Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

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Variability in the response to salinity within Chloris gayana (Rhodes grass) germplasm was evaluated under field conditions, and random amplified polymorphic DNA (RAPD) markers were used to assess genetic relatedness among cultivars/accessions. RAPD analysis showed a clustering of cultivars of known relatedness: cv. Pioneer and accessions Local and Trancas (derived from an old Pioneer pasture established in saline soil) belonged to the same cluster, Katambora to another and tetraploid Boma and Callide could be further separated, Boma belonging to a fourth, distant cluster. Field experiments were laid out in two types of plots: control [with electrical conductivity of the saturation extract (EC) = 3·64 dS m−1] and saline (EC=13·10 dS m−1) and two experiments were carried out: one to evaluate the effects of salinity on emergence and establishment, and the other, with a uniform number of plants per plot, to evaluate yield under saline conditions. All cultivars/accessions had salinity‐associated decreases in dry‐matter (DM) production during the establishment phase. After this stage, 1‐year DM yield was similar in all cultivars within each salinity level and production in the saline plots was significantly lower than in controls only in cv. Callide and accession Trancas. Second‐year production in the non‐saline plots increased by 30% on average over the previous year, whereas an average 40% reduction was observed in the saline plots. Thus, salinity had a negative effect on Rhodes grass establishment and persistence. The cultivars could not be ranked unequivocally by production under saline conditions, but tetraploids Boma and Callide may be said to be less tolerant than the rest on the basis of an increased proportion of dead leaves and decreased number of stolons observed in the saline plot.

The Argentinean semiarid Chaco region is climatically suitable for cattle raising and has an average annual rainfall of 550 mm, concentrated from November to February. There, large areas are affected by high salinity; thus, perennial forages suitable for this region must combine adequate salt and drought tolerance. Panicum coloratum is a C4 perennial grass adapted over a wide range of soil and rainfall conditions, and the purpose of this study was to evaluate the response of two cultivars (Klein Verde and Bambatsi) to salinity. Under controlled conditions, 100 and 200 mmol l−1 NaCl delayed germination and significantly reduced germination percentages and seedling survival in both cultivars. However, in the field, factors other than salinity (possibly drought) had a large impact on plant survival. In short‐term experiments under controlled environmental conditions, the vegetative growth of cultivar Klein Verde was less affected by salinity than Bambatsi. The cumulative growth over one year in a saline plot was also higher in cultivar Klein Verde. This cultivar also had higher shoot K+/Na+ ratios under salinity, as a result of higher K+ concentrations, and accumulated more triglycerides in roots. These features have been associated with salt tolerance in other species.

ObjectiveTo evaluate the efficacy, safety, and quality of life of 5 mg mifepristone per day compared with a placebo in treating uterine fibroids.DesignRandomized, double-blind clinical study.LocationEusebio Hernández Gynecology and Obstetrics Teaching Hospital, Havana, Cuba.SubjectsOne hundred twenty-four subjects with symptomatic uterine fibroids.TreatmentOne daily capsule of 5 mg mifepristone or a mifepristone placebo over 3 months.Variables in evaluating safetyChanges in fibroid and uterine volumes, changes in symptom prevalence and intensity, and changes in quality of life.ResultsThree months into treatment, fibroid volume was reduced by 28.5% in the mifepristone group with an increase of 1.8% in the placebo group (P = 0.031). There were significant differences between the groups with respect to pelvic pain prevalence (P = 0.006), pelvic pressure (P = 0.027), rectal pain (P = 0.013), hypermenorrhea (P < 0.001), and metrorrhagia (P = 0.002) at the end of treatment. Amenorrhea was 93.1% and 4.3% in the mifepristone and placebo groups, respectively (P < 0.001). Treatment side effects were significantly greater in the mifepristone group. Estradiol levels did not differ significantly between the placebo and mifepristone groups at the end of treatment. Improvement in quality of life was significantly greater in the categories of “symptoms” (P = 0.004) and “activity” (P = 0.045) in the mifepristone group.ConclusionThe 5 mg dosage of mifepristone presented significantly superior efficacy compared to the placebo.

In this study we report the synthesis and pharmacological evaluation, in vivo as well as in vitro, of four new progesterone derivatives 4-7. The evaluation in vivo was carried out on gonadectomized male hamsters that were injected subcutaneously daily with 1 mg/Kg of testosterone (T) and/or 1 mg/Kg of finasteride, or with 2 mg/Kg of the novel compounds. It was observed that when testosterone (T) and finasteride or compound 4 were injected together, the weight of the prostate decreased significantly as compared to that oftestosterone-treated animals. Compounds 5-7 did not show any in vivo activity. The 5alpha-reductase inhibitory activity of the novel compounds was determined in vitro using human prostate homogenates; the steroids 4-7 inhibited the 5alpha-reductase activity with IC50 values lower than that for the reference compound finasteride. 3. The effect of compounds 4-7 on the growth of lymphocytes and prostate cancer culture cells line was that steroid 4 inhibited the growth of both cells lines at a concentration of 50 microM and showed a cytotoxic effect whereas compounds 5-7 showed a much lower inhibition. Nevertheless steroids 4-7 didn't exhibit any toxic effects in vivo since the animals remained alive during the six days of treatment.

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Effects of hydroxychloride (OHCl) and sulfate form of zinc and manganese supplementation on immune responses of birds fed marginally lower levels of zinc and manganese during an experimental lipopolysaccharide (LPS) injection were studied. In experiment I, 30-week-old layer birds were fed 50 mg/kg Zn+45 mg/kg Mn or 100 mg/kg Zn+90 mg/kg Mn in sulfate or OHCl form and injected with 0 or 500 μg/kg LPS in a 2 (50 mg Zn+45 mg Mn and 100 mg Zn+90 mg Mn) X 2 (sulfate and OHCl) X 2 (0 and 500 μg LPS) factorial setup of treatments for 10 weeks. Among LPS-injected birds, those receiving 50 mg ZnOHCl+45 mg MnOHCl had comparable heterophil and monocyte superoxide dismutase (SOD) activity compared to the birds fed 100 mg Zn+90 mg Mn. Compared to the birds injected with PBS, LPS injection upregulated cathelicidin and IL-1 relative mRNA amounts in monocytes from birds fed 100 mg Zn+90 mg Mn, both in sulfate and OHCl form, and in birds fed 50 mg ZnOHCl+45 mg MnOHCl, but not in the birds fed 50 mg ZnSO4+45 mg MnSO4. In experiment II, one-day-old broiler birds were fed 50 mg ZnOHCl+45 mg MnOHCl, 50 mg ZnOHCl+90 mg MnOHCl, 100 mg ZnOHCL+45 mg MnOHCl, 100 mg ZnOHCl+90 mg MnOHCl, 50 mg ZnSO4+45 mg MnSO4, or 100 mg ZnSO4+90 mg MnSO4 for 21 and 42 days. Birds fed 100 mg ZnOHCl+45 mg MnOHCl form had a comparable heterophil and monocyte SOD activity and monocyte cathelicidin mRNA amounts compared to the group fed 100 mg Zn+90 mg Mn. Increasing the ZnOHCl content from 50 mg to 100 mg/kg Zn reversed (P > 0.05) the decrease in SOD activity and monocyte cathelicidin mRNA levels of the 50 mg ZnOHCl+45 mg MnOHCL fed group, and increasing the MnOHCl content from 45 mg to 90 mg/kg in the 100 mg ZnOHCl+45 mg MnOHCl group further increased SOD activity. In conclusion, birds fed diets with lower amounts of zinc and manganese in sulfate form decreased SOD activity and IL-1 and cathelicidin amounts during inflammation, and either increasing the dietary zinc and manganese content or feeding zinc and manganese in OHCl form synergistically increased the SOD activity and IL-1 and cathelicidin mRNA amounts in immune cells.