The Open acidification Tank Controller: An open-source device for the control of pH and temperature in ocean acidification experiments.

Ocean acidification is the process by which the increase in atmospheric CO2 causes a corresponding increase in seawater CO2 and results in lowering the seawater pH. While this process is likely to have substantial impacts on marine ecosystems, research into the effect of ocean acidification has been limited by the high costs of quality tools to perform ocean acidification treatments in the lab. The Open Acidification Tank Controller is designed to reduce the cost of ocean acidification research by providing a device that can monitor and control pH and temperature of aquaria as well as or better than commercially available research-grade devices, but for less than $250 USD per aquarium. The device is centered around an Arduino Mega 2560 and is assembled into a 3D printed housing. It monitors pH using a BNC glass pH probe and temperature using a three-wire waterproof PT100 temperature sensor. The Open Acidification Tank Controller also features web-based parameter reporting, and data storage to a micro-SD card. This device can hold aquarium pH and temperature at given setpoints, ramp between two values over a user-defined time period, or produce a sine-wave fluctuation in values.

Clinical Characteristics, Treatment Persistence, and Outcomes Among Patients With COPD Treated With Single- or Multiple-Inhaler Triple Therapy: A Retrospective Analysis in Spain.

BACKGROUND: COPD is a leading cause of death and disability. COPD therapy goals include reducing exacerbations and improving symptom control. Single-inhaler triple therapy (SITT) or multiple-inhaler triple therapy (MITT) is indicated for patients with frequent exacerbations despite bronchodilator therapy. No available evidence compares SITT vs MITT in Spain in terms of treatment persistence, exacerbations, and other outcomes. RESEARCH QUESTION: Do COPD patients in Spain initiating SITT vs MITT have improved persistence, exacerbations, and health care resource utilization? STUDY DESIGN AND METHODS: This real-world, observational, retrospective cohort study analyzed electronic health records in the Spanish National Healthcare System BIG-PAC database to identify COPD patients aged ≥ 40 years initiating SITT or MITT (using two or three inhalers) between June 1, 2018 and December 31, 2019. Comparative data on persistence (allowing up to 60 days without prescription refill), exacerbation rates, and health care resource utilization and costs during 12-month follow-up were analyzed. Multivariate adjusted analyses were performed. RESULTS: Eligible patients (N = 4,625) initiating SITT (n = 1,011) or MITT (n = 3,614) had a mean age of 70.9 years; most were male (73.9%) with mainly moderate (62.0%) or severe (26.5%) airflow limitation. Between-cohort baseline characteristics were similar. At 12-month follow-up, SITT patients had higher persistence (hazard ratio [HR] = 1.37; 95% CI = 1.22-1.53; P < .001), reduced risk of exacerbations (HR = 0.68; 95% CI = 0.61-0.77; P = .001), and lower all-cause mortality risk (HR = 0.67; 95% CI = 0.63-0.71, P = .027), compared with MITT patients. SITT was associated with significantly reduced health care resource use (mean annual cost savings: €403 vs MITT). For both SITT and MITT, persistence was associated with improved exacerbation rates vs nonpersistence, and substantial adjusted mean annual cost savings (€2,115 and €2,700, respectively). INTERPRETATION: Patients initiating SITT had a clinically relevant improvement in persistence leading to reductions in mortality, incidence of exacerbations, and health care resource use with consequent mean cost savings.

Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer.

Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08-2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17-2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.

Does hemofiltration protect the brain after head trauma? An experimental study in rabbits.

BACKGROUND: Traumatic brain injury (TBI) is one of the most frequent and severe neurological diseases. In the last few decades, significant advances have been made in TBI pathophysiology and monitoring, however new treatments have not emerged. Although the central nervous system (CNS) has been historically defined as an immunologically privileged organ, recent studies show the increasingly predominant role of inflammatory and apoptotic phenomena in the pathogenesis of TBI. Inflammatory response mediators can be eliminated with continuous renal replacement therapies (CRRT). Our aim was to investigate whether hemofiltration protects the brain after head trauma in an experimental study in animals. METHODS AND RESULTS: A model of TBI and CVVH was performed in anesthetized New Zealand white rabbits without acute renal failure. The experimental group TBI ( +)-CVVH ( +) was compared with a TBI ( +)-CVVH (-) and a TBI (-)-CVVH ( +) control groups. Rabbits were assessed immediately (NES1) and 24 h hours after (NES2) TBI and/or CVVH using a functional Neurological Evaluation Score (NES) and histology of the brains after sacrifice. There was evidence to support a difference of NES1 comparing with the TBI (-)-CVVH ( +), but not with TBI ( +)-CVVH (-) with only 15% of the rabbits treated with CVVH and TBI showing a favorable neurological course. The final neurological outcome (mortality at 24 h) was 0%, 22% and 53% in the TBI(-) + CVVH( +), TBI( +)-CVVH(-) and TBI( +)-CVVH( +) groups respectively. The use of hemofiltration before or after TBI did not make a difference in regards the outcome of the rabbits. There was evidence in the histology to support an increase of mild ischemia, hemorrhage and edema in the experimental group compared with the other two groups. CONCLUSIONS: CVVH in rabbits without renal failure used with the intention to protect the brain may worsen the prognosis in TBI.

Desarrollo y evaluación de las propiedades psicométricas de la escala Etapas de Cambio en la Reducción del Sobrepeso Infantil (ECARSI) / Development and evaluation of the psychometric properties of the Stage to Change in the Reduction of Childhood Overweight Scale (SCROS)

INTRODUCCIÓN: el sobrepeso y la obesidad infantil alrededor del mundo siguen en aumento; sin embargo, los padres de niños con sobrepeso y obesidad suelen subestimarlos, por lo cual no se preocupan por los riesgos que se asocian al sobrepeso y la obesidad, lo cual obstaculiza su tratamiento oportuno. OBJETIVO: el objetivo del presente trabajo fue desarrollar y evaluar las características psicométricas de la escala "Etapas de cambio para la reducción del sobrepeso Infantil" (ECARSI). MÉTODO: participaron un total de 484 mujeres con hijos en edad escolar, clasificados con sobrepeso el 34,1 % y con obesidad el 65,9 %, quienes respondieron la escala. Se realizaron análisis de discriminación de ítems y de consistencia interna por medio de la alfa de Cronbach y el análisis factorial exploratorio. RESULTADOS: se obtuvo una consistencia interna, por medio de la alfa de Cronbach, de 0,789 con 16 elementos; el AFE arrojó 4 factores con valores propios mayores de 1, que explican el 62,89 % de la varianza total. Los ítems se agruparon en las siguientes dimensiones: Precontemplación (4 ítems), Contemplación (4 ítems), Preparación (4 ítems) y Acción (4 ítems). CONCLUSIONES: la ECARSI cuenta con adecuados índices de confiabilidad y evidencias de validez para evaluar la etapa de disposición al cambio en que se encuentran los padres de los niños(as) con sobrepeso y obesidad, lo cual permitirá un mejor tamizaje para determinar el tipo de intervención más pertinente para cada niño(a) y su familia

OBJECTIVES: the purpose of this paper is to evaluate the psychometric properties of the "Stage of change in the reduction of childhood overweight" scale by means of an exploratory factor analysis, and its reliability. This questionnaire is a new measure to identify the stage of awareness of the problem, and the willingness to change, in parents of children with overweight and obesity, based on the transtheoretical model by Prochaska and DiClemente (1983). METHOD: the study involved 484 women with school-aged children, of which 65.9 % were classified with obesity, and 34.1 % with overweight. RESULTS: the SCROS psychometric characteristics were assessed, obtaining an internal consistency of 0.789 using Cronbach's alpha with 16 elements (items). By means of the Exploratory Factor Analysis four factors were obtained with eigen values higher than one, which explained 62.89 % of the total variance. The items were grouped in the following dimensions: Preparation (4 items), Precontemplation (4 items), Contemplation (4 items), and Action (4 items). CONCLUSIONS: the SCROS is a valid and reliable questionnaire to evaluate the stage in which parents of children with overweight and obesity problems are located, which will allow us to design more suitable interventions for these children and their families

[Development and evaluation of the psychometric properties of the Stage to Change in the Reduction of Childhood Overweight Scale (SCROS)]. / Desarrollo y evaluación de las propiedades psicométricas de la escala Etapas de Cambio en la Reducción del Sobrepeso Infantil (ECARSI).

INTRODUCTION: Objectives: the purpose of this paper is to evaluate the psychometric properties of the "Stage of change in the reduction of childhood overweight" scale by means of an exploratory factor analysis, and its reliability. This questionnaire is a new measure to identify the stage of awareness of the problem, and the willingness to change, in parents of children with overweight and obesity, based on the transtheoretical model by Prochaska and DiClemente (1983). Method: the study involved 484 women with school-aged children, of which 65.9 % were classified with obesity, and 34.1 % with overweight. Results: the SCROS psychometric characteristics were assessed, obtaining an internal consistency of 0.789 using Cronbach's alpha with 16 elements (items). By means of the Exploratory Factor Analysis four factors were obtained with eigen values higher than one, which explained 62.89 % of the total variance. The items were grouped in the following dimensions: Preparation (4 items), Precontemplation (4 items), Contemplation (4 items), and Action (4 items). Conclusions: the SCROS is a valid and reliable questionnaire to evaluate the stage in which parents of children with overweight and obesity problems are located, which will allow us to design more suitable interventions for these children and their families.

INTRODUCCIÓN: Introducción: el sobrepeso y la obesidad infantil alrededor del mundo siguen en aumento; sin embargo, los padres de niños con sobrepeso y obesidad suelen subestimarlos, por lo cual no se preocupan por los riesgos que se asocian al sobrepeso y la obesidad, lo cual obstaculiza su tratamiento oportuno. Objetivo: el objetivo del presente trabajo fue desarrollar y evaluar las características psicométricas de la escala "Etapas de cambio para la reducción del sobrepeso Infantil" (ECARSI). Método: participaron un total de 484 mujeres con hijos en edad escolar, clasificados con sobrepeso el 34,1 % y con obesidad el 65,9 %, quienes respondieron la escala. Se realizaron análisis de discriminación de ítems y de consistencia interna por medio de la alfa de Cronbach y el análisis factorial exploratorio. Resultados: se obtuvo una consistencia interna, por medio de la alfa de Cronbach, de 0,789 con 16 elementos; el AFE arrojó 4 factores con valores propios mayores de 1, que explican el 62,89 % de la varianza total. Los ítems se agruparon en las siguientes dimensiones: Precontemplación (4 ítems), Contemplación (4 ítems), Preparación (4 ítems) y Acción (4 ítems). Conclusiones: la ECARSI cuenta con adecuados índices de confiabilidad y evidencias de validez para evaluar la etapa de disposición al cambio en que se encuentran los padres de los niños(as) con sobrepeso y obesidad, lo cual permitirá un mejor tamizaje para determinar el tipo de intervención más pertinente para cada niño(a) y su familia.

Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer.

The inhibition of bromo- and extraterminal domains (BET) has shown an anti-proliferative effect in triple negative breast cancer (TNBC). In this article we explore mechanisms of resistance to BET inhibitors (BETi) in TNBC, with the aim of identifying novel ways to overcome such resistance. Two cellular models of acquired resistance to the BET inhibitor JQ1 were generated using a pulsed treatment strategy. MTT, colony formation, and cytometry assays revealed that BETi-resistant cells were particularly sensitive to PLK1 inhibition. Targeting of the latter reduced cell proliferation, especially in resistant cultures. Quantitative PCR analysis of a panel of mitotic kinases uncovered an increased expression of AURKA, TTK, and PLK1, confirmed by Western blot. Only pharmacological inhibition of PLK1 showed anti-proliferative activity on resistant cells, provoking G2/M arrest, increasing expression levels of cyclin B, pH3 and phosphorylation of Bcl-2 proteins, changes that were accompanied by induction of caspase-dependent apoptosis. JQ1-resistant cells orthotopically xenografted into the mammary fat pad of mice led to tumours that retained JQ1-resistance. Administration of the PLK1 inhibitor volasertib resulted in tumour regression. These findings open avenues to explore the future use of PLK1 inhibitors in the clinical setting of BETi-resistant patients.

Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an incurable disease where novel therapeutic strategies are needed. Proteolysis targeting chimeric (PROTAC) are novel compounds that promote protein degradation by binding to an ubiquitin ligase. In this work, we explored the antitumoral activity of two novel BET-PROTACs, MZ1 and ARV-825, in TNBC, ovarian cancer and in a BET inhibitor resistant model. METHODS: OVCAR3, SKOV3, BT549, MDA-MB-231 cell lines and the JQ1 resistant cell line MDA-MB-231R were evaluated. MTTs, colony-forming assay, three-dimensional cultures in matrigel, flow cytometry, and western blots were performed to explore the anti-proliferative effect and biochemical mechanism of action of MZ1 and ARV-825. In vivo studies included BALB/c nu/nu mice engrafted with MDA-MB-231R cells. RESULTS: The BET-PROTACs MZ1 and ARV-825 efficiently downregulated the protein expression levels of the BET protein BRD4, in MDA-MB-231 and MDA-MB-231R. MZ1 and ARV-825 also showed an antiproliferative effect on sensitive and resistant cells. This effect was corroborated in other triple negative (BT549) and ovarian cancer (SKOV3, OVCAR3) cell lines. MZ1 provoked G2/M arrest in MDA-MB-231. In addition, a profound effect on caspase-dependent apoptosis was observed in both sensitive and resistant cells. No synergistic activity was observed when it was combined with docetaxel, cisplatin or olaparib. Finally, in vivo administration of MZ1 rescued tumor growth in a JQ1-resistant xenograft model, reducing the expression levels of BRD4. CONCLUSIONS: Using both in vitro and in vivo approaches, we describe the profound activity of BET-PROTACs in parental and BETi-resistant TNBC models. This data provides options for further clinical development of these agents in TNBC.

Screening and Preliminary Biochemical and Biological Studies of [RuCl(p-cymene)(N,N-bis(diphenylphosphino)-isopropylamine)][BF4] in Breast Cancer Models.

Breast cancer is the second leading cause of cancer death worldwide. Despite progress in drug discovery, identification of the correct population is the limiting factor to develop new compounds in the clinical setting. Therefore, the aim of this study is to evaluate the effects of a new metallodrug, [RuCl(p-cymene)(N,N-bis(diphenylphosphino)-isopropylamine)][BF4] (pnpRu-14), as a lead pnp-Ru compound by screening and preliminary biochemical and biological studies in different breast cancer subtypes. The results show that complex pnpRu-14 is much more effective in promoting in vitro cytotoxic effects on HER2+ and RH+/HER2- breast cancer than the reference metallodrugs cisplatin, carboplatin, or RAPTA-C. It is important to highlight that pnpRu-14 shows an impressive cytotoxicity against BT474 cells. Caspase-dependent apoptosis is the mechanism of action for these compounds. In addition, treatment of SKBR3, BT474, T47D, and MCF7 cancer cells with pnpRu-14 caused an accumulation of cells in the G0/G1 phase cells. The human serum albumin, DNA, and H1 histones binding properties of the lead compound are reported. Pharmacokinetic and biodistribution studies show a quick absorption of pnpRu-14 in serum with no significant accumulation in any of the tested organs. This work provides evidence to support the preclinical and clinical development of pnpRu-14 in breast cancer.

Efecto de las estrategias de conservación sanguínea sobre la transfusión en pacientes con circulación extracorpórea / Effect of blood conservation strategies on the transfusion for patients with extracorporeal circulation

Introducción: Los pacientes sometidos a cirugía cardiaca son candidatos a recibir múltiples transfusiones sanguíneas homólogas por causas como el sangrado; el desarrollo de estrategias de conservación sanguínea (ECS) ha permitido proteger al paciente y limitar el riesgo de enfermedades infectocontagiosas, inmunológicas e inflamatorias. Objetivo: Analizar el efecto de las estrategias de conservación sanguínea sobre la transfusión de hemoderivados en los pacientes sometidos a cirugía cardiaca con derivación cardiopulmonar. Material y métodos: Estudio no experimental, exploratorio y transversal. Muestra no probabilística (n = 105) incluyó a pacientes adultos y pediátricos sometidos a cirugía cardiopulmonar con circulación extracorpórea (CEC) que utilizaron las ECS. Recolección de datos con cédula ex profeso de las variables demográficas, hematológicas y transfusionales, CEC, ECS. Datos analizados con frecuencias, porcentajes, medidas de tendencia central y de dispersión; así como prueba de Pearson, U de Mann Whitney y T de Student; significancia p < 0.05. Resultados: Prevalecieron las valvulopatías (42%), cirugías correctivas (98%), tipo de sangre O+. Se recuperaron 120,511 ml de sangre, en promedio 1,161 ml por paciente. Tiempo de CEC relacionado con volumen sangre transfundido (r = 0.318, p = 0.000). Mayor número ECS en la cirugía correctiva (Z = -2.467, p = 0.014), en pacientes con cirugías previas se recupera un mayor volumen (t = 2.072, p = 0.039), cantidad de sangre transfundida durante la CEC es mayor en la bomba centrífuga (t = -4.022, p = 0.000), pero no hay diferencias por sexo (t = 1.488, p = 0.137). La hemoglobina y hematocrito antes y después de la CEC fue semejante (p > 0.05). Conclusiones: Las ECS son una excelente opción de uso para evitar la transfusión homóloga, ya que logran recuperar una gran cantidad de sangre autóloga, potencializándose sus beneficios. (AU)

Background: Patients undergoing cardiac surgery are eligible to receive multiple blood transfusions counterparts for reasons such as bleeding; the development of blood conservation strategies (BCS) has protected the patient and limit the risk of infectious, immunologic and inflammatory diseases. Objective: To analyze the effect of blood conservation strategies on blood transfusion in patients undergoing cardiac surgery with cardiopulmonary bypass. Material and methods: Non-experimental, exploratory and transversal study. Probabilistic sample (n = 105) included adult and pediatric patients undergoing ardiopulmonary surgery with extracorporeal circulation (ECC) using the BCS. Data collection with charter expressly demographic, blood transfusion and variables, ECC, BCS. Data analyzed using frequencies, percentages, measures of central tendency and dispersion; and Pearson test, Mann Whitney and tudent t; significance p < 0.05. Results: A prevalence of valvular heart disease (42%), corrective surgeries (98%), blood type O+. 120,511 ml blood was recovered 1,161 ml per patient. ECC time related to transfused blood volume (r = 0.318, p = 0.000). BCS largest number in corrective surgery (Z = 2467, p = 0.014) in patients with previous surgeries increased volume (t = 2.072, p = 0.039), amount of blood transfused during ECC is recovered is greater in the pump centrifuge (t = 4,022, p = 0.000), but no sex differences (t = 1.488, p = 0.137). Hemoglobin and hematocrit before and after ECC was similar (p > 0.05). Conclusions: The BCS is an excellent choice for use to avoid homologous transfusion, and who manage to recover a large amount of autologous, enhancing its benefits. (AU)

Propiedades psicométricas de la Escala de Culpa por Obesidad o Sobrepeso para Niños y Adolescentes (ECOSNA).

Introducción: la obesidad es una enfermedad asociada a diferentes trastornos físicos y emocionales que inciden en la calidad de vida y que representan un problema de elevada prevalencia en el mundo. La etiología es múltiple y compleja; se ha señalado la culpa como consecuencia del sobrepeso y, al mismo tiempo, como factor asociado al aumento de peso. En México no existen instrumentos para evaluar la culpa por obesidad y sobrepeso en niños y adolescentes. Objetivos: analizar la fiabilidad y validez de la Escala de Culpa por Obesidad o Sobrepeso para Niños y Adolescentes (ECOSNA) en población de Morelia (México). Material y métodos: se elaboró una versión preliminar basada en la bibliografía que se sometió a la revisión de jueces expertos. La escala obtenida de 6 ítems se aplicó a una muestra de 1.418 estudiantes de educación básica de 7 a 15 años. Se realizó un análisis factorial confir- matorio y se estudió la relación de la escala con otras variables como autoestima, sintomatología depresiva y ansiedad. Resultados: la escala resultó unifactorial, se obtuvo un índice alfa de Cronbach de 0,853. La escala ECOSNA mostró una correlación moderada e inversa con la escala de autoestima, y directa y baja con la sintomatología depresiva y la ansiedad clínica. Conclusión: los datos empíricos indican que la escala presenta una validez y confiabilidad satisfactorias.

Propiedades psicométricas de la Escala de Culpa por Obesidad o Sobrepeso para Niños y Adolescentes (ECOSNA) / Psychometric properties of Guilt due to Obesity or Overweight Scale in Children and Adolescents (GOOSCA)

Introducción: la obesidad es una enfermedad asociada a diferentes trastornos físicos y emocionales que inciden en la calidad de vida y que representan un problema de elevada prevalencia en el mundo. La etiología es múltiple y compleja; se ha señalado la culpa como consecuencia del sobrepeso y, al mismo tiempo, como factor asociado al aumento de peso. En México no existen instrumentos para evaluar la culpa por obesidad y sobrepeso en niños y adolescentes. Objetivos: analizar la fiabilidad y validez de la Escala de Culpa por Obesidad o Sobrepeso para Niños y Adolescentes (ECOSNA) en población de Morelia (México). Material y métodos: se elaboró una versión preliminar basada en la bibliografía que se sometió a la revisión de jueces expertos. La escala obtenida de 6 ítems se aplicó a una muestra de 1.418 estudiantes de educación básica de 7 a 15 años. Se realizó un análisis factorial confirmatorio y se estudió la relación de la escala con otras variables como autoestima, sintomatología depresiva y ansiedad. Resultados: la escala resultó unifactorial, se obtuvo un índice alfa de Cronbach de 0,853. La escala ECOSNA mostró una correlación moderada e inversa con la escala de autoestima, y directa y baja con la sintomatología depresiva y la ansiedad clínica. Conclusión: los datos empíricos indican que la escala presenta una validez y confiabilidad satisfactorias (AU)

Introduction: Obesity is a disease associated with a number of physical and emotional disorders that affect the quality of life, and is a worldwide problem with high incidence rates. The cause of these diseases is complex and involves multiple factors. Guilt has been signaled as a consequence of obesity and at the same time as a factor contributing to weight gain. In Mexico there is no available method to evaluate the presence of guilt due to obesity and overweight in children and adults. Objectives: Analyze reliability and validity of a scale to measure guilt due to obesity or overweight in children and adolescents in the population of Morelia (Mexico). Material and methods: The construct of guilt was operationally defined and submitted for peer review judges. From the evaluation of judges a draft of 8 items that are applied to a sample of 1,418 elementary school students from 7 to 15 years. One confirmatory factor analysis was performed and the relationship of scale with other variables such as self-esteem, depressive symptoms and anxiety were studied. Results: The scale was unifactorial. The internal reliability was high. There was a moderate and inverse correlation with the scale of self-stem. A direct and low correlation was found with symptoms of depression and clinical anxiety. Conclusion: The empirical data shows that the validity and reliability of the scale are satisfactory (AU)

Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer.

Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.