A study of the psychometric properties of the Brazilian...Portuguese version of Bronchiectasis Health Questionnaire.

INTRODUCTION AND OBJECTIVE: The Bronchiectasis Health Questionnaire (BHQ) is a simple, repeatable, and self-reporting health status questionnaire for bronchiectasis. This study aims to cross-culturally adapt the BHQ into Brazilian Portuguese and evaluate its measurement properties. METHODS: The participants answered the Saint George...s Respiratory Questionnaire (SGRQ) and the modified Medical Research Council (mMRC) scale for dyspnea. The Brazilian-Portuguese version of the Bronchiectasis Health Questionnaire (BHQ-Brazil) was used at baseline (test) and after 14 days (retest). The psychometric analyses included internal consistency, test-retest reliability, and construct validity: factorial validity, convergent validity, and discriminative validity, agreement, and ceiling and floor effects. RESULTS: The BHQ-Brazil demonstrated adequate internal consistency (Cronbach...s alpha...=...0.92) and substantial reliability (intraclass correlation coefficient...=...0.86; 95%CI: 0.79...0.90). The exploratory factorial analysis was considered suitable. All items presented a factorial load >0.40. The convergent validity of the BHQ-Brazil with mMRC was moderate (r...=......0.53, p...<...0.001), while concurrent validity with the SGRQ was strong (symptoms: r...=......0.72, activities: r...=......0.60, impact: r...=......0.60, total score: r...=......0.75, all p...<...0.001). The standard error of measurement was 4.81 points. The discriminative validity demonstrated that individuals with more pulmonary exacerbations, colonization by Pseudomonas aeruginosa, worst dyspnea, and a higher number of affected lung lobes presented the lowest quality of life. No floor or ceiling effects were observed. CONCLUSION: The BHQ-Brazil presents adequate measurement properties to evaluate the impact of bronchiectasis on health-related quality of life, and can be used in clinical and research settings.

Reproducibility, validity, and reliability of the incremental step test for subjects with moderate to severe asthma.

OBJECTIVE: We investigated the measurement properties of the incremental step test in subjects with moderate to severe asthma. METHODS: Subjects with moderate to severe persistent asthma were recruited from a tertiary university hospital specializing in treating severe asthma. All subjects performed one cardiopulmonary exercise test (CPET) and two incremental step tests (IST) in random sequences. Pulmonary gas exchange was measured during all exercise tests. The measurement properties investigated were reliability by intraclass correlation coefficient (ICC), measurement error by the standard error of measurement and minimum detectable difference, construct validity by Pearson's correlation, and interpretability by the ceiling and floor effects. RESULTS: Fifty subjects (38 females, mean [SD], age 43.7 [11.6] yr, % FEV1 70 [14.3], BMI 28.5 [5.3] kg/m2) completed the study. The peak oxygen uptake (peak VO2) for the CPET was 27.6 [±6.8] ml/kg/min, for the first IST was 22.3 [±5.3] ml/kg/min and for the second IST was 23.3 [±5.3] ml/kg/min. The IST presented excellent reliability (ICC=0.93, CI95% 0.88-0.96), very good measurement error (2.5%), and construct validity for peak VO2 measurement compared to the CPET (r = 0.85; p < 0.001) to assess exercise capacity in subjects with moderate to severe asthma, with appropriate ceiling (10%) and floor (0%) effects. CONCLUSION: The IST presented excellent reliability and very good measurement error and validity to assess exercise capacity in subjects with moderate to severe asthma, without ceiling or floor effects.

Incremental step test in patients with pulmonary hypertension.

Cardiopulmonary exercise testing (CPET) on a treadmill or cycle ergometer provides an integrated assessment of the cardiorespiratory system during exertion and is widely used in clinical practice. An incremental step test (IST) can be an alternative for eliciting maximal exercise responses. Therefore, 20 patients with pre-capillary PH (65% female, 41 ±â€¯15 yrs) randomly performed a symptom-limited CPET on a cycle ergometer and IST. Metabolic, cardiovascular, ventilatory and gas exchange variables were recorded during both tests. There was a greater desaturation and higher V̇O2PEAK in IST compared to CPET. The V̇O2GET, HR PEAK (% pred), ΔV̇E/ΔV̇CO2 and ΔHR/ΔV̇O2 were similar in both IST and CPET. By linear regression analyses, the work performed on IST [W = (mass × 9,8 m/s2 x vertical distance)] was a predictor of peak V̇O2 independent of the gender and age (r2 = 077, p = 0001). In conclusion, IST elicited higher peak cardiopulmonary responses and has a good agreement with known severity markers in patients with pre-capillary PH.

Validation and reproducibility of the Glittre activities of daily living test for individuals with Parkinson's disease. / Validación y reproducibilidad de la prueba Glittre de actividades de la vida diaria en personas con enfermedad de Parkinson.

AIM: To investigate the validity and reproducibility of the Glittre Activities of Daily Living (Glittre-ADL) test for individuals with Parkinson's disease. SUBJECTS AND METHODS: Thirty individuals with Parkinson's disease and 19 healthy individuals (control group) were evaluated. Parkinson's disease group was evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS) and underwent the Glittre-ADL test, six-minute walk test (6MWT) and ten-meter walk test (10mWT). Control group performed the Glittre-ADL test. For the intraobserver analysis, two Glittre-ADL tests were performed. For the interobserver analysis, the Glittre-ADL test was repeated on a different day by a second examiner. RESULTS: The Glittre-ADL test was significantly correlated with UPDRS Section II, Section III, and total score. The Glittre-ADL test was inversely correlated with the 6MWT and positively correlated with the 10mWT. The time required to perform the Glittre-ADL test was shorter on the retest in the intraobserver analysis and in the interobserver analysis. The mean difference between the first and second tests, the standard error of measurement and minimum detectable change in minutes were 0.40, 0.08 and 0.24, respectively, for intraobserver, and 0.40, 0.22 and 0.62, for interobserver. CONCLUSION: The Glittre-ADL test is valid and reproducible to evaluate functional capacity in individuals with Parkinson's disease.

TITLE: Validación y reproducibilidad de la prueba Glittre de actividades de la vida diaria en personas con enfermedad de Parkinson.Objetivo. Investigar la validez y la reproducibilidad de la prueba Glittre de actividades de la vida diaria (AVD-Glittre) para personas con enfermedad de Parkinson. Sujetos y métodos. Se evaluó a 30 pacientes con enfermedad de Parkinson y 19 sujetos sanos (grupo de control). El grupo con enfermedad de Parkinson fue evaluado con la Unified Parkinson's Disease Rating Scale (UPDRS) y sometido a la prueba AVD-Glittre, la prueba de marcha de seis minutos (6MWT) y la prueba de marcha de 10 metros (10mWT). El grupo de control realizó la prueba AVD-Glittre. Para el análisis intraobservador se realizaron dos pruebas AVD-Glittre, y para el análisis interobservador, la prueba se repitió otro día con un segundo examinador. Resultados. La prueba AVD-Glittre se correlacionó significativamente con la sección II, la sección III y la puntuación total de la UPDRS. Se correlacionó inversamente con la 6MWT y positivamente con la 10mWT. El tiempo requerido para realizar la prueba AVD-Glittre fue más corto en la nueva prueba en el análisis intraobservador y en el análisis interobservador. La diferencia de medias entre la primera y la segunda pruebas, el error estándar de medición y el cambio mínimo detectable en minutos fueron 0,40, 0,08 y 0,24, respectivamente, para el análisis intraobservador, y 0,40, 0,22 y 0,62, respectivamente, para el análisis interobservador. Conclusión. La prueba AVD-Glittre es válida y reproducible para evaluar la capacidad funcional en personas con enfermedad de Parkinson.

Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gastroesophageal xenopatient cohort.

Amplification of the MET oncogene occurs in 2-4% of gastroesophageal cancers and defines a small and aggressive subset of tumors. Although in vitro studies have given very promising results, clinical trials with MET inhibitors have been disappointing, showing few and short lasting responses. The aim of the work was to exploit a MET-amplified patient-derived xenograft model to optimize anti-MET therapeutic strategies in gastroesophageal cancer. We found that despite the high MET amplification level (26 gene copies), in the absence of qualitative or quantitative alterations of EGFR, MET inhibitors induced only tumor growth inhibition, whereas dual MET/EGFR inhibition led to complete tumor regression. Importantly, the combo treatment completely prevented the onset of resistance, which quite rapidly appeared in tumors treated with MET monotherapy. We found that this secondary resistance was due to EGFR activation and could be overcome by dual MET/EGFR inhibition. Similar results were also obtained in a MET-addicted, established gastric cancer cell line. In vitro experiments performed on tumor-derived primary cells confirmed that MET inhibitors were not able to abrogate the activation of downstream transducers and that only the combined MET/EGFR treatment completely shut off the signaling. Previously reported cases, as well as those described here, showed only partial and transient sensitivity to anti-MET therapy. The finding that combined anti-MET/EGFR therapy-even in the absence of EGFR genetic alterations-induced complete and durable response, represents a proof of concept and guarantees further investigations, opening a new perspective of treatment for these patients.

SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.

SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.

Patients' understanding of how genotype variation affects benefits of tamoxifen therapy for breast cancer.

BACKGROUND: CYP2D6 is a critical enzyme in the metabolism of tamoxifen and potentially a key determinant in breast cancer outcomes. Our study examined patients' beliefs about how the CYP2D6 genotype would affect their prognoses. METHODS: Women enrolled in a pharmacogenomic clinical trial and on tamoxifen for prevention or treatment of breast cancer underwent CYP2D6 genotyping (EM = extensive, IM = intermediate, PM = poor metabolizing alleles). The informed consent said that the purpose of the trial was to examine effects of dose adjustment based on genotype, but that clinical benefits were uncertain. Our embedded sub-study surveyed 320 patients prior to receiving their genotypes. We experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, women gave their perceived recurrence risk (RR; 0-100%). RESULTS: Women believed that genotype would not affect their RR if they did not take tamoxifen (p = 0.06). However, women believed that if prescribed tamoxifen, genotype would affect their RR (22% if EM, 30% if IM and 40% if PM, p < 0.001). CONCLUSION: Women believed that extensive tamoxifen metabolizers had better prognoses, despite study materials stating uncertainty about any benefit. The rapidly changing nature of genomic science calls for caution when communicating clinical utility.

Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series.

BACKGROUND: To assess the long-term oncological outcome and the fertility of young women with early-stage epithelial ovarian cancer (ES/EOC) treated with fertility-sparing surgery (FSS). PATIENTS AND METHODS: All patients treated with FSS for ES/EOC in two Italian centers were considered for this analysis. Univariate and multivariate analyses were used to test demographic characteristics and clinical features for the association with overall survival (OS), recurrence-free survival (RFS) and fertility. RESULTS: From 1982 to 2010, 240 patients with malignant ES/EOC were treated with FSS in two tertiary centers in Italy. At a median follow-up of 9 years, 27 patients had relapsed (11%) and 11 (5%) had died of progressive disease. Multivariate analysis found only grade 3 negatively affected the prognosis of patients [hazard ratio (HR) for recurrence: 4.2, 95% confidence interval (CI): 1.5-11.7, P=0.0067; HR for death: 7.6, 95% CI: 2.0-29.3, P=0.0032]. Grade 3 was also significantly associated with extra-ovarian relapse (P=0.006). Of the 105 patients (45%) who tried to become pregnant, 84 (80%) were successful. CONCLUSIONS: Conservative treatment can be proposed to all young patients when tumor is limited to the ovaries, as ovarian recurrences can always be managed successfully. Patients with G3 tumors are more likely to have distant recurrences and should be closely monitored.

Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise.

We determined the response characteristics and functional correlates of the dynamic relationship between the rate (Δ) of oxygen consumption (VO(2)) and the applied power output (work rate = WR) during ramp-incremental exercise in patients with mitochondrial myopathy (MM). Fourteen patients (7 males, age 35.4 ± 10.8 years) with biopsy-proven MM and 10 sedentary controls (6 males, age 29.0 ± 7.8 years) took a ramp-incremental cycle ergometer test for the determination of the VO(2) on-exercise mean response time (MRT) and the gas exchange threshold (GET). The ΔVO(2)/ΔWR slope was calculated up to GET (S(1)), above GET (S(2)) and over the entire linear portion of the response (S(T)). Knee muscle endurance was measured by isokinetic dynamometry. As expected, peak VO(2) and muscle performance were lower in patients than controls (P < 0.05). Patients had significantly lower ΔVO(2)/ΔWR than controls, especially the S(2) component (6.8 ± 1.5 vs 10.3 ± 0.6 mL·min(-1)·W(-1), respectively; P < 0.001). There were significant relationships between ΔVO(2)/ΔWR (S(T)) and muscle endurance, MRT-VO(2), GET and peak VO(2) in MM patients (P < 0.05). In fact, all patients with ΔVO(2)/ΔWR below 8 mL·min(-1)·W(-1) had severely reduced peak VO(2) values (<60% predicted). Moreover, patients with higher cardiopulmonary stresses during exercise (e.g., higher Δ ventilation/carbon dioxide output and Δ heart rate/ΔVO(2)) had lower ΔVO(2)/ΔWR (P < 0.05). In conclusion, a readily available, effort-independent index of aerobic dysfunction during dynamic exercise (ΔVO(2)/ΔWR) is typically reduced in patients with MM, being related to increased functional impairment and higher cardiopulmonary stress.

Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise

We determined the response characteristics and functional correlates of the dynamic relationship between the rate (Δ) of oxygen consumption ( VO2) and the applied power output (work rate = WR) during ramp-incremental exercise in patients with mitochondrial myopathy (MM). Fourteen patients (7 males, age 35.4 ± 10.8 years) with biopsy-proven MM and 10 sedentary controls (6 males, age 29.0 ± 7.8 years) took a ramp-incremental cycle ergometer test for the determination of the VO2 on-exercise mean response time (MRT) and the gas exchange threshold (GET). The ΔVO2/ΔWR slope was calculated up to GET (S1), above GET (S2) and over the entire linear portion of the response (S T). Knee muscle endurance was measured by isokinetic dynamometry. As expected, peak VO2 and muscle performance were lower in patients than controls (P < 0.05). Patients had significantly lower ΔVO2/ΔWR than controls, especially the S2 component (6.8 ± 1.5 vs 10.3 ± 0.6 mL·min-1·W-1, respectively; P < 0.001). There were significant relationships between ΔVO2/ΔWR (S T) and muscle endurance, MRT-VO2, GET and peak VO2 in MM patients (P < 0.05). In fact, all patients with ΔVO2/ΔWR below 8 mL·min-1·W-1 had severely reduced peak VO2 values (<60 percent predicted). Moreover, patients with higher cardiopulmonary stresses during exercise (e.g., higher Δ ventilation/carbon dioxide output and Δ heart rate/ΔVO2) had lower ΔVO2/ΔWR (P < 0.05). In conclusion, a readily available, effort-independent index of aerobic dysfunction during dynamic exercise (ΔVO2/ΔWR) is typically reduced in patients with MM, being related to increased functional impairment and higher cardiopulmonary stress.

Expression of DNA repair genes in ovarian cancer samples: biological and clinical considerations.

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas. ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis. With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.

Silencing the MET oncogene leads to regression of experimental tumors and metastases.

In spite of the established knowledge of the genetic alterations responsible for cancer onset, the genes promoting and maintaining the invasive/metastatic phenotype are still elusive. The MET proto-oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF), senses unfavorable micro-environmental conditions and drives cell invasion and metastasis. MET overexpression, often induced by tumor hypoxia, leads to constitutive activation of the receptor and correlates with poor prognosis. To establish the role of MET in different phases of tumor progression, we developed an inducible lentiviral delivery system of RNA interference. Silencing the endogenous MET gene, overexpressed in tumor cells, resulted in (i) impairment of the execution of the full invasive growth program in vitro, (ii) lack of tumor growth and (iii) decreased generation of experimental metastases in vivo. Notably, silencing MET in already established metastases led to their almost complete regression. This indicates that persistent expression of the MET oncogene is mandatory until the advanced phases of cancer progression.

Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling.

Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

A phase II clinical trial of topotecan and carboplatin in patients with newly diagnosed advanced epithelial ovarian cancer.

A phase II clinical trial conducted to evaluate the efficacy and tolerability of topotecan and carboplatin as first-line therapy for women with advanced epithelial ovarian cancer was the objective of this study. Patients had histologically confirmed ovarian epithelial cancer with at least one measurable lesion. Patients received topotecan 1.5 mg/m(2) on days 1-3 and carboplatin at an area under the curve (AUC) of 5 on day 3 every 21 days for six cycles. All 42 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was six. Overall response rate was 71%, with 19 clinical complete responses (45%) and 11 clinical partial responses (26%). Median survival time was 47 months and 5-year survival was 42%. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 100% of patients. However, this toxicity was transient and easily manageable; no patients experienced febrile neutropenia. The combination of topotecan and carboplatin is active in advanced epithelial ovarian cancer. Delay of therapy by 1 week or topotecan dose reduction to 1.25 mg/m(2) is the first-choice option to reduce topotecan toxicity without affecting the efficacy. Moreover, a chemotherapy regimen using weekly topotecan, which is currently being tested, should be considered.

A step test to assess exercise-related oxygen desaturation in interstitial lung disease.

A 6-min step test (6MST) may constitute a practical method for routinely assessing effort tolerance and exercise-related oxyhaemoglobin desaturation (ERD) in the primary care of patients with interstitial lung disease. In total, 31 patients (19 males) with idiopathic pulmonary fibrosis (n = 25) and chronic hypersensitivity pneumonia were submitted, on different days, to two 6MSTs. Physiological responses were compared with those found on maximal and submaximal cycle ergometer tests at the same oxygen uptake (V'(O(2))). Chronic breathlessness was also determined, as measured by the baseline dyspnoea index (BDI). Responses to 6MST were highly reproducible: 1.3+/-2.0 steps x min(-1), +/-5 beats x min(-1) (cardiac frequency), +/-50 mL x min(-1) (V'(O(2))), +/-7 L x min(-1) (minute ventilation) and +/-2% (arterial oxygen saturation measured by pulse oximetry (S(p,O(2)))). The number of steps climbed in 6 min was correlated to peak V'(O(2)) and the BDI. There were significant associations among the tests in relation to presence (change in S(p,O(2)) between rest and exercise > or = 4%) and severity (S(p,O(2)) <88%) of ERD. Four patients, however, presented ERD only in response to 6MST. Resting diffusing capacity of the lung for carbon monoxide and alveolar-arterial oxygen tension difference were the independent predictors of the number of steps climbed. A single-stage, self-paced 6-min step test provided reliable and reproducible estimates of exercise capacity and exercise-related oxyhaemoglobin desaturation in interstitial lung disease patients.

Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS).

Overexpression of the c-Met/hepatocyte growth factor receptor(HGF-R) proto-oncogene and abnormal generation of intracellular oxygen species (reactive oxygen species (ROS)) have been linked, by independent lines of evidence, to cell transformation and to malignant growth. By comparing two subpopulations of the B16 mouse melanoma (B16-F0 and B16-F10) endowed with different lung metastasis capacities (low and high, respectively) we found that both the expression/phosphorylation of c-Met and the steady-state levels of ROS positively correlated with metastatic growth. shRNA-mediated downregulation of c-Met in F10 cells led to a parallel decrease in the generation of oxygen species and in metastatic capacity, suggesting that oxidants may mediate the pro-metastatic activity of the HGF receptor. c-Met activation by a ligand elicits the formation of oxidant species through the oxidase-coupled small GTPase Rac-1, a relevant downstream target of the HGF-R. Moreover, cell treatment with the catalytic ROS scavengers EUK-134 and EUK-189 attenuates Met signaling to ERKs and inhibits the anchorage-independent growth of F10 cells, consistent with a critical role for oxygen species in HGF signaling and in aggressive cell behavior. Finally, genetic manipulation of the Rac-ROS cascade at different levels demonstrated its crucial role in the pro-metastatic activity of c-Met in vivo. Thus, we have outlined a novel cascade triggered by c-Met and mediated by ROS, linked to metastasis and potentially targetable by new antimetastatic, redox-based therapies.

Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility.

Plexins encode receptors for semaphorins, molecular signals guiding cell migration, and axon pathfinding. The mechanisms mediating plexin function are poorly understood. Plexin activation in adhering cells rapidly leads to retraction of cellular processes and cell rounding "cell collapse"). Here we show that, unexpectedly, this response does not require the activity of Rho-dependent kinase (ROCK) nor the contraction of F-actin cables. Interestingly, integrin-based focal adhesive structures are disassembled within minutes upon plexin activation; this is followed by actin depolymerization and, eventually, by cellular collapse. We also show that plexin activation hinders cell attachment to adhesive substrates, blocks the extension of lamellipodia, and thereby inhibits cell migration. We conclude that plexin signaling uncouples cell substrate-adhesion from cytoskeletal dynamics required for cell migration and axon extension.

The pattern and timing of breathing during incremental exercise: a normative study.

Clinical evaluation of the pattern and timing of breathing during submaximal exercise can be valuable for the identification of the mechanical ventilatory consequences of different disease processes and for assessing the efficacy of certain interventions. Sedentary individuals (60 male/60 female, aged 20-80 yrs) were randomly selected from >8,000 subjects and submitted to ramp incremental cycle ergometry. Tidal volume (VT)/resting inspiratory capacity, respiratory frequency, total respiratory time (Ttot), inspiratory time (TI), expiratory time (TE), duty cycle (TI/Ttot) and mean inspiratory flow (VT/TI) were analysed at selected submaximal ventilatory intensities. Senescence and female sex were associated with a more tachypnoeic breathing pattern during isoventilation. The decline in Ttot was proportional to the TI and TE reductions, i.e. TI/Ttot was remarkably constant across age strata, independent of sex. The pattern, but not timing, of breathing was also influenced by weight and height; a set of demographically and anthropometrically based prediction equations are therefore presented. These data provide a frame of reference for assessing the normality of some clinically useful indices of the pattern and timing of breathing during incremental cycle ergometry in sedentary males and females aged 20-80 yrs.