Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation.

Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.

[Amniotic fluid analysis as a screening test in term and post-term pregnancy]. / La valutazione del liquido amniotico come test di screening nella gravidanza a termine ed oltre il termine.

BACKGROUND: To verify the hypothesis that isolated oligohydramnios in low-risk term or post-term pregnancy does not increase the risk of trauma to the fetus compared with a control group. METHODS: This prospective study compared a group of patients with low-risk pregnancy and oligohydramnios (AFI = or <50) and a control group which on ultrasonography performed 24 hours before delivery had an AFI volume >50 and = or <250 mm. The evaluation criteria included incidence of induction, modality of delivery and neonatal outcome. Statistical analysis was carried out using Student's "t"-test and the data set of categories was compared using the chi square test. RESULTS: From January 1997 to April 1999, 105 cases of oligohydramnios were compared with a control group (105 patients) matched for maternal age, gestation period and parity. The incidence of induction, fetal distress and variable deceleration was significantly higher in the group with AFI = or <50. The incidence of vacuum extractor, cesarean section, duration of labor and late deceleration did not differ between the two groups. No significant differences in neonatal outcome were found between the two groups. CONCLUSIONS: In patients with oligohydramnios without risk factors, the modality of delivery and neonatal outcome do not differ compared with those with normal amniotic fluid volume.

[Reproductive outcome of hysteroscopic lysis of intrauterine adhesions]. / Outcome riproduttivo dopo sinechiolisi isteroscopica.

OBJECTIVE: To analyze the reproductive outcome in women undergoing hysteroscopic lysis of intrauterine adhesions, according to their localization and severity. STUDY DESIGN: Retrospective study. MATERIALS AND METHODS: Fifty-three patients affected by intrauterine adhesions of different degree, subdivided according to localization and morphologic aspect: three isthmic, thirteen marginal, fourteen central, moreover twenty were complex and three complete. All the interventions were performed by means of the resectoscope. RESULTS: Hysteroscopic surgery restored an acceptable menstrual cycle in almost all the patients affected by intrauterine isolated adhesions, in 52% of women affected by complex incomplete adhesions, and in none of the three patients with entirely obliterated cavity. Concerning fertility, while in isolated, isthmic, central or marginal synechias we observed a pregnancy rate of 73.3% (22 out of 30) with a pregnancy rate to term respectively of 63.3% (19 out of 30 cases) and of 86.3% (19 out of 22 total pregnancies), in case of complex but not complete adhesions we reported, on 20 cases, 5 pregnancies (25%) with only two gone to term. We had no pregnancy in three cases of complex synechias. CONCLUSIONS: The basic parameter to define the functional and reproductive prognosis of the hysteroscopic lysis of intrauterine adhesions is not the menstrual profile or the histological characteristic of the lesions, but rather their extension.