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)

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

El Fan Page como estrategia de aprendizaje para la comprensión lectora de la obra «La Mujer Habitada» de Gioconda Belli (1988)

El presente trabajo investigativo describe la estrategia de aprendizaje “El Fan Page” para la comprensión lectora de novelas. El propósito de esta investigación es explicar el uso de una Fan Page como estrategia que contribuya a la comprensión lectora de la obra «La Mujer Habitada», con el fin de fortalecer la motivación y las macro habilidades de la comunicación de los estudiantes en el proceso de aprendizaje. El tema de investigación se seleccionó tomando en cuenta algunas experiencias vividas en las aulas de clase, durante las prácticas de profesionalización, donde se observó que la mayor parte de los estudiantes tienen acceso a un celular o Tablet con internet. Por otro lado, motivó el estudio del lanzamiento del aula virtual del MINED, como parte de la ejecución del programa tecnología educativa e igualmente, la estrategia está sugerida en temas y planes de estudio que expresa textualmente “La novela en otros formatos narrativos” (YouTube, audio libros) (MINED, 2019). La investigación se realizó con base al método de recopilación bibliográfica y registros documentales, luego se realizó la lectura y revisión de la información para seleccionar los aspectos más vinculados a la estrategia que se plantea: las definiciones, los pasos para crear una Fan Page y la metodología a seguir al momento de utilizarse en el aula de clase. En conclusión, una Fan Page es una estrategia de aprendizaje fácil de aplicar, adaptable a centros educativos que poseen aulas tecnológicas

Conocimientos, actitudes y prácticas sobre el Papanicolaou de hombre y mujeres de 15 a 49 años de la Comunidad El Carrizo, San José de Cusmapa Madríz II semestre 2018

El presente estudio tiene como objetivo general determinar los conocimientos, actitudes, prácticas que tienen los hombre y mujeres de 15-49 años de la comunidad del El Carrizo del municipio de San José de Cusmapa, Madriz, en el período comprendido del II semestre 2018. Estudio de tipo descriptivo, de corte transversal; se seleccionó al azar de una población t o t a l de 1106 habitantes de la comunidad entre hombres y mujeres, una muestra de 171 hombres y mujeres mediante una fórmula estadística. Se diseñó una encuesta para la evaluación del conocimiento, actitudes, prácticas en relación con la prueba de Papanicolaou, obteniendo los resultados de una fuente de información primaria. La información obtenida se procesó mediante el programa estadístico de EPI INFO, posteriormente representada en tablas y gráficos. La mayoría de la población del estudio se ubican en el grupo de edad de 20-34 años, predominando el sexo femenino, con un estado civil en su mayoría de unión estable, con un grado de escolaridad que en la mayoría tienen más de primaria incompleta, la mayoría son amas de casa y profesan la religión católica. En general el nivel de conocimiento es bueno, conocen la utilidad de la prueba, reconocen la importancia de la toma de la muestra, conocen sobre las condiciones que deben de tener para realizarse la prueba de Papanicolaou,saben que toda mujer que inicio vida sexual activa debe de realizarse la prueba de Papanicolaou. La mayor parte de la población en el estudio presentó un nivel de actitud favorable. En referencia a las prácticas la negación de la prueba del Pap encontramos con mayor frecuencia: el pena/vergüenza a la prueba, poca importancia. Las mujeres recogen los resultados y los conocen. En su mayoría las prácticas se clasificaron adecuadas. La información sobre el pap la han obtenido en su mayoría a través de los trabajadores de la salud y medios de comunicació