Small-Molecule-Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death.

High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061-induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy that is primarily detected at the metastatic stage. Most HGSOC originates from the fallopian tube epithelium (FTE) and metastasizes to the ovary before invading the peritoneum; therefore, it is crucial to study disease initiation and progression using FTE-derived models. We previously demonstrated that loss of PTEN from the FTE leads to ovarian cancer. In the present study, loss of PTEN in FTE led to the enrichment of cancer stem cell markers such as LGR5, WNT4, ALDH1, CD44. Interestingly, loss of the transcription factor PAX2, which is a common and early alteration in HGSOC, played a pivotal role in the expression of cancer stem-like cells (CSC) markers and cell function. In addition, loss of PTEN led to the generation of two distinct subpopulations of cells with different CSC marker expression, tumorigenicity, and chemoresistance profiles. Taken together, these data suggest that loss of PTEN induces reprogramming of the FTE cells into a more stem-like phenotype due to loss of PAX2 and provides a model to study early events during the FTE-driven ovarian cancer tumor formation.

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion.

The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.

Reduced PAX2 expression in murine fallopian tube cells enhances estrogen receptor signaling.

High-grade serous ovarian cancer (HGSOC) is thought to progress from a series of precursor lesions in the fallopian tube epithelium (FTE). One of the preneoplastic lesions found in the FTE is called a secretory cell outgrowth (SCOUT), which is partially defined by a loss of paired box 2 (PAX2). In the present study, we developed PAX2-deficient murine cell lines in order to model a SCOUT and to explore the role of PAX2 loss in the etiology of HGSOC. Loss of PAX2 alone in the murine oviductal epithelium (MOE) did not induce changes in proliferation, migration and survival in hypoxia or contribute to resistance to first line therapies, such as cisplatin or paclitaxel. RNA sequencing of MOE PAX2shRNA cells revealed significant alterations in the transcriptome. Silencing of PAX2 in MOE cells produced a messenger RNA expression pattern that recapitulated several aspects of the transcriptome of previously characterized human SCOUTs. RNA-seq analysis and subsequent qPCR validation of this SCOUT model revealed an enrichment of genes involved in estrogen signaling and an increase in expression of estrogen receptor α. MOE PAX2shRNA cells had higher estrogen signaling activity and higher expression of putative estrogen responsive genes both in the presence and absence of exogenous estrogen. In summary, loss of PAX2 in MOE cells is sufficient to transcriptionally recapitulate a human SCOUT, and this model revealed an enrichment of estrogen signaling as a possible route for tumor progression of precursor lesions in the fallopian tube.

Intervención educativa comunitaria sobre escabiosis en el ámbito de la Atención Primaria / Community educational intervention about escabiosis in the Primary Health Care realm

Objetivo: Ofrecer una alternativa de educación sobre escabiosis, adaptada a las condiciones locales y a las necesidades sentidas por las madres. Métodos: Se describe la metodología utilizada en una intervención educativa sobre escabiosis, dirigida al primer nivel de atención. El estudio se realizó en el Policlínico de Primero de Enero. En la primera etapa se practicó una encuesta para evaluar el nivel de conocimientos, actitudes y prácticas de las madres con relación a la escabiosis. A partir de este resultado, se desarrolló la metodología educativa, para la cual se elaboró un material de apoyo docente (folleto), y dos actividades para dar sostenibilidad al programa educativo, uno dirigido a la promoción de medidas de protección y prevención y otro destinado a la identificación de conductas de riesgo. Ocho meses después se aplicó la misma encuesta para conocer el nivel de conocimientos con relación al inicial. Resultados: Antes de la aplicación de la metodología educativa, un grupo importante de madres tenía deficiente higiene y bajo nivel de conocimientos con relación a la escabiosis. Después de la capacitación mejoraron los conocimientos, se modificaron hábitos y prácticas; las mujeres reconocieron la utilidad de la higiene personal y ambiental en la prevención de complicaciones durante los episodios activos de escabiosis. Conclusiones: A pesar del corto tiempo transcurrido entre la aplicación de la experiencia educativa y la encuesta final, los hallazgos encontrados después de su aplicación demuestran que el programa aplicado puede mejorar los conocimientos de la población con relación a la escabiosis y sus complicaciones.

Purpose: to provide an educative alternative about escabiosis, adapted to the local conditions and the necessities felt by mothers. Methods. The methodology used in an educational intervention on escabiosis is described, being directed to the first attention level. This study was conducted in Primero de Enero Polyclinic. In the first stage, a survey was carried out, to evaluate the level of knowledge, attitudes etc. Stemming from the results, an educational methodology was developed, for which a teaching aid was created (a pamphlet), plus two activities to provide sustainability for the educational program. Mothers were polled again Eight months later, by means of the same survey, in order to know their acquisition of knowledge up to now. Results. Before the new methodology was applied, a number of mothers had insufficient hygiene habits and low level of knowledge with regards to escabiosis. After doing this training, women recognized the usefulness of developing appropriate personal and environmental hygiene habits to prevent complications during its occurrence. Conclusions. In inspire of the short period of time elapsed from the implementation of the educational intervention and the last survey, it showed its effectiveness to improve people knowledge in regards of escabiosis, as well as the main complications that may occur.

Intervención educativa sobre nutrición en un grupo poblacional con riesgo de malnutrición por defecto / Educative intervention on nutrition in a population group at the risk of malnutrition by default

Se realizó un estudio experimental prospectivo sobre el nivel de conocimientos de la población con relación a la nutrición infantil. Se estudiaron 41 pacientes con riesgo de malnutrición por defecto, de los consultorios urbanos 8 y 9 del Policlínico José Agustín Mas Naranjo del municipio de Primero de Enero, desde el 1ro de enero de 2006 al 30 de junio de 2007. Se diseñó y aplicó una estrategia educativa para elevar el nivel de conocimientos de la familia sobre nutrición infantil, y de esta forma lograr cambios en la conducta de los padres y cuidadores con respecto a la alimentación del niño menor de 2 años. La aplicación inicial de la encuesta (anexo 1) evidenció que un grupo de niños no recibía lactancia materna durante el primer semestre de la vida (31,3 por ciento). Se conoció que la diversificación y suplementación de la dieta en el mayor de 6 meses se hacía sólo en el 19,5 por ciento (8 casos), después de la intervención el 87,8 por ciento la utilizó (36 casos). Con la aplicación de la estrategia educativa se logró aumentar el nivel de conocimientos de los participantes. Este trabajo demostró la importancia y la asequibilidad de métodos participativos para mejorar la comprensión sobre esta problemática.

A prospective experimental study was done on the population knowledge regarding children nutrition. 41 patients at the risk of malnutrition by default were analyzed, being registered in urban surgeries 8 and 9 of the Policlinic Jose Agustín Mas Naranjo in Primero de Enero Municipality from January 1st, 2006 to June 30, 2007. For the execution of the work, the investigation equipment designed and applied an educative strategy to elevate the family knowledge on children nutrition, and thus to obtain changes in the parents and caretakers behaviour regarding the feeding of younger-than- 2 years- old children. The initial application of the survey (addendum 1) showed an important group of children who never were breast feeded during the first three months of their lives (31, 3 percent). It was also known that diversification and supplementation of older-than- 6 -months –old children diet was carried out a 19,5 percent only (8cases). It was used in 36 cases (87, 8 percent) after doing the intervention. It was increased the participants knowledge on this matter after the application of the educative strategy. This work demonstrated the importance and attainability of participative methods to improve the understanding on this topic.

Influencia de la educación sanitaria para la prevención de las diarreas agudas en niños / Influence of the sanitary education for the prevention of the acute diarrhoeas in children

Objetivo: Ofrecer una alternativa de educación sobre diarreas agudas en niños, adaptada a las condiciones locales y a las necesidades sentidas por las madres. Método: Se describe la metodología utilizada en una intervención educativa comunitaria sobre diarreas agudas, dirigida al primer nivel de atención. El estudio se realizó en el Policlínico Comunitario José Agustín Mas Naranjo del municipio Primero de Enero. En la primera etapa se practicó una encuesta para evaluar el nivel de conocimientos, actitudes y prácticas de las madres con relación a las diarreas. A partir de esto, se desarrolló la metodología educativa, para la cual se elaboró un material de apoyo docente (video-casete) y dos actividades para dar sostenibilidad al programa educativo. Ocho meses después de concluir la actividad se aplicó la misma encuesta para conocer el nivel de conocimientos con relación al inicial. Resultados: Antes de la aplicación de la metodología educativa, un grupo importante de madres tenía deficiente higiene y bajo nivel de conocimientos con relación a las diarreas. Después de la capacitación mejoraron los conocimientos, se modificaron hábitos y prácticas; las mujeres reconocieron la utilidad del suero oral en el tratamiento y prevención de complicaciones durante los episodios agudos de diarreas. Conclusiones: A pesar del corto tiempo transcurrido entre la aplicación de la experiencia educativa y la encuesta final, los hallazgos encontrados después de su aplicación demuestran que el programa aplicado puede mejorar los conocimientos de la población sobre las diarreas y sus complicaciones.

Objectives: To offer an education alternative on acute diarrhoeas in children, adapted to the local conditions and the needs felt by mothers. Method: The methodology used in a communitarian educative intervention on acute diarrhoeas is described, aim at the first level of attention. The study was carried out in the Communitarian Policlinic Jose Agustín Mas Naranjo of the municipality Primero de Enero. In the first stage a survey was applied to evaluate the level of knowledge, attitudes and practices of the mothers in relation to the diarrhoeas. From this result, the educative methodology was developed, for which a material of educational support was elaborated (videotape), and two activities to give sustainability to the educative program. Eight months after concluding the activity the same survey was applied to know the level of knowledge in relation to the initial one. Results: Before applying the educative methodology, a group of mothers had deficient hygiene and low level of knowledge in relation to the diarrhoeas. After the qualification they improved the knowledge and modified their habits and practices; the women recognized the utility of the oral serum in the treatment and prevention of complications during the acute episodes of diarrhoeas. Conclusions: In spite of the short time passed between the application of the educative experience and the final survey, the findings found after their application demonstrate that the applied program can improve the knowledge of the population on the diarrhoeas and their complications.

Beneficios del ingreso en el hogar en pacientes pediátricos de un área de salud / Benefits of the admission of pediatric patients to the home in a health area

Se realizó una investigación observacional descriptiva para estimar los beneficios del ingreso en el hogar en niños y jóvenes del área de trabajo correspondiente al Policlínico Comunitario de Primero de Enero. Los grupos etáreos donde más se utilizó la técnica fueron: los niños con edades entre 1 y 4 años y el menor de un año; el sexo predominante fue el masculino; los medicamentos más utilizados estuvieron en correspondencia con las enfermedades y su disponibilidad. Las principales causas de ingreso fueron las infecciones respiratorias y diarreicas agudas. El estudio demostró que el 89,3 por ciento se curó, se complicó el 5,4 por ciento y no se produjeron defunciones.

A observational descriptive investigation was conducted in order to stimulate the benefits of admission to the Home of children and young people of the work area corresponding to the communitarian policlinic of “Primero de enero” municipality. The age groups where this technique was more commonly used were: Children in ages between 1-4 years and infants, males were predominant , the most utilized medicines were in correspondence with the diseases and their availability. The main causes of admission were respiratory infections and the acute diarrheal diseases. This study demonstrated that (89.3%) was cured, (5.4%) encountered complications and fatalities did not occur.

Educación prenatal y lactancia materna / Prenatal education and breastfeeding

Se realizó un estudio experimental prospectivo de cohortes con todas las madres, y sus hijos, que concurrieron a control prenatal de embarazo desde el 01/03/03 y cuyos niños cumplieron seis meses antes del 01/03/05, atendidos en los consultorios urbanos del municipio 1ro de Enero, el grupo de estudio estuvo constituido por 69 madres que cumplieron con los requisitos exigidos por el equipo de investigación, y el grupo control por 41casos. De las variables estudiadas la que tuvo repercusión negativa fue la ocupación materna. Se encontró que hubo abandono temprano de lactancia materna en un grupo importante de casos. Quedó demostrado que la educación prenatal sobre lactancia materna es un recurso simple y de bajo costo capaz de incrementar el uso y permanencia de esta durante el primer semestre de la vida.

A prospective experimental study of cohorts with all mothers and sons that went to prenatal care of pregnancy since March 1st ,2003 whose babies were months old before March 1st,2005 treated in urban dispensaries in 1ro de Enero municipality was done .The study group was composed 69 mothers tha fulfil the requirements demanded by the search team and contrpl group by 41 cases .Of the studied variables the one that had negative influence was maternal employment .It was shown that prenatal education about breastfeeding is a simple resource and of low cost able of increasing the use and duration in the first semester of life.