Luminescent Pt-II and Pt-IV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N')PtIV compounds derived from amine- imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross57 resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs

Effect of inactivated nature-derived microbial composition on mouse immune system

Introduction: The hygiene hypothesis suggests that decrease in early life infections due to increased societal-level hygiene standards subjects one to allergic and autoimmune diseases. In this report, we have studied the effect of sterilized forest soil and plant-based material on mouse immune system and gut microbiome. Methods: Inbred C57Bl/6 mice maintained in normal sterile environment were subjected to autoclaved forest soil-derived powder in their bedding for 1 h a day for 3 weeks. Immune response was measured by immune cell flow cytometry, serum cytokine enzyme-linked immunoassay (ELISA) and quantitative polymerase chain reaction (qPCR) analysis. Furthermore, the mouse gut microbiome was analyzed by sequencing. Results: When compared to control mice, mice treated with soil-derived powder had decreased level of pro-inflammatory cytokines namely interleukin (IL)-17F and IL-21 in the serum. Furthermore, splenocytes from mice treated with soil-derived powder expressed less IL-1b, IL-5, IL-6, IL-13, and tumor necrosis factor (TNF) upon cell activation. Gut microbiome appeared to be stabilized by the treatment. Conclusions: These results provide insights on the effect of biodiversity on murine immune system in sterile environment. Subjecting mice to soil-based plant and microbe structures appears to elicit immune response that could be beneficial, for example, in type 2 inflammation-related diseases, that is, allergic diseases.Peer reviewe

Ansiedad dimensional: Un análisis desde la teoría clásica del formulario autodiligenciado de Zung

RESUMEN Introducción: A pesar del uso extendido del formulario de Zung para ansiedad no se encontraron artículos sobre la invarianza de la prueba. Objetivo: Establecer la invarianza por género del formulario para ansiedad autodiligenciado de Zung desde la Teoría Clásica. Métodos: Muestra no aleaotoria de 336 mujeres y 205 hombres estudiantes de varias universidades colombianas que diligenciaron el formulario. El análisis se realizo con análisis confimatorio de factores. Se investigó la invarianza dimensional, de configuración y métrica. Resultados: Se encontró que las invarianzas dimensional y de configuración se cumplen al demostrarse que el constructo es unidimensional en los 2 géneros, seleccionando los modelos con el Criterio de información Bayesiano y que la carga de los ítems es en general alta. No así la invarianza métrica para la cual debieron eliminarse 9 ítems para lograr invarianza en las cargas. Conclusión: El formulario de Zung presenta invarianzas dimensional, de configuración y métrica con 11 ítems. Salud UIS 2011; 43 (2): 159-166 Palabras clave: Formulario autodiligenciado de Zung, invarianza, análisis de factores   ABSTRACT Introduction: There is not a published report of the invariance of anxiety Zung test, although is widely used. Objective: To stablish gender invariance of the Zung self-rating anxiety scale using Classical Test Theory. Methods: A non random sample of 336 women and 205 men students from several colombian universities that answered the scale. Confirmatory factor analysis was performed. Dimensional, configurational and metric invariance were investigated. Results: Dimensional and configurational invariance are met because for both genders theres is one dimension, using Bayesian Information Crietria as the model selection strategy, and the loadings are generally high. The metric invariance was obtained after deleting 9 items. Conclusion: Eleven items of The Zung self-rating anxiety scale show dimensional, configurational and metric invariance. Salud UIS 2011; 43 (2): 159-166 Keywords: The Zung self-rating scale, invariance, factor analysi

Ansiedad dimensional: Un análisis desde la teoría clásica del formulario autodiligenciado de Zung

RESUMEN Introducción: A pesar del uso extendido del formulario de Zung para ansiedad no se encontraron artículos sobre la invarianza de la prueba. Objetivo: Establecer la invarianza por género del formulario para ansiedad autodiligenciado de Zung desde la Teoría Clásica. Métodos: Muestra no aleaotoria de 336 mujeres y 205 hombres estudiantes de varias universidades colombianas que diligenciaron el formulario. El análisis se realizo con análisis confimatorio de factores. Se investigó la invarianza dimensional, de configuración y métrica. Resultados: Se encontró que las invarianzas dimensional y de configuración se cumplen al demostrarse que el constructo es unidimensional en los 2 géneros, seleccionando los modelos con el Criterio de información Bayesiano y que la carga de los ítems es en general alta. No así la invarianza métrica para la cual debieron eliminarse 9 ítems para lograr invarianza en las cargas. Conclusión: El formulario de Zung presenta invarianzas dimensional, de configuración y métrica con 11 ítems. Salud UIS 2011; 43 (2): 159-166 Palabras clave: Formulario autodiligenciado de Zung, invarianza, análisis de factores   ABSTRACT Introduction: There is not a published report of the invariance of anxiety Zung test, although is widely used. Objective: To stablish gender invariance of the Zung self-rating anxiety scale using Classical Test Theory. Methods: A non random sample of 336 women and 205 men students from several colombian universities that answered the scale. Confirmatory factor analysis was performed. Dimensional, configurational and metric invariance were investigated. Results: Dimensional and configurational invariance are met because for both genders theres is one dimension, using Bayesian Information Crietria as the model selection strategy, and the loadings are generally high. The metric invariance was obtained after deleting 9 items. Conclusion: Eleven items of The Zung self-rating anxiety scale show dimensional, configurational and metric invariance. Salud UIS 2011; 43 (2): 159-166 Keywords: The Zung self-rating scale, invariance, factor analysi

Long-Term Increased Carnitine Palmitoyltransferase 1A Expression in Ventromedial Hypotalamus Causes Hyperphagia and Alters the Hypothalamic Lipidomic Profile

Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. Carnitine palmitoyltransferase (CPT) 1A is the rate-limiting enzyme in mitochondrial fatty acid boxidation and it has been proposed as a crucial mediator of fasting and ghrelin orexigenic signalling. However, the relationship between changes in CPT1A activity and the intracellular downstream effectors in the VMH that contribute to appetite modulation is not fully understood. To this end, we examined the effect of long-term expression of a permanently activated CPT1A isoform by using an adeno-associated viral vector injected into the VMH of rats. Peripherally, this procedure provoked hyperghrelinemia and hyperphagia, which led to overweight, hyperglycemia and insulin resistance. In the mediobasal hypothalamus (MBH), long-term CPT1AM expression in the VMH did not modify acyl-CoA or malonyl-CoA levels. However, it altered the MBH lipidomic profile since ceramides and sphingolipids increased and phospholipids decreased. Furthermore, we detected increased vesicular c-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions, both transporters involved in this orexigenic signal. Taken together, these observations indicate that CPT1A contributes to the regulation of feeding by modulating the expression of neurotransmitter transporters and lipid components that influence the orexigenic pathways in VMH

SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L

The long isoform of Fas apoptosis inhibitory molecule (FAIM-L) is a neuron-specific death receptor antagonist that modulates apoptotic cell death and mechanisms of neuronal plasticity. FAIM-L exerts its antiapoptotic action by binding to X-linked inhibitor of apoptosis protein (XIAP), an inhibitor of caspases, which are the main effectors of apoptosis. XIAP levels are regulated by the ubiquitin-proteasome pathway. FAIM-L interaction with XIAP prevents the ubiquitination and degradation of the latter, thereby allowing it to inhibit caspase activation. This interaction also modulates non-apoptotic functions of caspases, such as the endocytosis of AMPA receptor (AMPAR) in hippocampal long-term depression (LTD). The molecular mechanism of action exerted by FAIM-L is unclear since the consensus binding motifs are still unknown. Here, we performed a two-hybrid screening to discover novel FAIM-L-interacting proteins. We found a functional interaction of SIVA-1 with FAIM-L. SIVA-1 is a proapoptotic protein that has the capacity to interact with XIAP. We describe how SIVA-1 regulates FAIM-L function by disrupting the interaction of FAIM-L with XIAP, thereby promoting XIAP ubiquitination, caspase-3 activation and neuronal death. Furthermore, we report that SIVA-1 plays a role in receptor internalization in synapses. SIVA-1 is upregulated upon chemical LTD induction, and it modulates AMPAR internalization via non-apoptotic activation of caspases. In summary, our findings uncover SIVA-1 as new functional partner of FAIM-L and demonstrate its role as a regulator of caspase activity in synaptic function

Learning to make informed health choices : Protocol for a pilot study in schools in Barcelona

The Informed Health Choices (IHC) project has developed learning resources to teach primary school children (10 to 12-year-olds) to assess treatment claims and make informed health choices. The aim of our study is to explore both the students' and teachers' experience when using these resources in the context of Barcelona (Spain). During the 2019-2020 school year, we will conduct a pilot study with 4 th and 5 th-year primary school students (9 to 11-year-olds) from three schools in Barcelona. The intervention in the schools will include: 1) assessment of the IHC resources by the teachers before the lessons, 2) non-participatory observations during the lessons, 3) semi-structured interviews with the students after a lesson, 4) assessment of the lessons by the teachers after a lesson, 5) treatment claim assessment by the students at the end of the lessons, and 6) assessment of the IHC resources by the teachers at the end of the lessons. We will use ad hoc questionnaires and guides to register the data. We will perform a quantitative and qualitative analysis of the data to explore understandability, desirability, suitability, usefulness, facilitators and barriers of the resources. The most relevant results will be discussed and some recommendations on how to use, how to adapt (if needed), and how to implement the IHC resources to this context will be agreed. The findings of the contextualization activities could inform the design of a cluster-randomised trial, to determine the effectiveness of the IHC resources in this context prior to scaling-up its use. The study protocol has obtained an approval exemption from the Ethics Committee of the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain)

SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L

Altres ajuts: This work was funded by grants awarded by the Spanish "Ministerio de Economía y Competitividad" , the Generalitat de Catalunya, and the Fundació La Marató de TV3 (201414-30) to J.X.C. E.C. is supported by a predoctoral fellowship from the Vall d'Hebron Research Institute (VHIR). R.B. is supported by a predoctoral fellowship from the Spanish "Ministerio de Economía y Competitividad".The long isoform of Fas apoptosis inhibitory molecule (FAIM-L) is a neuron-specific death receptor antagonist that modulates apoptotic cell death and mechanisms of neuronal plasticity. FAIM-L exerts its antiapoptotic action by binding to X-linked inhibitor of apoptosis protein (XIAP), an inhibitor of caspases, which are the main effectors of apoptosis. XIAP levels are regulated by the ubiquitin-proteasome pathway. FAIM-L interaction with XIAP prevents the ubiquitination and degradation of the latter, thereby allowing it to inhibit caspase activation. This interaction also modulates non-apoptotic functions of caspases, such as the endocytosis of AMPA receptor (AMPAR) in hippocampal long-term depression (LTD). The molecular mechanism of action exerted by FAIM-L is unclear since the consensus binding motifs are still unknown. Here, we performed a two-hybrid screening to discover novel FAIM-L-interacting proteins. We found a functional interaction of SIVA-1 with FAIM-L. SIVA-1 is a proapoptotic protein that has the capacity to interact with XIAP. We describe how SIVA-1 regulates FAIM-L function by disrupting the interaction of FAIM-L with XIAP, thereby promoting XIAP ubiquitination, caspase-3 activation and neuronal death. Furthermore, we report that SIVA-1 plays a role in receptor internalization in synapses. SIVA-1 is upregulated upon chemical LTD induction, and it modulates AMPAR internalization via non-apoptotic activation of caspases. In summary, our findings uncover SIVA-1 as new functional partner of FAIM-L and demonstrate its role as a regulator of caspase activity in synaptic function

Conocimientos, actitudes y prácticas sobre virus de papiloma humano (VPH) y cáncer de cuello uterino en mujeres de 30 y más años de edad, de un barrio ribereño de Asunción, (Bañado Sur). 2012

Introduction: Cervix cancer is a public health problem in Paraguay. Objective: To determine knowledge, attitudes and practices on human papilloma virus (HPV) and uterine cervix cancer in women from 12 Family Health Units (FHU) of the Bañado Sur- Asunción, April-October 2,012 period. Methodology: Descriptive cross-sectional study that used self-administered structured questionnaires. Results: The mean age was 42 years, most of them cohabitated or were married (70%); 65% had elementary and secondary education and 56% was housewife; 83% had medical insurance and 78% heard about uterine cervix cancer, 74% of them in health posts. Only 10% knew HPV and related it to a disease, 90% heard about Papanicolaou test, but only 27% knew what is, 90% showed favorable attitude and 56% favorable practices in relation to the disease prevention. Conclusion: The study provided information on the perception that a population of women from a marginal zone of the capital have in relation to cervical cancer and its main risk factor. This will allow increasing the supply of prevention services for this type of cancer, along with promoting inter-institutional and inter-sectorial work on the prevention and control of this disease in the country.Introducción: El cáncer de cuello uterino es un problema de salud pública en Paraguay. Objetivo: Determinar conocimientos, actitudes y prácticas sobre virus del papiloma humano (VPH) y cáncer de cuello uterino en mujeres de 12 Unidades de Salud Familiar (USF) de Bañado Sur-Asunción, periodo abril-octubre 2012. Metodología: Estudio descriptivo de corte transversal, utilizando cuestionario estructurado autoadministrado. Resultados: La edad promedio de las encuestadas fue 42 años, la mayoría en unión libre o casadas (70%); 65% tienen educación básica y media, 56% son amas de casa. El 83% tienen seguro médico; 78% escuchó hablar sobre cáncer de cuello uterino, 74% de éstas en los centros de salud. El 10% de las encuestadas conoce el VPH y lo relaciona con la enfermedad, 90 % escuchó hablar sobre la prueba de Papanicolaou, el 27 % de ellas sabe en qué consiste; 90% de las mujeres demostró actitud favorable y 56% prácticas favorables respecto a la prevención de la enfermedad. Conclusión: El estudio permite conocer la percepción que tiene una población de mujeres de un barrio marginal de la capital del país, respecto al cáncer de cuello uterino y el principal factor de riesgo que lo produce, a fin de incrementar la prestación de servicios de prevención de este tipo de cáncer, además de propiciar el trabajo interinstitucional e intersectorial en la prevención y control de la enfermedad en el país