Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1.

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB-H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA-H). Antiprogestins and progestins inhibited metastatic burden in PRA-H and PRB-H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA-H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB-H compared to PRA-H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA-H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA-H or PRB-H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA-H tumours. The therapeutic effect of progestins in PRB-H tumours is suggested.

Rescue high-frequency jet ventilation versus conventional ventilation for severe pulmonary dysfunction in preterm infants.

BACKGROUND: Chronic lung disease (CLD) is a major cause of mortality and morbidity in very low birth weight infants despite increased use of antenatal steroids and surfactant therapy. Ventilator injury and oxygen toxicity are thought to be important factors in the pathogenesis of chronic pulmonary disease. Evidence from animal studies and from adult human studies indicates that high-frequency jet ventilation may reduce the severity of lung injury associated with mechanical ventilation. OBJECTIVES: To compare use of high-frequency jet ventilation (HFJV) versus conventional ventilation (CV) in preterm infants with severe pulmonary dysfunction.Subgroup analyses include the following.• Trials with and without surfactant replacement therapy.• Trials with and without strategies to maintain lung volume.• Trials with infants of different gestational ages and birth weights (specific subgroups to include < 28 weeks' gestation and < 1000 grams).• Trials with and without adequate humidification of inspired gases. SEARCH METHODS: The original search included MEDLINE (1966 to August 2005), the Cochrane Central Register of Controlled Trials (CENTRAL; 2005, Issue 3) and EMBASE (1988 to August 2005). We also obtained information from experts in the field and checked cross-references. We updated the electronic search in June 2013 and again in June 2015. SELECTION CRITERIA: We included in this systematic review randomised and quasi-randomised controlled trials of rescue high-frequency jet ventilation versus conventional ventilation in preterm infants born at less than 35 weeks' gestation or with birth weight less than 2000 grams in respiratory distress. DATA COLLECTION AND ANALYSIS: We used standard methods of the Cochrane Neonatal Review Group, including independent trial assessment and data extraction. We analysed data using risk ratios (RRs) and risk differences (RDs). MAIN RESULTS: We included only one trial in the review. Keszler 1991 randomly assigned 166 preterm infants; reported data on 144 infants; and permitted cross-over to the alternate treatment if initial treatment failed. Investigators found no statistically significant differences in overall mortality (including survival after cross-over) between the two groups (RR 1.07, 95% confidence interval (CI) 0.67 to 1.72). In a secondary analysis of infants up to the time of cross-over, rescue treatment with HFJV was associated with lower mortality (RR 0.66, 95% CI 0.45 to 0.97). Researchers reported no significant differences in the incidence of CLD among survivors at 28 days of age, nor in the incidence of intraventricular haemorrhage, new air leaks, airway obstruction and necrotising tracheobronchitis. AUTHORS' CONCLUSIONS: Study authors reported no significant differences in overall mortality between rescue high-frequency jet ventilation and conventional ventilation and presented highly imprecise results for important adverse effects such as intraventricular haemorrhage, new air leaks, airway obstruction and necrotising tracheobronchitis.The overall quality of evidence is affected by limitations in trial design and by imprecision due to the small number of infants in the included study. Existing evidence does not support the use of high-frequency jet ventilation as rescue therapy in preterm infants.Studies that target populations at greatest risk and that have sufficient power to assess important outcomes are needed. These trials should incorporate long-term pulmonary and neurodevelopmental outcomes.

Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness.

Background: Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics. Methods: We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted for Ribo-Zero-Seq sequencing to evaluate differentially expressed genes. Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry. All statistical tests were two-sided. Results: One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64 (28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively ( P = .03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P = .02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P < .001). PRB-H tumors showed increased tumor size ( P < .001), Ki-67 levels ( P < .001), human epidermal growth factor receptor 2 expression ( P = .04), high grades ( P = .03), and decreased total PR ( P = .004) compared with PRA-H tumors. MUC-2 ( P < .001) and KRT6A ( P = .02) were also overexpressed in PRB-H tumors. Conclusion: The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer.

Assessing Soil Salinity Risk in the RUT Irrigation District, Colombia / Evaluación del riesgo de salinización de los suelos del distrito de riego RUT Colombia / Avaliação do risco de salinização dos solos do distrito de irrigação RUT Colômbia

Abstract The water resources mismanagement is a common concern in the agriculture, and this issue is boosting salinity processes in the Colombian lands. Thus, this paper aimed to assess the soil salinity risk in the RUT irrigation district for sugarcane, grape, and passion fruit by coupling SOSALRIEGO-GIS. First, sources of surface water and their influence areas were identified in the RUT irrigation district. Afterwards, inputs (water ionic constituents, electrical conductivity of rainwater, annual rainfall, crop salt tolerance, soil texture, and leaching fraction) fed in the SOSALRIEGO model, and then, the leaching requirement (LR) of each zone was computed (output) for each crop. Finally, employing GIS, LR values were arranged in categories in order to map the soil salinity risk in the RUT irrigation district for each crop and zone. The soil salinity risk fell into a medium rank for sugarcane, medium to high ranks for grape, and high to very high ranks for passion fruit. Furthermore, the soil salinity risk was higher in zones with poor irrigation water quality. Zones II and III, which canals convey domestic wastewater and drained water fell in greater salinity risk category than zone I, which bears water withdrawal from the Cauca River.

Resumen La inadecuada gestión de los recursos hídricos es una preocupación común en la agricultura, y este hecho está impulsando procesos de salinización en los suelos de Colombia. Por lo tanto, este trabajo tuvo como objetivo evaluar el riesgo de salinización del suelo en el distrito de riego RUT para cultivos de caña de azúcar, uva, maracuyá integrando el modelo SOSALRIEGO con SIG. En primer lugar, se identificaron las fuentes hídricas y sus áreas de influencia. Posteriormente, los parámetros de entrada (composición iónica del agua, conductividad eléctrica del agua de lluvia, precipitación anual, tolerancia de cultivos a la salinidad, cultivos, textura del suelo y la eficiencia de lavado) alimentaron el modelo SOSALRIEGO y, a continuación, el Requerimiento de Lavado de sales (RL) fue calculado para cada cultivo. Por último, utilizando SIG, los valores RL se organizaron en categorías con el fin de mapear el riesgo de salinización del suelo en el distrito de riego RUT para cada cultivo en cada zona. El riesgo de salinización se clasificó como medio para caña de azúcar, medio a Alto para la uva, y alto a muy alto para maracuyá. Además, el riesgo salinización del suelo encontrado fue mayor en zonas con baja calidad del agua de riego. Las Zonas II y III, en las cuales los canales conducen aguas residuales domésticas y el agua drenada fueron calificados en categorías superiores de riesgo de salinización que la Zona I, la cual recibe agua extraída directamente del río Cauca.

Resumo A inadequada gestão dos recursos hídricos é uma preocupação comum na agricultura, este fato está impulsando processos de salinização nos solos da Colômbia. Portanto, esta pesquisa objetivou avaliar o risco da salinização dos solos no distrito de irrigação RUT às culturas de cana-de-açúcar, uva e maracujá; integrando o modelo SOSALRIEGO com os Sistemas de Informações Geográficas (SIG). Em primeiro lugar, os parâmetros de entrada (composição iônica da água de irrigação, condutividade elétrica da água de precipitação, precipitação anual, tolerância das culturas à salinidade, culturas, textura do solo e eficiência de lavado de sais) alimentaram o modelo SOSALRIEGO e, seguidamente o requerimento de lavado de sais (RL) foi calculado. Finalmente, usando os SIG, os valores de RL foram categorizados com o objetivo de mapear o risco de salinização dos solos na área de estudo para cada cultura em cada zona. O risco de salinização foi classificado como Médio para a cultura da cana-de-açúcar, Médio a Elevado para a cultura da uva, e Elevado a Muito Elevado para o maracujá. Além disso, o risco de salinização foi maior nas zonas com menor qualidade da água de irrigação. As zonas II e III, cujos canais conduzem águas residuais e de drenagem foram qualificados em categorias maiores de risco do que a zona I, a qual extrai a água diretamente do Rio Cauca.

H2O2 scavenging inhibits G1/S transition by increasing nuclear levels of p27KIP1.

The aim of the present study was to evaluate cell cycle regulation by scavenging H(2)O(2) in tumor cells. A significant arrest in the G1 phase of the cell cycle was demonstrated in CH72-T4 carcinoma cells exposed to catalase, associated with a decrease in cyclin D1 and an increase in the CDK inhibitory protein p27(KIP1). Moreover, we found a differential intracellular distribution of p27(KIP1), which remained in the nucleus after catalase treatment. In vivo experiments showed an increase in nuclear levels of p27(KIP1) associated with the inhibition of tumor growth by H(2)O(2) scavenging, confirming in vitro results. To conclude, H(2)O(2) scavenging may induce cell cycle arrest through the modulation of cyclin D1 and p27(KIP1) levels and nuclear localization of p27(KIP1). To our knowledge, this is the first report that demonstrates that the modulation of ROS alters the intracellular localization of a key regulatory protein of G1/S transition.