Showing papers by "Autonomous University of Barcelona published in 2001"

Trastuzumab (Herceptin), a Humanized Anti-HER2 Receptor Monoclonal Antibody, Inhibits Basal and Activated HER2 Ectodomain Cleavage in Breast Cancer Cells

Abstract: HER2 is a ligand-less tyrosine kinase receptor of the ErbB family that is frequently overexpressed in breast cancer. It undergoes proteolytic cleavage that results in the release of the extracellular domain and the production of a truncated membrane-bound fragment, p95. We show that HER2 shedding is activated by 4-aminophenylmercuric acetate (APMA), a well-known matrix metalloprotease activator, in HER2-overexpressing breast cancer cells. The HER2 p95 fragment, which appears after APMA-induced cleavage, is phosphorylated. We analyzed 24 human breast cancer specimens, and a phosphorylated M(r) 95,000 HER2 band could be detected in some of them, which indicated that the truncated receptor is also present in vivo. The activation of HER2 shedding by APMA in cells was blocked with batimastat, a broad-spectrum metalloprotease inhibitor. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody directed at the HER2 ectodomain, which has been shown to be active in patients with HER2-overexpressing breast cancer, inhibited basal and induced HER2 cleavage and, as a consequence, the generation of phosphorylated p95. This inhibitory effect of trastuzumab was not shared by 2C4, an antibody against a different epitope of the HER2 ectodomain. The inhibition of basal and APMA-induced cleavage of HER2 by trastuzumab preceded antibody-induced receptor down-modulation, which indicated that the effect of trastuzumab on cleavage was not attributable to a decrease in cell-surface HER2 induced by trastuzumab. We propose that the inhibition of HER2 cleavage and prevention of the production of an active truncated HER2 fragment represent a novel mechanism of action of trastuzumab.

Responses to a Warming World

Abstract: Animal and plant life cycles are increasingly shown to depend on temperature trends and patterns. In their Perspective, PeA±uelas and Filella review the evidence that global warming during the 20th century has affected the growth period of plants and the development and behavior of animals from insects to birds. The authors warn that changes in the interdependence between species could have unpredictable consequences for ecosystems, that the lengthening of the plant growing season contributes to the global increased carbon fixation, and that changes in phenology may affect not only ecosystems but also agriculture and sanitation.

Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study

Abstract: Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P=0.004, HR 1.3) and overall survival (P=0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P=0.008, HR 1.5, overall survival P=0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P=0.46, HR 1.12, overall survival P=0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. ⌐ 2001 Cancer Research Campaign.

Validation and utility of the patient health questionnaire in diagnosing mental disorders in 1003 general hospital Spanish inpatients

Abstract: OBJECTIVE To determine whether the Spanish version of the patient health questionnaire (PHQ) has validity and utility for diagnosing mental disorders in general hospital inpatients. METHODS Participants in the study were 1003 general hospital inpatients, randomly selected from all admissions over an 18-month period. All of them completed the PHQ, the Beck Depression Inventory (BDI), and measures of functional status, disability days, and health care use, including length of hospital stay. They also had a structured interview with a mental health professional. RESULTS A total of 416 (42%) of the 1003 general hospital inpatients had a PHQ diagnosis. There was good agreement between PHQ diagnoses and those of an independent mental health professional (for the diagnosis of any PHQ disorder, kappa = 0.74; overall accuracy, 88%; sensitivity, 87%; specificity, 88%), similar to the original English version of the PHQ in primary care patients. Patients with PHQ diagnoses had more functional impairment, disability days, and health care use than did patients without PHQ diagnoses (group main effects for functional status measures and disability days, p < .001; group main effects for health care use, p < .01). The group main effect for hospital length of stay was not significant. An index of depression symptom severity calculated from the PHQ correlated significantly both with the number of depressive symptoms detected at interview and the total BDI score. PHQ administration was well accepted by patients. CONCLUSIONS The Spanish version of the PHQ has diagnostic validity in general hospital inpatients comparable to the original English version in primary care.

The role of root exudates in aluminium resistance and silicon‐induced amelioration of aluminium toxicity in three varieties of maize (Zea mays L.)

Abstract: Aluminium (Al) toxicity is widely considered to be the most important growth-limiting factor for plants in strongly acid soils (pH<5.0). The inhibition of root elongation in three varieties of maize (Zea mays L. vars Clavito, HS701b and Sikuani) was followed over the first 48 h of Al treatment, and during the initial 10 h elongation was determined on an hourly basis. The silicon (Si)-induced amelioration of Al toxicity was investigated by pre-treating seedlings for 72 h in nutrient solutions with 1000 microM Si before transfer into solutions with 0, 20 or 50 microM Al (without Si). Plants were either grown in complete low ionic strength nutrient solutions (CNS) or in low salt solutions of 0.4 mM CaCl2 (LSS). In addition, the role of root exudation of organic compounds as a mechanism of Si-induced alleviation of Al toxicity was investigated. Aluminium-induced inhibition of root elongation in the maize var. HS701b was observed within 1 h of Al exposure. After a lag time of at least 8 h, Si-induced alleviation of Al toxicity was observed in this variety when grown in LSS. In the Al-resistant var. Sikuani, Al-resistance was only observed after exposure to 50 microM Al, and not after exposure to 20 microM Al, suggesting that there exists a threshold Al concentration before the mechanisms of Al resistance are activated. Aluminium stimulated root exudation of oxalic acid in all three varieties, but exudate concentrations did not increase with either Al resistance or with Si pretreatment. Aluminium and Si triggered release of catechol and of the flavonoid-type phenolics: catechin, and quercetin. In the Al-resistant variety, Sikuani, Al-exposed plants pretreated with Si exuded up to 15 times more phenolics than those plants not pretreated with Si. The flavonoid-type phenolics, to date unconsidered, appear to play a role in the mechanism(s) of Si-induced amelioration of Al toxicity.

Spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings.

Abstract: Aspergillosis is a serious pathologic condition caused by Aspergillus organisms and is frequently seen in immunocompromised patients. At computed tomography (CT), saprophytic aspergillosis (aspergilloma) is characterized by a mass with soft-tissue attenuation within a lung cavity. The mass is typically separated from the cavity wall by an airspace ("air crescent" sign) and is often associated with thickening of the wall and adjacent pleura. CT findings in allergic bronchopulmonary aspergillosis consist primarily of mucoid impaction and bronchiectasis involving predominantly the segmental and subsegmental bronchi of the upper lobes. Aspergillus necrotizing bronchitis may manifest as an endobronchial mass, obstructive pneumonitis or collapse, or a hilar mass. Bronchiolitis is characterized by centrilobular nodules and branching linear or nodular areas of increased attenuation ("tree-in-bud" pattern). Obstructing bronchopulmonary aspergillosis mimics allergic bronchopulmonary aspergillosis at CT and manifests as bilateral bronchial and bronchiolar dilatation, large mucoid impactions, and diffuse lower lobe consolidation caused by postobstructive atelectasis. Characteristic CT findings in angioinvasive aspergillosis consist of nodules surrounded by a halo of ground-glass attenuation ("halo sign") or pleura-based, wedge-shaped areas of consolidation. Although imaging findings in pulmonary aspergillosis may be nonspecific, in the appropriate clinical setting, familiarity with the CT findings may suggest or even help establish the diagnosis.

Prevalence of Leishmania infantum infection in dogs living in an area of canine leishmaniasis endemicity using PCR on several tissues and serology.

Abstract: We studied and compared the prevalence of Leishmania infection and the seroprevalence and the prevalence of canine leishmaniasis in an area where canine leishmaniasis is endemic. One hundred dogs living on the island of Mallorca (Spain) were studied. In this study, we clinically examined each dog for the presence of symptoms compatible with leishmaniasis, determined the titer of anti-Leishmania antibodies, and investigated the presence of Leishmania DNA by PCR in skin, conjunctiva, and bone marrow samples of each dog. The prevalence of the disease and the seroprevalence were 13 and 26%, respectively. In 63% of the dogs, Leishmania DNA could be detected by PCR in at least one of the tissues studied. The results of positive PCR in the bone marrow, the conjunctiva, and the skin were 17.8, 32, and 51%, respectively. The prevalence of the infection, 67%, was calculated using all animals that were seropositive and/or positive by PCR with any tissue. The results showed that the majority of dogs living in an area where canine leishmaniasis is endemic are infected by Leishmania and that the prevalence of infection is much greater than the prevalence of overt Leishmania-related disease.

Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome

Abstract: Background—Patients with irritable bowel syndrome (IBS) frequently complain of excessive gas but their fasting volume of intestinal gas is apparently normal. We hypothesised that the pathophysiological mechanism involved may be impairment of intestinal gas transit. Aim—To investigate intestinal gas transit and tolerance in IBS patients compared with healthy subjects. Methods—A gas mixture (N2 ,O 2, and CO2 in venous proportions) was infused into the jejunum of 20 patients with IBS and 20 healthy controls at 12 ml/min for four hours. Gas evacuation, initially flatus from the anus (two hours) and then intrarectally (two hours), was continuously recorded. Symptom perception (0‐6 scale) and abdominal distension were measured at 10 minute intervals. Results—After two hours of external gas (flatus) collection, 18 of 20 IBS patients had developed gas retention (>400 ml), increased gastrointestinal symptoms (score >3), or abdominal distension (>3 mm girth increment) compared with only four of 20 control subjects. During intrarectal gas collection, 13 of 17 patients still exhibited abnormal responses. Conclusion—A large proportion of patients with IBS can be shown to have impaired transit and tolerance of intestinal gas loads.This anomaly may represent a possible mechanism of IBS symptoms, specifically pain and bloating. (Gut 2001;48:14‐19)

Cosmic antifriction and accelerated expansion

Abstract: We explain an accelerated expansion of the present Universe, suggested from observations of supernovae of type la at high redshift, by introducing an antifrictional force that is self-consistently exerted on the particles of the cosmic substratum. Cosmic antifriction. which is intimately related to "particle production," is shown to give rise to an effective negative pressure of the cosmic medium. While other explanations for an accelerated expansion (cosmological constant, quintessence) introduce a component of dark energy in addition to "standard" cold dark matter (CDM) we resort to a phenomenological one-component model of CDM with internal self-interactions. We demonstrate how the dynamics of the cold dark matter model with a cosmological constant may be recovered as a special case of cosmic antifriction. We discuss the connection with two-component models and obtain an attractor behavior for the ratio of the energy densities of both components which provides a possible phenomenological solution to the coincidence problem.

Activated Extracellular Signal-regulated Kinases: Association with Epidermal Growth Factor Receptor/Transforming Growth Factor α Expression in Head and Neck Squamous Carcinoma and Inhibition by Anti-Epidermal Growth Factor Receptor Treatments

Abstract: The expression of the activated mitogen-activated kinases/extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 humanhead and neck squamous carcinoma specimens Activated ERK1/2were detected at different levels in the majority of these tumors, as assayed by immunostaining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2 ERK1/2 activation levels were higher in tumors with advanced regional lymph node metastasis (P = 0048) and in relapsed tumors (P = 0021) The expression of epidermal growth factor (EGF) receptor (P = 0037), transforming growth factor alpha (TGF-alpha; P < 0001), and HER2 (P = 0066; positive trend) correlated with activation of ERK1/2 In a multivariate analysis, both TGF-alpha (P < 00001) and HER2 (P = 0045) were independently correlated with ERK1/2 activation In turn, activation of ERK1/2 was associated with a higher Ki-67 proliferative index (P = 0002) In EGF receptor-dependent model cells (A431 and DiFi), a specific EGF receptor tyrosine kinase inhibitor ("Iressa"; ZD1839) and a chimeric anti-EGF receptor antibody ("Cetuximab"; C225) inhibited ERK 1/2 activation at concentrations that inhibited autocrine cell proliferation In patients on treatment with C225, the activation of ERK1/2 in skin, an EGF receptor-dependent tissue, was lower compared with control skin Parallel changes were seen in keratinocyte Ki67 proliferation indexes in skin from C225-treated patients Taken together, these studies provide support for a role of activation of ERK1/2 in head and neck squamous carcinoma and a correlation with EGF receptor/TGF-alpha expression The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies

Variations of the arterial pattern in the upper limb revisited: a morphological and statistical study, with a review of the literature.

Abstract: A total of 192 embalmed cadavers were examined in order to present a detailed study of arterial variations in the upper limb and a meta-analysis of them. The variable terminology previously used was unified into a homogenous and complete classification, with 12 categories covering all the previously reported variant patterns of the arm and forearm.

Thyroid Autoimmune Disease: Demonstration of Thyroid Antigen-Specific B Cells and Recombination-Activating Gene Expression in Chemokine-Containing Active Intrathyroidal Germinal Centers

Abstract: Autoimmune thyroid disease--Hashimoto thyroiditis and Graves' disease--patients produce high levels of thyroid autoantibodies and contain lymphoid tissue that resembles secondary lymphoid follicles (LFs). We compared the specificity, structure, and function of tonsil and lymph node LFs with those of the intrathyroidal LFs to assess the latter's capability to contribute to autoimmune response. Thyroglobulin and thyroperoxidase binding to LFs indicated that most intrathyroidal LFs were committed to response to thyroid self-antigens and were associated to higher levels of antibodies to thyroglobulin, thyroperoxidase, and thyroid-stimulating hormone receptor. Intrathyroidal LFs were microanatomically very similar to canonical LFs, ie, they had well-developed germinal centers with mantle, light, and dark zones and each of these zones contained B and T lymphocytes, follicular dendritic and interdigitating dendritic cells with typical phenotypes. Careful assessment of proliferation (Ki67) and apoptosis (terminal dUTP nick-end labeling) indicators and of the occurrence of secondary immunoglobulin gene rearrangements (RAG1 and RAG2) confirmed the parallelism. Unexpected high levels of RAG expression suggested that receptor revision occurs in intrathyroidal LFs and may contribute to generate high-affinity thyroid autoantibodies. Well-formed high endothelial venules and a congruent pattern of adhesion molecules and chemokine expression in intrathyroidal LFs were also detected. These data suggest that ectopic intrathyroidal LFs contain all of the elements needed to drive the autoimmune response and also that their microenvironment may favor the expansion and perpetuation of autoimmune response.

Severe Drought Effects on Mediterranean Woody Flora in Spain

Abstract: The severe drought in 1994 damaged the woody flora of central and southern Spain (80% of the 190 studied sites presented drought-damaged species). In 1996, after a wet year, 67% of the sites were still affected. Different degrees of damage and recovery were found among different functional types (trees or shrubs), and genera of different evolutionary history (Mediterranean or pre- Mediterranean). The Mediterranean genera, mostly shrubs evolved under Mediterranean climate conditions, i.e., later than 3.2 M years ago in the Pliocene, were more damaged by the drought than the earlier evolved pre-Mediterranean genera, mostly trees. However, the Mediterranean genera were more resilient and recovered much better after the following wet year. FOR. SCI. 47(2):214-218.

Cosmic acceleration without quintessence

Abstract: It is argued that Brans-Dicke theory may explain the present accelerated expansion of the universe without resorting to a cosmological constant or quintessence matter.

The Complexity of Factors Driving Volatile Organic Compound Emissions by Plants

Abstract: The emissions of volatile organic compounds, VOC, from plants have strong relevance for plant physiology, plant ecology, and atmospheric chemistry. We report here on the current knowledge of the many internal (genetic and biochemical) and external (abiotic - temperature, light, water availability, wind, ozone, and biotic - animal, plant and microorganisms interactions) factors that control emission rates of different VOC by altering their synthesis, vapour pressure or diffusion to the atmosphere. The complex net of these factors, their interactions and the different responses of the different VOC produces the large qualitative and quantitative, spatial and temporal variability of emissions and the frequent deviations from current standard emission models. The need for a co-operative multidisciplinary multiscale research to disentangle this complex and important issue of plant VOC emissions is reminded.

Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.

Abstract: We report a family with a new phenotype of autosomal recessive muscle dystrophy caused by a dysferlin mutation. The onset of the illness is distal, in the muscles of the anterior compartment group. The disease is rapidly progressive, leading to severe proximal weakness. Muscle biopsy showed moderate dystrophic changes with no vacuoles. Dysferlin immunostaining was negative. Gene analysis revealed a frameshift mutation in the exon 50 (delG5966) of the DYSF gene. This phenotype further demonstrates the clinical heterogeneity of the dysferlinopathies.

Imaging of pneumonia: trends and algorithms

Abstract: Pneumonia is one of the major infectious diseases responsible for significant morbidity and mortality throughout the world. Imaging plays a crucial role in the detection and management of patients with pneumonia. This review article discusses the different imaging methods used in the diagnosis and management of suspected pulmonary infections. The imaging examination should always begin with conventional radiography. When the results of routine radiography are inconclusive, computed tomography is mandatory. A combination of pattern recognition with knowledge of the clinical setting is the best approach to the pulmonary infectious processes. A specific pattern of involvement can suggest a likely diagnosis in many instances. In acquired immune deficiency syndrome patients, diffuse ground-glass and interstitial infiltrates are most commonly present in Pneumocystis carinii pneumonia whereas in the nonimmunosuppressed patients, a segmental lobar infiltrate is suggestive of a bacterial pneumonia. Round pneumonia is most often encountered in children than adults and is most often caused by Streptococcus pneumoniae. Different combinations of parenchymal and pleural abnormalities may be suggestive for additional diagnoses. When an infectious pulmonary process is suspected, knowledge of the varied radiographic manifestations will narrow the differential diagnosis, helping to direct additional diagnostic measures, and serving as an ideal tool for follow-up examinations.