Safety and pharmacokinetic study of the combination of trastuzumab emntansine and non-pegylated liposomal doxorubicin for the treatment of advanced HER2 positive breast cancer

Este estudio es un ensayo fase Ib, de un solo brazo, abierto (NCT02562378) en el que se incluyeron pacientes con cáncer de mama metastásico Her2 positivo que no habían recibido tratamiento previo con antraciclinas, y que además habían progresado a trastuzumab y taxanos. Tiene un diseño 3+3 de escalada de dosis seguido de una fase de expansión. Los pacientes recibieron un máximo de 6 ciclos de doxorrubicina liposomal no pegilada intravenosa a varios niveles de dosis (45, 50, and 60 mg/m2) en la parte de escalada de dosis y a 60 mg/m2 durante la fase de expansión, cada 3 semanas junto con T-DM1 a una dosis estándar. El objetivo principal fue establecer la máxima dosis tolerada y las toxicidades limitantes de dosis de esta combinación. Se incluyeron un total de 15 pacientes (12 pacientes durante la parte de escalada de dosis y tres pacientes más adicionales en la parte de expansión). Un paciente sufrió una toxicidad limitante de dosis a 60 mg/m2 (neutropenia grado 4 durante 13 días). La máxima dosis tolerada de doxorrubicina liposomal pegilada fue 60 mg/m2. No se reportó un deterioro clínicamente relevante de la función cardiaca. La tasa de respuesta global fue el 40.0% con una mediana de duración de la respuesta de 6.9 meses, la tasa de beneficio clínico fue del 66.7%, y la mediana de supervivencia libre de progresión fue de 7.2 meses (95%CI, 4.5–9.6). No se observó una influencia significativa de la doxorrubicina liposomal pegilada en la farmacocinética del T-DM1

Endothelial Aging Associated with Oxidative Stress Can Be Modulated by a Healthy Mediterranean Diet

Aging is a condition which favors the development of atherosclerosis, which has been associated with a breakdown in repair processes that occurs in response to cell damage. The dysregulation of the biological systems associated with aging are produced partly through damage which accumulates over time. One major source of this injury is oxidative stress, which can impair biological structures and the mechanisms by which they are repaired. These mechanisms are based on the pathogenesis of endothelial dysfunction, which in turn is associated with cardiovascular disease, carcinogenesis and aging. The dependent dysfunction of aging has been correlated with a reduction in the number and/or functional activity of endothelial progenitor cells, which could hinder the repair and regeneration of the endothelium. In addition, aging, inflammation and oxidative stress are endogenous factors that cause telomere shortening, which is dependent on oxidative cell damage. Moreover, telomere length correlates with lifestyle and the consumption of a healthy diet. Thus, diseases associated with aging and age may be caused by the long-term effects of oxidative damage, which are modified by genetic and environmental factors. Considering that diet is a very important source of antioxidants, in this review we will analyze the relationship between oxidative stress, aging, and the mechanisms which may be involved in a higher survival rate and a lower incidence of the diseases associated with aging in populations which follow a healthy diet

A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other Tumors

Pan-notch inhibitor CB-103; Advanced adenoid cystic carcinomaInhibidor pan-notch CB-103; Carcinoma adenoide quístic avançatInhibidor pan-notch CB-103; Carcinoma adenoide quístico avanzadoPurpose: CB-103 selectively inhibits the CSL–NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor activity. Experimental Design: Patients ≥18 years of age with selected advanced solid tumors [namely, adenoid cystic carcinoma (ACC)] and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28 days at escalating doses until disease progression. Notch-activating mutations were required in a dose confirmatory cohort. Endpoints included dose-limiting toxicities (DLT), safety, tumor response, pharmacokinetics, and pharmacodynamics. Exploratory analyses focused on correlates of Notch and target gene expression. Results: Seventy-nine patients (64, 12 dose-escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3–4 treatment-related adverse events occurred in 15 patients (19%), including elevated liver function tests (LFTs), anemia, and visual changes. Five (6%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease; including 23 of 40 (58%) patients with ACC. In the ACC cohort, median progression-free survival was 2.5 months [95% confidence interval (CI), 1.5–3.7] and median overall survival was 18.4 months (95% CI, 6.3–not reached). Conclusions: CB-103 had a manageable safety profile and biological activity but limited clinical antitumor activity as monotherapy in this first-in-human study. Significance: CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL–NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of CB-103. We observed a favorable safety profile with good tolerability and biological activity but limited clinical single-agent antitumor activity. Some disease stabilization was observed among an aggressive NOTCH-mutant ACC type-I subgroup where prognosis is poor and therapies are critically needed. Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs

A single-arm study design with non-inferiority and superiority time-to-event endpoints: a tool for proof-of-concept and de-intensification strategies in breast cancer

Clinical trial; Single-arm; SuperiorityEnsayo clínico; Un solo brazo; SuperioridadAssaig clínic; Un sol braç; SuperioritatDe-escalation trials in oncology evaluate therapies that aim to improve the quality of life of patients with low-risk cancer by avoiding overtreatment. Non-inferiority randomized trials are commonly used to investigate de-intensified regimens with similar efficacy to that of standard regimens but with fewer adverse effects (ESMO evidence tier A). In cases where it is not feasible to recruit the number of patients needed for a randomized trial, single-arm prospective studies with a hypothesis of non-inferiority can be conducted as an alternative. Single-arm studies are also commonly used to evaluate novel treatment strategies (ESMO evidence tier B). A single-arm design that includes both non-inferiority and superiority primary objectives will enable the ranking of clinical activity and other parameters such as safety, pharmacokinetics, and pharmacodynamics data. Here, we describe the statistical principles and procedures to support such a strategy. The non-inferiority margin is calculated using the fixed margin method. Sample size and statistical analyses are based on the maximum likelihood method for exponential distributions. We present example analyses in metastatic and adjuvant settings to illustrate the usefulness of our methodology. We also explain its implementation with nonparametric methods. Single-arm designs with non-inferiority and superiority analyses are optimal for proof-of-concept and de-escalation studies in oncology.The authors declare that this study received funding from Medica Scientia Innovation Research (MEDSIR)

Organizational culture and performance in Spanish-Moroccan strategic alliances

This study was funded by the Spanish Agency for International Cooperation for Development through the "Interuniversity Cooperation and Scientific Research" for the years 2007 and 2008 for the project A/021477/98 "Survey of Business Relationships between Spain and Morocco: the case of strategic alliances.”Strategic alliances have been used by companies to expand its business to emerging economies, specifically to countries with Arabic culture. Organizational culture is an issue that affects the management of the alliance and their performance, particularly affects the member satisfaction. These issues have been widely discussed in the doctrine in large companies, but not in SMEs and even less in the field of business relations between developed and emerging countries. Therefore, the purpose of this study was to characterize the organizational culture that rules on Spanish-Moroccan SME’s strategic alliances and analyze the impact that the choice of a particular organizational culture has on the whole partner’s satisfaction. The results indicated that the greater involvement of staff and the more centralized decision making, the more satisfied the partners are in these strategic alliances

Potential Role of Insulin Growth-Factor-Binding Protein 2 as Therapeutic Target for Obesity-Related Insulin Resistance

Evidence from observational and in vitro studies suggests that insulin growth-factor-binding protein type 2 (IGFBP2) is a promising protein in non-communicable diseases, such as obesity, insulin resistance, metabolic syndrome, or type 2 diabetes. Accordingly, great efforts have been carried out to explore the role of IGFBP2 in obesity state and insulin-related diseases, which it is typically found decreased. However, the physiological pathways have not been explored yet, and the relevance of IGFBP2 as an important pathway integrator of metabolic disorders is still unknown. Here, we review and discuss the molecular structure of IGFBP2 as the first element of regulating the expression of IGFBP2. We highlight an update of the association between low serum IGFBP2 and an increased risk of obesity, type 2 diabetes, metabolic syndrome, and low insulin sensitivity. We hypothesize mechanisms of IGFBP2 on the development of obesity and insulin resistance in an insulin-independent manner, which meant that could be evaluated as a therapeutic target. Finally, we cover the most interesting lifestyle modifications that regulate IGFBP2, since lifestyle factors (diet and/or physical activity) are associated with important variations in serum IGFBP2

Alkaline pretreatment of Mexican pine residues for bioethanol production

The locally sourced residue samples of Pinus arizonica, Pinus cooperi, and Pinus durangensis from the state of Durango in Mexico were analyzed for optimal yield of ethanol production. The samples were mixed at an equal proportion using a particle size of 0.59 mm. Each individual mixture was pretreated with either NaOH or Ca (OH)2 (at 0.5, 1.0 and 1.5% w/v) for periods of 30, 60, and 90 min at 60, 90, and 120°C. The pretreated blending was subjected to enzymatic hydrolysis for 130 h at 80 rpm and 50°C with an enzymatic load of 25 filter paper units (FPU) and 50 IU β-glucosidase per gramme of cellulose to obtain a maximum yield of reducing sugars (RS) with NaOH subject at 120°C for 90 min. The results show that the hydrolysis yield depends on temperature and alkali concentration particularly (NaOH), which increased from 2.0 to 3.5% w/v. The best yield of glucose (41.33% w/w) was obtained using a pretreatment of 2.5% NaOH for 90 min, 120°C, and a hydrolysis residence time of 130 h. The removal of lignin and hemicellulose acetylation was observed to have influence on the enzymatic digestibility of cellulose. This process could theoretically produce a maximum yield of 90.19% of ethanol / substrate (glucose) and about 80 L of bioethanol per dry ton of woody biomass from pine residues.Keywords: Lignocellulosic biomass, alkaline pretreatment, enzymatic hydrolysis, fermentable sugars, fermentationAfrican Journal of Biotechnology Vol. 12(31), pp. 4956-496

Circulating miRNAs as predictive biomarkers of type 2 diabetes mellitus development in coronary heart disease patients fromt he CORDIOPREV study

Circulating microRNAs (miRNAs) have been proposed as type 2 diabetes biomarkers, and they may be a more sensitive way to predict development of the disease than the currently used tools. Our aim was to identify whether circulating miRNAs, added to clinical and biochemical markers, yielded better potential for predicting type 2 diabetes. The study included 462 non-diabetic patients at baseline in the CORDIOPREV study. After a median follow-up of 60 months, 107 of them developed type 2 diabetes. Plasma levels of 24 miRNAs were measured at baseline by qRT-PCR, and other strong biomarkers to predict diabetes were determined. The ROC analysis identified 9 miRNAs, which, added to HbA1c, have a greater predictive value in early diagnosis of type 2 diabetes (AUC = 0.8342) than HbA1c alone (AUC = 0.6950). The miRNA and HbA1cbased model did not improve when the FINDRISC was included (AUC = 0.8293). Cox regression analyses showed that patients with low miR-103, miR-28-3p, miR-29a, and miR-9 and high miR-30a-5p and miR-150 circulating levels have a higher risk of disease (HR = 11.27; 95% CI = 2.61–48.65). Our results suggest that circulating miRNAs could potentially be used as a new tool for predicting the development of type 2 diabetes in clinical practice

Anteproyecto arquitectónico de complejo eco-turístico en Mina de Plata, Murra, Departamento de Nueva Segovia.

Presenta un anteproyecto arquitectónico de un complejo eco-turístico en la comarca Mina de Plata, municipio de Murra, Departamento de Nueva Segovia. Con este proyecto se pretende mejorar la economía local ofreciendo servicios de calidad a los turistas nacionales y extranjeros que visiten la zona