Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: A phase 2 trial

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial

Chemical decoration in cubic approximant and quasicrystal in the Al-Cu-Fe system

International audienceThe local order in the Al--Cu--Fe quasicrystal and in two of its approximants has been investigated by extended X-ray absorption fine structure (EXAFS) studies at the Cu and Fe Kedges. The chemical occupation of the crystallographic sites in the 1/1 cubic α--Al55Si7Cu25.5Fe12.5 phase is revisited. From these results, a model for the chemical short--range order in the Al62.5Cu25.5Fe 12.5 quasicrystal is proposed

The Batten disease gene CLN3 is required for the response to oxidative stress

Mutations in the CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early onset neurodegenerative disorder. JNCL is the most common of the NCLs, a group of disorders with infant or childhood onset that are caused by single gene mutations. The NCLs, although relatively rare, share many pathological and clinical similarities with the more common late-onset neurodegenerative disorders, while their simple genetic basis makes them an excellent paradigm. The early onset and rapid disease progression in the NCLs suggests that one or more key cellular processes are severely compromised. To identify the functional pathways compromised in JNCL, we have performed a gain-of-function modifier screen in Drosophila. We find that CLN3 interacts genetically with the core stress signalling pathways and components of stress granules, suggesting a function in stress responses. In support of this, we find that Drosophila lacking CLN3 function are hypersensitive to oxidative stress yet they respond normally to other physiological stresses. Overexpression of CLN3 is sufficient to confer increased resistance to oxidative stress. We find that CLN3 mutant flies perceive conditions of increased oxidative stress correctly but are unable to detoxify reactive oxygen species, suggesting that their ability to respond is compromised. Together, our data suggest that the lack of CLN3 function leads to a failure to manage the response to oxidative stress and this may be the key deficit in JNCL that leads to neuronal degeneration

Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies

Combination; Drug therapy; ImmunotherapyCombinació; Teràpia farmacològica; ImmunoteràpiaCombinación; Terapia farmacológica; InmunoterapiaBackground Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab. Methods Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). Results In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline. Conclusions Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.This study was sponsored by Novartis Pharmaceuticals Corporation and preliminary results were previously presented at ASCO 2018

Sistema de control interno administrativo y contable para la empresa Authesa S.A., del cantón Ibarra, provincia de Imbabura

Determinar la situación actual de AUTHESA S.A. para identificar las fortalezas, oportunidades, debilidades y amenazas referentes al control interno de las áreas administrativa y contable.Los controles empíricos en AUTHESA S.A., han dado lugar a gastos innecesarios debido a duplicidad de funciones y pesar de tener un margen de utilidades esta se ha reducido por la mala utilización de recursos materiales, ante lo cual es necesario el desarrollo de un sistema de control interno administrativo y contable que vele por el fortalecimiento institucional a través de normas y controles para las actividades cotidiana, para lo cual se aplicó la investigación cuantitativa sustentada en (Herrera J, 2017), se utilizaron las técnicas de entrevista, encuesta y observación, para sustentar el desarrollo de la presente investigación consideramos como referente teórico a (Estupiñán Gaitán, 2015), el cual indica que el control interno son las políticas, procedimientos, prácticas y estructuras organizacionales diseñadas para proporcionar razonable confianza en que los objetivos de los negocios estarán alcanzados y que los eventos indeseados serán prevenidos o detectados y corregidos, es así que podemos concluir que la creación del sistema de control interno administrativo y contable genera impactos positivos a nivel empresarial, económico y social, demostrando una vez más la importancia del mismo

Fish and Coral Reef Communities of the Parque Nacional Sistema Arrecifal Veracruzano (Veracruz Coral Reef System National Park) Veracruz, Mexico: Preliminary Results

Effective resource management requires robust baseline datasets and efficient monitoring programs to identify and quantify temporal change. The Parque Nacional Sistema Arrecifal Veracruzano (Veracruz Coral Reef System National Park) encompasses a total of 52000ha including 23 coral reefs in two island groups separated by the mouth of the Jamapa River; one near the port of Veracruz, Mexico and one approximately 20km south near Punta Antón Lizardo. Both groups receive substantial fisheries pressure and other anthropogenic impacts. Using non-destructive, visual methods we surveyed fish and benthic assemblages at 18 sites, which included 10 individual coral reefs within the Park. For fishes, 221 point-count and 97 rover-diver surveys were conducted. In total, 92975 fish of 155 species were recorded. Using point-count data, fish abundance differed between Veracruz and Antón Lizardo sites (mean ± SEM: Veracruz = 535.52 ± 78.13; Antón Lizardo = 300.08 ± 30.68; p\u3c0.01, ANOVA). In contrast, there was no difference in fish species richness between these sites (Veracruz = 18.22 ± 0.36; Antón Lizardo = 18.75 ± 0.45); nor were there apparent differences in the MDS plot of Bray-Curtis similarity indices. A total of 27 stony coral species was identified on 170, 30-m point-intercept transects. Species richness ranged from 8 to 14 per site. Stony coral cover ranged from 4% to 38% with a mean of 22%. Other important functional groups included turf algae, macroalgae, and coralline algae. These groups generally contributed more to benthic cover than sponges or octocorals. Evidence of disease within the stony coral community was seen at all sites

Características relevantes en el comportamiento empresarial. Aplicación en la transformación curricular en una universidad ecuatoriana

In Ecuador, as well as in the world, it is evident that most companies were created by entrepreneurs’ ideas. The problem is the gap that exists between students who want to undertake and those who evidence the creation of a company during their career. The objective of this study is to validate the most relevant entrepreneurial behaviours of the State Polytechnic University of Carchi (UPEC) students, which contributes to modify the curriculum. Students measure 50 assertions with Likert scale which expose behaviours related to 10 business behaviours, allowing an Exploratory Factor Analysis (EFA) to explain the needs raised by McClelland in four latent variables such as: determined, effective, systematic, and safe. This statistical exercise fulfills the assumption of multivariate normality using the Mardia test and the Kayser Meyer Olkin (KMO) test, whose threshold must be greater than the value of Maximum Likelihood Extraction and Promax Rotation methods. Confirmatory Factor Analysis (CFA) was applied and the psychometric assumptions were validated: FC, AVE and VD. The results show how in Ecuador, some curriculum variables can be intervened, to make the students with entrepreneurial ideas become entrepreneurs. These students are systematic because they plan projects with pertinent information and execute the roadmap. They are effective, so they strive to deliver as planned. They are confident, since they confident in succeeding, and do excellent work to achieve inclusive solutions.En Ecuador, así como en el mundo, se evidencia que la mayoría de las empresas fueron creadas con las ideas de los emprendedores. El problema es la brecha que existe entre los estudiantes que quieren emprender y los que evidencian la creación de una empresa durante el transcurso de la carrera. El objetivo del estudio es valida  las conductas emprendedoras más relevantes en el comportamiento empresarial de los estudiantes de la Universidad Politécnica Estatal del Carchi (UPEC), con el fin de aportar a la modificación del currículo. Se obtuvo una medición de los estudiantes en torno a 50 aseveraciones con escala de Likert que exponen comportamientos en relación con 10 conductas empresariales, permitiendo un Análisis Factorial Exploratorio (AFE) para explicar las necesidades planteadas por McClelland en cuatro variables latentes: decidido, efectivo, sistemático y seguro. Este ejercicio estadístico cumple el supuesto de normalidad multivariante mediante la prueba de Mardia y la prueba Kayser Meyer Olkin (KMO), cuyo umbral debe ser mayor al valor de 0,70 con métodos de Extracción Máxima Verosimilitud y de Rotación Promax. Se aplicó el Análisis Factorial Confirmatorio (AFC) y se validaron los supuestos psicométricos: FC, AVE y VD. Los resultados muestran cómo en Ecuador desde el currículo se pueden intervenir algunas variables para hacer que los estudiantes con ideas emprendedoras se conviertan en empresarios. Estos estudiantes son sistemáticos, planifican proyectos con información pertinente y ejecutan la hoja de ruta. Son efectivos al esmerarse por hacer que las cosas se cumplan como lo planificaron. Son seguros de sí mismos, tienen confianza en el éxito realizando trabajos excelentes paraalcanzar soluciones incluyentes

Plan estratégico de marketing para el posicionamiento de la marca tropifruta en el mercado nacional

Presenta un plan estratégico de marketing para la marca TROPIFRUTA en el mercado nacional. Realizar un análisis de los factores del entorno influyentes en el negocio desde la perspectiva del sistema económico y social general, determinar la tendencia del mercado para la TROPIFRUTA mediante el análisis de la 5 fuerzas de PORTER del negocio, establecer estrategias de marketing para el posicionamiento del negocio mediante el desarrollo de la herramienta FODA, elaborara el presupuesto para las actividades derivadas de las estrategias identificado de los costos asociados al desarrollo de las misma

Immunologic responses to xenogeneic tyrosinase DNA vaccine administered by electroporation in patients with malignant melanoma

BACKGROUND: Prior studies show that intramuscular injection and particle-mediated epidermal delivery of xenogeneic melanosomal antigens (tyrosinase or Tyr, gp100) induce CD8(+) T cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a phase I study of in vivo electroporation (EP) of a murine Tyr DNA vaccine (pINGmuTyr) in malignant melanoma patients. METHODS: Human leukocyte antigen (HLA)-A1, A2, A24 or B35 stage IIb-IV melanoma patients received up to five doses of the mouse tyrosinase DNA vaccine by EP every three weeks at dose levels of 0.2 mg, 0.5 mg, or 1.5 mg per injection. Peripheral blood mononuclear cells (PBMC) were collected, cultured with a peptide pool containing eight HLA class I-restricted Tyr-specific T-cell epitopes, and analyzed by HLA-A*0101-restricted tetramers and intracellular cytokine staining (ICS). RESULTS: Twenty-four patients received ≥1 dose of the pINGmuTyr vaccine; PBMCs from 21 patients who completed all five doses were available for Tyr immune assays. The only common toxicity was grade 1 injection site reaction. Six of 15 patients (40%) in the 1.5 mg dose cohort developed Tyr-reactive CD8(+) T cell responses following stimulation, defined as a ≥3 standard deviation increase in baseline reactivity by tetramer or ICS assays. No Tyr-reactive CD8(+) T cell response was detected in the 0.2 mg and 0.5 mg dose cohort patients. Epitope spreading of CD8(+) T cell response to NY-ESO-1 was observed in one patient with vitiligo. One patient subsequently received ipilimumab and developed an enhanced Tyr-reactive response with polyfunctional cytokine profile. After a median follow-up of 40.9 months, median survival has not been reached. CONCLUSIONS: A regimen of five immunizations with pINGmuTyr administered by EP was found to be safe and resulted in Tyr-reactive immune responses in six of 15 patients at 1.5 mg dose cohort. TRIAL REGISTRATION: ClinicalTrials.gov NCT0047113