Thyroid Hormone Controls Breast Cancer Cell Movement via Integrin αV/β3/SRC/FAK/PI3-Kinases

Thyroid hormones (TH) play a fundamental role in diverse processes, including cellular movement. Cell migration requires the integration of events that induce changes in cell structure towards the direction of migration. These actions are driven by actin remodeling and stabilized by the development of adhesion sites to extracellular matrix via transmembrane receptors linked to the actin cytoskeleton. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that promotes cell migration and invasion through the control of focal adhesion turnover. In this work, we demonstrate that the thyroid hormone triiodothyronine (T3) regulates actin remodeling and cell movement in breast cancer T-47D cells through the recruitment of FAK. T3 controls FAK phosphorylation and translocation at sites where focal adhesion complexes are assembled. This process is triggered via rapid signaling to integrin αV/β3, Src, phosphatidylinositol 3-OH kinase (PI3K), and FAK. In addition, we established a cellular model with different concentration of T3 levels: normal, absence, and excess in T-47D breast cancer cells. We found that the expression of Src, FAK, and PI3K remained at normal levels in the excess of T3 model, while it was significantly reduced in the absence model. In conclusion, these results suggest a novel role for T3 as an important modulator of cell migration, providing a starting point for the development of new therapeutic strategies for breast cancer treatment.     

Improvement of child survival in Mexico: the diagonal approach

Public health interventions aimed at children in Mexico have placed the country among the seven countries on track to achieve the goal of child mortality reduction by 2015. We analysed census data, mortality registries, the nominal registry of children, national nutrition surveys, and explored temporal association and biological plausibility to explain the reduction of child, infant, and neonatal mortality rates. During the past 25 years, child mortality rates declined from 64 to 23 per 1000 livebirths. A dramatic decline in diarrhoea mortality rates was recorded. Polio, diphtheria, and measles were eliminated. Nutritional status of children improved significantly for wasting, stunting, and underweight. A selection of highly cost-effective interventions bridging clinics and homes, what we called the diagonal approach, were central to this progress. Although a causal link to the reduction of child mortality was not possible to establish, we saw evidence of temporal association and biological plausibility to the high level of coverage of public health interventions, as well as significant association to the investments in women education, social protection, water, and sanitation. Leadership and continuity of public health policies, along with investments on institutions and human resources strengthening, were also among the reasons for these achievements.     

Perception of sleep in recovering alcohol-dependent patients with insomnia: relationship with future drinking

BACKGROUND: Subjective and objective measures of poor sleep in alcoholic insomniacs predict relapse to drinking. Nonalcoholic insomniacs underestimate their total sleep time (TST) and overestimate their sleep onset latency (SOL) and wake time after sleep onset (WASO) compared with polysomnography (PSG). This study evaluated 3 hypotheses: (1) subjective SOL would predict frequency of future drinking; (2) participants would overestimate SOL and WASO and underestimate TST; and (3) higher amounts of over- and underestimates of sleep at baseline would predict worse drinking outcomes prospectively. METHODS: Participants (N=18), mean age 44.6 years (+/-13.2), underwent an adaptation night and then 2 nights of PSG 3 weeks apart. They also provided morning estimates of SOL, WASO, TST, and sleep efficiency (SE). Following the baseline PSG, participants were followed over 12 weeks. A 2-way ANOVA (night x method of measuring sleep) compared results and regression analyses predicted drinking. Drinking outcomes were defined as number of days drinking (DD) and number of heavy-drinking days (HDD) during 2 consecutive 6-week follow-up periods. RESULTS: Most participants (72%) overestimated SOL by a mean of 21.3 (+/-36) minutes compared with PSG [F(1, 14)=7.1, p<0.03]. Unexpectedly, 89% underestimated WASO by a mean difference of 48.7 (+/-49) minutes [F(1, 14)=15.6, p<0.01]. Drinking during the first 6-week study period was predicted by both subjective estimates of WASO and their accuracy, whereas drinking during the second 6-week period was predicted by both subjective estimations of sleep and rapid eye movement sleep latency. CONCLUSION: Greater subjective accuracy of wakefulness at night provided by the patient predicted drinking during the study. Unlike nonalcoholic insomniacs, this alcoholic sample significantly underestimated WASO compared with PSG values. The predictive ability of sleep parameters depended on the selected measure of drinking outcomes and when outcomes were measured. Subjective sleep measures were better predictors of future drinking than corresponding PSG measures.     

Directional atherectomy before stenting versus stenting alone in percutaneous coronary interventions: a meta-analysis

Plaque debulking before stenting is still controversial. We performed a meta-analysis of 12 randomized and non-randomized trials comparing directional coronary atherectomy (DCA) before stenting versus stenting alone. Angiographic end points were acute gain, late loss and angiographic restenosis rate. Clinical end points were early major adverse cardiac events [MACEs: death, Q-wave myocardial infarction (MI), non-Q-wave MI], late MACEs (death, Q-wave MI) and target lesion revascularization (TLR). Data are expressed as odds ratio (OR) with 95% confidence intervals (CI) or weighted mean difference (WMD) with 95% CI, as appropriate. A total of 1216 patients undergoing DCA before stent and 1484 patients undergoing stent alone have been included. DCA before stent was associated to a better acute gain compared to stenting alone (WMD 0.23, [0.18-0.28]; p<0.0001), to a striking reduction of angiographic restenosis rate (OR of 0.67, [0.54-0.84], p=0.0003) and to a significantly lower rate of late TLR (OR 0.73 [0.59-0.91], p=0.006). Late loss did not differ between the two groups (WMD 0.00 [-0.08 and 0.08], p=0.98). We found a higher rate of early MACEs for the combined approach (OR 1.87 [1.16-3.02], p=0.01), with similar prevalence of late MACEs (OR 0.83 [0.65-1.06], p=0.13). In conclusion, this meta-analysis demonstrates that DCA before stenting is superior to stenting alone with regard to acute angiographic results and TLR with a similar prevalence of late MACEs. The higher prevalence of early MACEs with DCA before stenting, however, is disturbing and probably related to distal embolization.     

Airway eosinophilia in children with severe asthma: predictive values of noninvasive tests

RATIONALE: Children with severe asthma experience persistent symptoms despite maximal conventional treatment. Fraction of exhaled nitric oxide (Fe(NO)) and sputum eosinophils are used as markers of airway inflammation to guide treatment with steroids, but no data are available on how reliable they are in predicting airway eosinophilia assessed bronchoscopically in these children. OBJECTIVES: To determine how Fe(NO) and sputum eosinophils predict airway eosinophilia measured in both bronchoalveolar lavage (BAL) and endobronchial biopsy. METHODS: Twenty-seven children with moderate to severe persistent asthma attempted measurement of Fe(NO) and sputum eosinophils, followed by bronchoscopy, BAL, and endobronchial biopsy within 24 h. MAIN RESULTS: Significant correlations were found between eosinophils in sputum and both BAL eosinophils (n = 20, r = 0.45, p = 0.045) and Fe(NO) (n = 23, r = 0.42, p = 0.049). The relationship between Fe(NO) and BAL eosinophils was also significant with a stronger correlation (n = 24, r = 0.54, p = 0.006). The positive predictive value (PPV) for increased sputum eosinophil percentage (> 2.5%) to detect elevated eosinophils in BAL (> 1.19%) was 75%; the negative predictive value (NPV) was 63%. All patients with both increased sputum eosinophils and an elevated Fe(NO) value (> 23 ppb) had elevated eosinophils in BAL (PPV, 100%); the NPV of these two markers was 65%. Eight of nine patients without any sputum eosinophils had normal subepithelial eosinophil numbers (< 1.2%; NPV, 89%). However, the PPV of any sputum eosinophils for increased subepithelial eosinophilia was only 36.4%. CONCLUSIONS: There was moderate agreement between both Fe(NO) and sputum eosinophils and BAL eosinophils. There was good NPV, but only poor PPV for these markers for mucosal eosinophilia.     

Lung function and airway hyperresponsiveness in adult patients with sickle cell disease

BACKGROUND: Lung disease is a major cause of morbidity and death in sickle cell disease. Although airway hyperresponsiveness has been noted in children, there are no studies in adult sickle cell patients. The aim of this study was to investigate the prevalence of airway hyperresponsiveness in adult sickle cell patients. METHODS: Twenty-six patients with sickle cell disease (10 HbSC, 9 HbSS, and 7 HbSbeta) were compared with 28 normal control subjects. Pulmonary function tests, including spirometry, measurements of single-breath diffusing capacity and the methacholine challenge test were performed. RESULTS: There were no significant differences in age, gender, or height between groups. Restrictive ventilatory defect was observed in six patients (24%) in the sickle cell disease group. Obstructive ventilatory defect and reduced diffusing lung DLCO capacity was observed in all sickle cell disease subgroups. A positive methacholine challenge test was obtained in eight (31%) sickle cell patients and in two of the 28 controls (7%). CONCLUSION: These features suggest that there is a high prevalence of airway hyperresponsiveness in adult patients with sickle cell disease without a history of reactive airway disease.