Nucleolar detention of NONO shields DNA double-strand breaks from aberrant transcripts.

RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA-RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.

Characterization of mutant versions of the R-RAS2/TC21 GTPase found in tumors.

The R-RAS2 GTP hydrolase (GTPase) (also known as TC21) has been traditionally considered quite similar to classical RAS proteins at the regulatory and signaling levels. Recently, a long-tail hotspot mutation targeting the R-RAS2/TC21 Gln72 residue (Q72L) was identified as a potent oncogenic driver. Additional point mutations were also found in other tumors at low frequencies. Despite this, little information is available regarding the transforming role of these mutant versions and their relevance for the tumorigenic properties of already-transformed cancer cells. Here, we report that many of the RRAS2 mutations found in human cancers are highly transforming when expressed in immortalized cell lines. Moreover, the expression of endogenous R-RAS2Q72L is important for maintaining optimal levels of PI3K and ERK activities as well as for the adhesion, invasiveness, proliferation, and mitochondrial respiration of ovarian and breast cancer cell lines. Endogenous R-RAS2Q72L also regulates gene expression programs linked to both cell adhesion and inflammatory/immune-related responses. Endogenous R-RAS2Q72L is also quite relevant for the in vivo tumorigenic activity of these cells. This dependency is observed even though these cancer cell lines bear concurrent gain-of-function mutations in genes encoding RAS signaling elements. Finally, we show that endogenous R-RAS2, unlike the case of classical RAS proteins, specifically localizes in focal adhesions. Collectively, these results indicate that gain-of-function mutations of R-RAS2/TC21 play roles in tumor initiation and maintenance that are not fully redundant with those regulated by classical RAS oncoproteins.

Needs Assessment in Parents of Children Affected by Cancer: A Qualitative Perspective.

BACKGROUND: Childhood cancer is a "stressful experience" for parents in their role as caregivers. The aim of this study is to analyze the needs of a group of parents who have children diagnosed with cancer. The assessment looks at all areas of their daily life using a qualitative content analysis approach. METHODS: This study uses open questions designed to investigate the main problems faced by the parents of children with cancer. All the answers were analyzed using MAXQDA 20 software. The study was conducted according to the Consolidated Criteria for Reporting Qualitative Research (COREQ). RESULTS: The content analysis of the answers from 13 mothers and 7 fathers is presented. The main themes as priority areas of need were: "informal social support", "coping", "stressors/imbalances" and "health problems". Dissatisfaction with the support provided from the informal network was detected. Although the participants expressed active coping, they also exhibited helplessness, as well as concerns regarding possible sequelae and the impact of this situation on the family's economic/work context. Conciliation problems were a source of stress. All this is consistent with the participants suffering from a variety of health issues. CONCLUSIONS: the results show the effect of childhood cancer on different aspects of family life. They provide essential information for designing psychosocial interventions.

A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors.

A missense change in RRAS2 (Gln72 to Leu), analogous to the Gln61-to-Leu mutation of RAS oncoproteins, has been identified as a long-tail hotspot mutation in cancer and Noonan syndrome. However, the relevance of this mutation for in vivo tumorigenesis remains understudied. Here we show, using an inducible knockin mouse model, that R-Ras2Q72L triggers rapid development of a wide spectrum of tumors when somatically expressed in adult tissues. These tumors show limited overlap with those originated by classical Ras oncogenes. R-Ras2Q72L-driven tumors can be classified into different subtypes according to therapeutic susceptibility. Importantly, the most relevant R-Ras2Q72L-driven tumors are dependent on mTORC1 but independent of phosphatidylinositol 3-kinase-, MEK-, and Ral guanosine diphosphate (GDP) dissociation stimulator. This pharmacological vulnerability is due to the extensive rewiring by R-Ras2Q72L of pathways that orthogonally stimulate mTORC1 signaling. These findings demonstrate that RRAS2Q72L is a bona fide oncogenic driver and unveil therapeutic strategies for patients with cancer and Noonan syndrome bearing RRAS2 mutations.

When Your Child Has Cancer: A Path-Analysis Model to Show the Relationships between Flourishing and Health in Parents of Children with Cancer.

BACKGROUND: Childhood cancer is a disease with a psychosocial impact on parents who experience health problems and distress. Their reactions depend on the relationship of multiple factors. The objective of this paper is to evaluate the interrelationships between flourishing and the variables linked to the health and wellbeing of parents of children with cancer. METHODS: Mothers/fathers of children with cancer participated in an exploratory study in response to a series of questionnaires. Likert-type scales were used to measure perceived health, wellbeing, flourishing, stress, coping, and social support. RESULTS: Out of a total of 94 children, 138 parents (60 men/78 women) are represented. Participants show physical symptoms and an unstable coping pattern. A path analysis model is presented. As to the goodness of adjustment of the statistics used, good results were obtained. Flourishing tends to coexist with wellbeing, while flourishing coexists negatively with symptoms. There is an indirect relationship between flourishing and poor health. There is a positive relationship between flourishing and coping, as well as between flourishing and satisfaction with the support received (especially from sons/daughters). This support was negatively related to the subjective health report. CONCLUSIONS: Flourishing is shown as a healthy coping strategy. The results can enrich the development of psychosocial interventions aimed at promoting adequate adaptation.

Recent advances in the nucleolar responses to DNA double-strand breaks.

DNA damage poses a serious threat to human health and cells therefore continuously monitor and repair DNA lesions across the genome. Ribosomal DNA is a genomic domain that represents a particular challenge due to repetitive sequences, high transcriptional activity and its localization in the nucleolus, where the accessibility of DNA repair factors is limited. Recent discoveries have significantly extended our understanding of how cells respond to DNA double-strand breaks (DSBs) in the nucleolus, and new kinases and multiple down-stream targets have been identified. Restructuring of the nucleolus can occur as a consequence of DSBs and new data point to an active regulation of this process, challenging previous views. Furthermore, new insights into coordination of cell cycle phases and ribosomal DNA repair argue against existing concepts. In addition, the importance of nucleolar-DNA damage response (n-DDR) mechanisms for maintenance of genome stability and the potential of such factors as anti-cancer targets is becoming apparent. This review will provide a detailed discussion of recent findings and their implications for our understanding of the n-DDR. The n-DDR shares features with the DNA damage response (DDR) elsewhere in the genome but is also emerging as an independent response unique to ribosomal DNA and the nucleolus.

Identification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis.

Technical problems intrinsic to the purification of preribosome intermediates have limited our understanding of ribosome biosynthesis in humans. Addressing this issue is important given the implication of this biological process in human disease. Here we report a preribosome purification and tagging strategy that overcomes some of the existing technical difficulties. Using these tools, we find that the pre-40S precursors go through two distinct maturation phases inside the nucleolus and follow a regulatory step that precedes late maturation in the cytoplasm. This regulatory step entails the intertwined actions of both PARN (a metazoan-specific ribonuclease) and RRP12 (a phylogenetically conserved 40S biogenesis factor that has acquired additional functional features in higher eukaryotes). Together, these results demonstrate the usefulness of this purification method for the dissection of ribosome biogenesis in human cells. They also identify distinct maturation stages and metazoan-specific regulatory mechanisms involved in the generation of the human 40S ribosomal subunit.

Spanish Version of the Flourishing Scale (FS) on the Parents of Children With Cancer: A Validation Through Rasch Analysis.

The interest in the study of flourishing is due to the fact that it has been proven that it contributes to a good adjustment to the demands of the environment, relating to indicators of health and well-being. There are many researches that have tried to find out what dimensions make it up. The goal of this study is to validate the Spanish Version of The Flourishing Scale (FS), being the first time it is applied to Spanish parents of children with cancer. A total of 138 parents of children with cancer participated in a semi-structured interview. Through IBM SPSS and Winsteps descriptive analyzes and the internal consistency of the FS were calculated. Rasch analysis was used to study the dimensionality of the scale, the adjustment of each one of the items, the reliability values for the items and for the people, the validity of the construct, the functioning of the response categories, and the differential item functioning (DIF). The external construct validity of the FS was examined with associated measures. Results found that parents indicated a flourishing attitude (M = 3.85; sd = 0.63). We confirm that the FS maintains an adequate internal consistency and a unidimensional structure. We observed a good alignment between the question and the person's abilities as soon as a high reliability for the items. Although the sample is large enough to corroborate the difficulty hierarchy of the items, the construct validity could be improved by introducing items of moderate and high difficulty. On the other hand, the answer category 3 overlaps with the 2 and 4, so we propose possible solutions. Regarding a possible DIF, this exists in relation to "gender," "level of education" and "by the situation with respect to treatment." Finally, the convergent validity of the FS is demonstrated, there being a significant correlation with well-being, satisfaction with social support and coping. In general, the results show adequate psychometric properties of the Spanish version of the FS, so we recommend integrating it in psychosocial interventions aimed at parents of children with cancer, in order to provide them with resources to deal with the disease.

Repercusiones psicosociales del cáncer infantil: apoyo social y salud en familias afectadas / Psychosocial consequences of childhood cancer, social support and health in families affected

El propósito de esta investigación es analizar las repercusiones psicosociales que genera el cáncer infantil en los progenitores. Para ello, se han estudiado variables ligadas a síntomas físicos y psicológicos y el papel del apoyo social percibido sobre la salud. La muestra está compuesta por 51 padres pertenecientes a una asociación de familias afectadas de Almería (España), que respondieron a un cuestionario semiestructurado enviado por correo postal. Aunque los progenitores manifiestan fundamentalmente síntomas de cansancio, dolores de cabeza y nerviosismo, no se observan valores especialmente negativos respecto a su salud percibida y su satisfacción con la vida. Existen relaciones significativas entre el estrés ante situaciones asociadas a la enfermedad y la salud y el bienestar de los participantes. El apoyo social percibido del núcleo familiar incide significativa-mente en la salud. Los análisis de regresión permiten contrastar la relevancia de las variables asociadas al estrés y el apoyo de la pareja y de los hijos sobre la percepción de síntomas y bienestar. Estos resultados destacan la importancia de seguir analizando los factores psicosociales que afectan a las familias afectadas con la finalidad de favorecer su adaptación a la enfermedad y minimizar el impacto que esta puede tener en la salud. © 2015, Fundación Universitaria Konrad Lorenz.

The purpose of this study is to analyze the psychosocial impact on parents generated by childhood cancer. An evaluation was carried out in variables related to physical and psychological symptoms, and the role of perceived social support in their health. The sample consisted of 51 parents that belonged to an association of affected families from Almeria (Spain), who answered a semi-structured questionnaire sent by post. Although these parents showed fatigue, headaches and nervousness, they did not particularly give negative scores for perceived health and satisfaction with life. There are significant differences between stressful situations related to this illness and health and well-being of participants. Perceived social support of the family unit has a significant impact on health. Regression analyses allow contrasting the relevance of the variables associated with stress and social support of the parents and children on the perception of symptoms and well-being. These results indicate the importance of continuing to analyze in depth the psychosocial factors that have an impact on the families affected, in order to facilitate their adaptation to the disease and minimize the impact it may have on health. © 2015, Konrad Lorenz University Foundation.

Monitoring of Official Degree Qualifications: The Key Role of Academic Quality Assurance Systems (AQAS) / El proceso de seguimiento de los títulos oficiales: El papel "clave" de los Sistemas de Garantía de Calidad

The purpose of this article is focused on the development of a protocol designed to facilitate the monitoring process of the official degrees of a Spanish university. In response to the criteria and guidelines established in the Royal Decree 1393/2007, this proposal seeks to make available to the focus groups a useful and flexible tool, tailored to the different existing regulations, which assesses progress in the development of the curriculum, ensures the effective implementation of the degrees, and publishes the information available, relevant and appropriate. It also helps to identify weaknesses, potential improvements and best practices for dissemination. All this, with the ultimate aim of assuring the accreditation of Official Degrees. The monitoring protocol articulates the assessment, as a Check-List, in fulfillment of an annual series of indicators set out in the Academic Quality Assurance Systems (AQAS) included in the Proceedings of Degrees. Finally, the monitoring of new degrees comes up as a result of adaptation to the requirements of the European Higher Education Area.

El propósito de este artículo se centra en el desarrollo de un protocolo diseñado para facilitar el proceso de seguimiento de las titulaciones oficiales en las Universidades Españolas. En respuesta a los criterios y directrices establecidos en el Real Decreto 1393/2007, la presente propuesta tiene por objeto poner a disposición de los grupos de interés una herramienta útil y flexible, adaptada a las diferentes regulaciones existentes, que evalúa el progreso en el desarrollo del plan de estudios, asegura la aplicación efectiva de los grados, y publica la información disponible, relevante y apropiada. También ayuda a identificar los puntos débiles, las posibles mejoras y las prácticas más adecuadas para su difusión. Todo esto, con el fin último de garantizar la acreditación de los Títulos Oficiales. El protocolo de seguimiento articula la evaluación, así como una lista de control, en cumplimiento de una serie de indicadores establecidos en los Sistemas de Garantía de Calidad (SGC) incluidos en los Procedimientos de Grado. Por último, el seguimiento de los nuevos Títulos de Grado surge como resultado de la adaptación a los requerimientos del Espacio Europeo de Educación Superior.

Prevalencia y factores de riesgo de colelitiasis en pacientes menores de 18 años en un hospital de segundo nivel / Prevalence and risk factors for cholelithiasis in patients under 18 years of age at a second level health care hospital

Objetivo: Observar la prevalencia de litiasis vesicular y factores de riesgo en menores de 18 años, en un hospital de segundo nivel. Sede: Hospital General de Matamoros ''Dr. Alfredo Pumarejo Lafaurie'', Tamaulipas. Diseño: Estudio retrospectivo, transversal, observacional, descriptivo. Análisis estadístico: Porcentajes como medida de resumen para variables cualitativas. Pacientes y métodos: Se revisaron 706 expedientes clínicos de pacientes con diagnóstico de colelitiasis en un periodo comprendido entre enero de 2003 a diciembre de 2008. Las variables estudiadas fueron: edad menor de 18 años, sexo, antecedentes familiares de litiasis vesicular, enfermedades hemolíticas, uso de hormonales, embarazos, índice de masa corporal, síntoma predominante, complicaciones (coledocolitiasis y pancreatitis), tiempo de estancia hospitalaria y estudio histopatológico vesicular. Resultados: Se identificaron 26 casos con edad promedio de 12.8 años, todas mujeres, 16 pacientes (61.5%) con antecedente de embarazo. Sólo una paciente presentó peso normal, sobrepeso en siete pacientes, obesidad grado l en ocho pacientes, grado II en seis pacientes, grado III en cuatro pacientes, el 100% con antecedentes de litiasis vesicular materna. Conclusión: La prevalencia de colelitiasis en menores de 18 años fue de 3.6%. Los factores de riesgo asociados a pacientes mayores de 18 años fueron similares en la población estudiada menor de 18 años.

Objective: To observe the prevalence of gallbladder lithiasis and risk factors in patients under 18 years in a second level health care hospital. Setting: General Hospital of Matamoros ''Dr. Alfredo Pumarejo Lafaurie'', Tamaulipas. Mexico. Design: Retrospective, cross-sectional, descriptive, observational study. Statistical analysis: Percentages as summary measure for qualitative variables. Patients and methods: We reviewed 706 clinical files of patients with choledocholithiasis diagnosed between January 2003 and December 2008. Studied variables were: age below 18 years, sex, familial antecedents of gallbladder lithiasis, hemolytic diseases, use of hormones, pregnancies, body mass index, predominating symptom, length of in-hospital stay, and histopathological study of the gallbladder. Results: We identified 26 cases with an average age of 12.8 years; all were women, 16 patients (61.5%) with antecedents of pregnancy. Only one patient had a normal weight, seven patients were overweight, eight patients coursed with obesity grade I, six with grade II, and four with grade III. All (100%) had antecedents of maternal gallbladder lithiasis. Conclusion: Prevalence of choledocholithiasis in patients under 18 years of age was of 3.6%. Associated risk factors for patients below 18 years of age are similar to those encountered over 18 years of age.

ADAPTATION TO COMPETITION BY NEW MUTATION IN CLONES OF ALEXANDRIUM MINUTUM.

We describe two competition experiments between clones of the dinoflagellate Alexandrium minutum. In the first experiment, two clones originating from a single haploid cell competed until one of the clones was almost driven to extinction. In the second experiment, these two clones were allowed to compete with the original populations, which were previously kept as cysts. The results indicate that an improvement of the competitive ability in both clones has occurred during the history of competition. This adaptation to competition must be attributed to selection acting on the new genetic variation that has arisen by mutation.