción del ser humano, sin embargo, la calidez y acompañamiento que ofrece este profesional a los pacientes y familiares no podrán ser sustituidos.

Objective: The general objective of the research was to analyze humanized care: Challenge for the nursing professional. Method: It was developed from a quantitative approach with a descriptive methodology with non-experimental design, which is supported by documentary-bibliographic analysis. A research process was organized in which the study population was based primarily on written documents such as theses, peer-reviewed journals and scientific articles. Results: The idea of deconstructing the meaning of humanizing and reconstructing the concept of care from humanization was proposed. In conclusion: Undoubtedly, the nursing professional faces great challenges in the management of humanized care, in a globalized world where technologies are being developed that seek to displace the action of the human being, however, the warmth and accompaniment offered by this professional to patients and family members cannot be replaced.

Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K.

Ras proteins are molecular switches that control signaling pathways critical in the onset of a variety of human cancers. The signaling pathways activated by Ras proteins are those controlled by its direct effectors such as the serine-threonine protein kinase Raf-1, the exchange factor for other GTPases Ral-GDS, and the lipid kinase PI3K. As a consequence of Ras activation, a number of additional enzymes are affected, including several members of the serine-threonine intracellular proteins kinases as well as enzymes related to phospholipid metabolism regulation such as phospholipases A2 and D, and choline kinase. The precise mechanisms by which ras oncogenes impinge into these later molecules and their relevance to the onset of the carcinogenic process is still not fully understood. Here we have investigated the mechanism of regulation of choline kinase by Ras proteins and found no direct link between PLD and choline kinase activation. We provide evidence that Ras proteins regulate the activity of choline kinase through its direct effectors Ral-GDS and PI3K, while the Raf pathways seems to be not relevant in this process. The importance of Ras-dependent activation of choline kinase is discussed.

Modulation of phospholipase D by Ras proteins mediated by its effectors Ral-GDS, PI3K and Raf-1.

Transformation by ras oncogenes induces the deregulation of intracellular signalling cascades that are critical elements in cell growth control. Ras proteins are molecular switches with the ability to interact and activate several effector molecules. Among those, Raf-1 kinase, PI3K and Ral-GDS are the best characterised. Raf activates the mitogenic MEK/ERK kinases pathway, while PI3K regulates the PKB/Akt cascade, involved in the control of proliferation, metabolism and apoptotic responses. Finally, Ral-GDS belongs to a family of guanine nucleotide exchange factors that activate Ral GTPases. While Raf and PI3K have emerged as critical elements in regulating cell growth and apoptosis, little is known about the role of the Ral-GDS family. We have previously reported that Ras proteins are critical elements in the regulation of phospholipase D (PLD), a proposed target for the Ral-GDS/RalA pathway. Physiological regulation of PLD by growth factors requires the simultaneous activation of the endogenous, wild-type Ras proteins, and a PKC-dependent mechanism. Transformation by ras oncogenes induces drastic alterations in PLD activity and the usual response to external stimuli, through a PKC-independent mechanism. Here we provide further evidence on the mechanisms by which oncogenic Ras proteins induces the deregulation of PLD and here we try to identify the specific effectors involved. A complex system for PLD regulation is unravelled which implies the existence of two positive regulatory pathways, mediated by Ral-GDS and PI3K, and two negative feedback mechanisms mediated by Raf and Ral-GDS. These results strongly support participation of PLD in Ras-mediated signalling. Furthermore, we provide evidence that oncogenic Ras proteins constitutively activate PLD by mechanisms different to those used by normal Ras proteins.