A gene signature of bone metastatic colonization sensitizes for tumor-induced osteolysis and predicts survival in lung cancer.

Bone metastasis of lung adenocarcinoma (AC) is a frequent complication of advanced disease. The purpose of this study was to identify key mediators conferring robust prometastatic activity with clinical significance. We isolated highly metastatic subpopulations (HMS) using a previously described in vivo model of lung AC bone metastasis. We performed transcriptomic profiling of HMS and stringent bioinformatics filtering. Functional validation was assessed by overexpression and lentiviral silencing of single, double and triple combination in vivo and in vitro. We identified HDAC4, PITX1 and ROBO1 that decreased bone metastatic ability after their simultaneous abrogation. These effects were solely linked to defects in osseous colonization. The molecular mechanisms related to bone colonization were mediated by non-cell autonomous effects that include the following: (1) a marked decrease in osteoclastogenic activity in vitro and in vivo, an effect associated with reduced pro-osteoclastogenic cytokines IL-11 and PTHrP expression levels, as well as decreased in vitro expression of stromal rankl in conditions mimicking tumor-stromal interactions; (2) an abrogated response to TGF-ß signaling by decreased phosphorylation and levels of Smad2/3 in tumor cells and (3) an impaired metalloproteolytic activity in vitro. Interestingly, coexpression of HDAC4 and PITX1 conferred high prometastatic activity in vivo. Further, levels of both genes correlated with patients at higher risk of metastasis in a clinical lung AC data set and with a poorer clinical outcome. These findings provide functional and clinical evidence that this metastatic subset is an important determinant of osseous colonization. These data suggest novel therapeutic targets to effectively block lung AC bone metastasis.

[High-frequency oscillatory ventilation as salvage strategy in the newborn infant. Spanish multicenter study. I]. / Ventilación de alta frecuencia oscilatoria como estrategia de rescate en el recién nacido. Estudio multicéntrico Español. I.

OBJECTIVE: The aim of this study was to evaluate the results of high frequency ventilation (HFV) used as a rescue strategy in newborn infants with severe lung disease who either failed conventional mechanical ventilation (CMV) or had an air block. PATIENTS AND METHODS: From April 1995 to June 1998, 241 infants with severe lung disease and managed according to a common protocol of HFV used as a rescue strategy were prospectively evaluated in the nine participating level III Spanish Neonatal Intensive Care Units. The most frequent diagnoses were respiratory distress syndrome (119), meconium aspiration (24), pneumonia (19) and congenital diaphragm hernia (18). RESULTS: Mean +/- SD gestational age and birth weight were 32.0 +/- 5.5 weeks and 1,187 +/- 1,071 g, respectively. All babies were previously manages with CMV for a mean of 59 hours. HFV was started at a mean postnatal age of 82 hrs, with a mean oxygenation index (OI) of 28.3 +/- 15.3 and an a/A DO2 of 0.10 +/- 0.08. Initial mean HFV settings were: mean airway pressure 12.8 +/- 3.4 mbar, frequency 8.3 +/- 1.4 Hz, amplitude 53 +/- 20 percent, tidal volume 2.2 +/- 0.7 ml/kg and FiO2 0.88 +/- 0.2. At two hours of HFV there was a significant increase in the mean PaO2 (from 48 to 80 mmHg), with a concomitant decrease in FiO2 (from 0.88 to 0.79), PaCO2 (from 60 to 46 mmHg) and OI (from 28 to 18). Mean a/A DO2 increased from 0.10 to 0.19; these changes remained similar thereafter. HFV was suspended after a mean of 95 hrs because of improvement in 70%, death in 19% and failure to improve the clinical condition in the remaining 19%. Intrahospital death rate was 32%. The following complications were observed: pneumothorax (10%), interstitial emphysema (4%), intraventricular hemorrhage grades III and IV (14.5%) and bronchopulmonary dysplasia (35%). CONCLUSIONS: HFV is an effective rescue strategy that improves pulmonary gas exchange within two hours of its initiation.

[Electroencephalographic maturation in preterm newborn infants]. / Maduración electroencefalográfica en el recién nacido pretérmino.

We have studied 51 preterm infants [gestational age (GE) less than 32 weeks] by: a neurologic examination at 40 weeks of postconceptional age, serial cranial ultrasonographies, weekly electroencephalograms (EEG) until 42 weeks of postconceptional age, and Brunet-Lezine test of psychomotor developmental at 1 year old. Our objective is the longitudinal study of EEG maturation in preterm infants with or without neurologic injury. In preterm infants with the less gestational age are present the EEG characteristics reported for the older infants, the typical EEG pattern is the "sawtooth" (27-30 weeks GE). If these infants are "normal", the EEG maturation get adjusted to the previous reported pattern, except for the earlier presentation of transitory acute frontal waves and the disappearance of the preterm's discontinuous trace. The EEG maturation of preterm infants with perinatal neurologic injury are significantly delayed in contrast with "normal" preterm infants until 40 weeks of postconceptional age; this fact have a poor prognosis for these infants.

[Anorexia nervosa. Presentation of two cases]. / Anorexia nerviosa.

Two patients with anorexia nervosa were studied. One of them showed cerebral atrophy by computed tomography (CT) of the brain. This finding has been reported previously in three cases. No other reports have been found in Spanish literature. This data could be merely a CT finding. Etiopathogenic and therapeutic evolution is discussed. Behavior modification, based in experimental psychology was used in treatment. Hypercaloric and hyperproteic feeding was also used.