Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: Results from the randomized controlled I-COME Trial

Introduction: Imatinib trough plasma concentrations (Cmin) have been correlated with treatment response in chronic myeloid leukemia (CML) patients. The use of Cmin monitoring for optimizing imatinib dosage (therapeutic drug monitoring [TDM]) is therefore proposed for patients with unsatisfying response or tolerance ("rescue TDM"). A cycle of "routine TDM" for dosage individualization could also be beneficial to prevent unfavorable events, yet its clinical usefulness has not been evaluated. We aimed to assess prospectively whether a "routine TDM" intervention targeting imatinib Cmin of 1000 ng/mL (tolerance, 750-1500 ng/mL) could improve efficacy, tolerance, and persistence on treatment compared with "rescue TDM" use only. Patients (or Materials) and Methods: The Swiss Imatinib COncentration Monitoring Evaluation (I-COME) study was a multicenter randomized controlled trial (ISRCTN31181395). Adult patients in chronic or accelerated phase CML receiving imatinib ≤5 years were eligible. Patients were randomly (1:1) allocated to receive "routine TDM" intervention or to serve as controls with access only to "rescue TDM". All had 1-year follow-up. The primary endpoint was a combined efficacy-safety outcome (failure- and toxicity-free survival without imatinib discontinuation), analyzed in intention-to-treat. Results: Among 56 CML recruited patients, 55 had their molecular and cytogenetic response measured. 14/27 of patients receiving "routine TDM" (52% [33%-71%]) remained event-free versus 16/28 of control patients with "rescue TDM" only (57% [39%-75%]; P=0.69). In the "routine TDM" group, dosage recommendations were adopted entirely in 50% of patients (median Cmin at study end, 895 ng/mL; CV = 33%). These patients had fewer unfavorable events (28% [5%-52%]) compared with patients not receiving the advised dosage (77% [54%-99%]; P = 0.03; median Cmin at study end, 648 ng/mL; CV = 38%). Conclusion: This first prospective target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" of imatinib, especially due to a small patient number and limited prescriber's adherence to dosage recommendations. Nevertheless, the patients receiving the advised dosage more often met target concentrations and the combined outcome (efficacy, tolerance, and persistence). A cycle of routine TDM could thus be favorable, at least in patients eligible for dosage adjustment. Its usefulness should, however, be further confirmed in larger trials.

Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome.

INTRODUCTION: We investigated whether mRNA levels of E2F1, a key transcription factor involved in proliferation, differentiation and apoptosis, could be used as a surrogate marker for the determination of breast cancer outcome. METHODS: E2F1 and other proliferation markers were measured by quantitative RT-PCR in 317 primary breast cancer patients from the Stiftung Tumorbank Basel. Correlations to one another as well as to the estrogen receptor and ERBB2 status and clinical outcome were investigated. Results were validated and further compared with expression-based prognostic profiles using The Netherlands Cancer Institute microarray data set reported by Fan and colleagues. RESULTS: E2F1 mRNA expression levels correlated strongly with the expression of other proliferation markers, and low values were mainly found in estrogen receptor-positive and ERBB2-negative phenotypes. Patients with low E2F1-expressing tumors were associated with favorable outcome (hazard ratio = 4.3 (95% confidence interval = 1.8-9.9), P = 0.001). These results were consistent in univariate and multivariate Cox analyses, and were successfully validated in The Netherlands Cancer Institute data set. Furthermore, E2F1 expression levels correlated well with the 70-gene signature displaying the ability of selecting a common subset of patients at good prognosis. Breast cancer patients' outcome was comparably predictable by E2F1 levels, by the 70-gene signature, by the intrinsic subtype gene classification, by the wound response signature and by the recurrence score. CONCLUSION: Assessment of E2F1 at the mRNA level in primary breast cancer is a strong determinant of breast cancer patient outcome. E2F1 expression identified patients at low risk of metastasis irrespective of the estrogen receptor and ERBB2 status, and demonstrated similar prognostic performance to different gene expression-based predictors.

G-CSF-induced remission in two cases of acute myeloid leukemia.

We report on two elderly patients with newly diagnosed acute myeloid leukemia (AML) who were treated in palliative intention because of comorbidities and intermediate or poor risk cytogenetics. Both received G-CSF to reduce the risk of infection related to neutropenia. Interestingly, one patient achieved a full hematological remission and the other a peripheral remission with dramatic reduction of the bone marrow blast count. Although a direct therapeutic effect of myeloid growth factors seems to be unusual in AML, the use of G-CSF or GM-CSF may be recommended in patients such as elderly patients who are not suited for intensive chemotherapy.

Evaluation of potential breath biomarkers for active smoking: assessment of smoking habits

Different compounds have been reported as biomarkers of a smoking habit, but, to date, there is no appropriate biomarker for tobacco-related exposure because the proposed chemicals seem to be nonspecific or they are only appropriate for short-term exposure. Moreover, conventional sampling methodologies require an invasive method because blood or urine samples are required. The use of a microtrap system coupled to gas chromatography–mass spectrometry analysis has been found to be very effective for the noninvasive analysis of volatile organic compounds in breath samples. The levels of benzene, 2,5-dimethylfuran, toluene, o-xylene, and m- p-xylene have been analyzed in breath samples obtained from 204 volunteers (100 smokers, 104 nonsmokers; 147 females, 57 males; ages 16 to 53 years). 2,5-Dimethylfuran was always below the limit of detection (0.005 ppbv) in the nonsmoker population and always detected in smokers independently of the smoking habits. Benzene was only an effective biomarker for medium and heavy smokers, and its level was affected by smoking habits. Regarding the levels of xylenes and toluene, they were only different in heavy smokers and after short-term exposure. The results obtained suggest that 2,5-dimethylfuran is a specific breath biomarker of smoking status independently of the smoking habits (e.g., short- and long-term exposure, light and heavy consumption), and so this compound might be useful as a biomarker of smoking exposure

Bacterial membrane injuries induced by lactacin F and nisin

The combined action of nisin and lactacin F, two bacteriocins produced by lactic acid bacteria, is additive. In this report, the basis of this effect is examined. Channels formed by lactacin F were studied by experiments using planar lipid bilayers, and bactericidal effects were analyzed by flow cytometry. Lactacin F produced pores with a conductance of 1 ns in black lipid bilayers in 1 mM KClat 10 mV at 20°C. Pore formation was strongly dependent on voltage. Although lactacin F formed pores at very low potential (10 mV), the dependence was exponentialabov e 40 mV. The injuries induced by nisin and lactacin F in the membranes of Lactobacillus helveticus produced different flow cytometric profiles. Probably, when both bacteriocins are present, each acts separately; their cooperation may be due to an increase in the number of single membrane injuries

La naturalesa de l'enllaç químic. Contribucions de Linus Pauling

Aquest treball comença amb un breu repàs de l'evolució històrica del concepte d'enllaç químic, seguit d'una introducció als dos models que, en el marc de la mecànica quàntica, es fan servir actualment per explicar aquell concepte (orbitals moleculars i enllaç-valència). Després d'aquesta introducció, es presenten les principals aportacions fetes per Linus Pauling en relació amb l'enllac, la major part de les quals s'enquadren en el context enllaç-valència. El treball de Heitler i London, considerat com l'inici del model enllaç-valència, posa de manifest que, quan els electrons que formen l'enllaç tenen els seus spins antiparal•lels, se situen preferentment entre els nuclis i poden llavors atreure'ls amb intensitat sufficient per vèncer la repulsió internuclear. En paraules de Pauling, la força química és una força d'origen electrostàtic, que pot ser atractiva o repulsiva depenent de l'orientació relativa dels spins electronics. El treball de Pauling relacionat amb la comprensió de l'enllaç és molt ampli. Una de les claus per entendre el seu èxit es deu a la concurrència de dos factors: la seva condició de químic, d'una Banda, i, de l'altra, el seu coneixement de la mecànica quàntica quan tot just s'estava desenvolupant en un restringit cercle de físics teòrics. Aquesta formació li permeté entroncar els conceptes quàntics amb el model de Lewis, ben conegut per la resta de químics. Destaquem l'especial rellevància de les publications dels anys trenta, les quals inclouen les contribucions més importants en relació amb la naturalesa de l'enllaç. Una d'aquestes és el concepte d'hibridació, el qual, malgrat el seu actual desprestigi per part de molts químics quàntics, ha tingut una importància històrica cabdal, en permetre racionalitzar l'estructura de la major part de les molècules i, en particular, dels complexos dels metalls de transició. Una altra contribució rellevant es el concepte de ressonància, desenvolupat per explicar l'estructura de les molècules que, com el benzè, no es poden representar amb una sola estructura de Lewis. Una aplicació menys coneguda d'aquest concepte fou el model introduït per Pawling per explicar les especials propietats dels metalls. El treball conclou amb una breu incursió en les actuals perspectives del mètode enllaç-valència. En els últims anys, aquest mètode ha recuperat interès gràcies als seus avantatges de cara a la interpretació dels resultats de sofisticats càlculs mecanoquàntics utilitzant les idees intuïtives que, de manera quasi constant, fan servir els químics en els seus raonaments. Aquest és, de fet, el punt clau que Pauling ha defensat al llarg de la seva carrera científica i que, malgrat el seu indiscutible interès, queda, de vegades, relegat a un segon terme a causa d'una excessiva preocupació per la precisió dels càlculs.

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

Evaluation of potential breath biomarkers for active smoking: assessment of smoking habits

Different compounds have been reported as biomarkers of a smoking habit, but, to date, there is no appropriate biomarker for tobacco-related exposure because the proposed chemicals seem to be nonspecific or they are only appropriate for short-term exposure. Moreover, conventional sampling methodologies require an invasive method because blood or urine samples are required. The use of a microtrap system coupled to gas chromatography–mass spectrometry analysis has been found to be very effective for the noninvasive analysis of volatile organic compounds in breath samples. The levels of benzene, 2,5-dimethylfuran, toluene, o-xylene, and m- p-xylene have been analyzed in breath samples obtained from 204 volunteers (100 smokers, 104 nonsmokers; 147 females, 57 males; ages 16 to 53 years). 2,5-Dimethylfuran was always below the limit of detection (0.005 ppbv) in the nonsmoker population and always detected in smokers independently of the smoking habits. Benzene was only an effective biomarker for medium and heavy smokers, and its level was affected by smoking habits. Regarding the levels of xylenes and toluene, they were only different in heavy smokers and after short-term exposure. The results obtained suggest that 2,5-dimethylfuran is a specific breath biomarker of smoking status independently of the smoking habits (e.g., short- and long-term exposure, light and heavy consumption), and so this compound might be useful as a biomarker of smoking exposure

Anàlisi d'un spot televisiu segons el model proposat per Frederic Chaume : Estudi d'un cas: Beauty is nothing without brains

L’estudi de les situacions comunicatives sempre m’ha atret de manera significativa. El món de la publicitat, també. L’assignatura de Semiòtica audiovisual ha estat el vincle que ha inspirat el tema d’aquest treball. L’idea inicial era la d’analitzar des d’una perspectiva semiòtica un document audiovisual, concretament, Beauty is nothing without brains, un espot televisiu de Mercedes-Benz emès als Estats Units l’any 2007. Es pretenia identificar i analitzar cadascun dels elements que configuren la comunicació audiovisual i presentar possibles versions traductològiques del mateix. La dificultat de crear un esquema d’anàlisi que em permetés estructurar-ne l’estudi va conduir-me a Frederic Chaume. És llavors quan aconsegueixo concretar el tema del treball: es pretén analitzar aquest document audiovisual seguint el model proposat per Chaume, responent a un hipotètic encàrrec de traducció el qual demana la seva adaptació al mercat català.

Hidrocarbonetos policíclicos aromáticos (HPAS) em cachaça, rum, uísque e álcool combustível

The concentration of 15 polycyclic aromatic hydrocarbons (PAHs) in 57 samples of distillates (cachaça, rum, whiskey, and alcohol fuel) has been determined by HPLC-Fluorescence detection. The quantitative analytical profile of PAHs treated by Partial Least Square - Discriminant Analysis (PLS-DA) provided a good classification of the studied spirits based on their PAHs content. Additionally, the classification of the sugar cane derivatives according to the harvest practice was obtained treating the analytical data by Linear Discriminant Analysis (LDA), using naphthalene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benz[a]anthracene, benz[b]fluoranthene, and benz[g,h,i]perylene, as a chemical descriptors.

Estudo da reatividade do estado excitado triplete de 1,4-diaza-9-fluorenonas frente a doadores de hidrogênio e de elétron

The effect of the introduction of nitrogen atoms upon the triplet excited state reactivity of 1,4-diaza-9-fluorenone (1) and 1,4-diaza-9-benz[b]fluorenone (2), in acetonitrile, was investigated employing the nanosecond laser flash photolysis technique. The intersystem crossing quantum yield (Φces) for 1 and 2 was determined using 9-fluorenone as a secondary standard (Φces= 0.48, in acetonitrile) and for both diazafluorenones a value of Φces= 0.28 was found. Quenching rate constants ranged from 8.17x10(4) L mol-1 s-1 (2-propanol) to 1.02x10(10) L mol-1 s-1 (DABCO) for 1,4-diaza-9-fluorenone and from 6.95x10(5) L mol-1 s-1 (2-propanol) to 5.94x10(9) L mol-1 s-1 (DABCO) for 1,4-diaza-9-benz[b]fluorenone, depending if the quenching process involves energy, hydrogen or electron transfer. A comparison between quenching rate constants for both diazaflurenones and the parent compound, i.e. 9-fluorenone, a ketone with lowest triple state of ππ* configuration, lead to the conclusion that the reactive triplet excited state for 1,4-diaza-9-fluorenone and 1,4-diaza-9-benz[b]fluorenone has ππ* configuration.

Avaliação de parâmetros de consumo de combustível do Tritrem no transporte de madeira

Analisou-se o efeito dos parâmetros marcha lenta, excesso de rotação do motor para valores superiores a 2.000 rpm, pontos neutros e velocidades superiores a 80 km/h, com o objetivo de monitorar o consumo de combustível de veículos de transporte rodoviário de duas transportadoras de madeira (A e B), com base nas informações obtidas de um computador de bordo instalado no cavalo-mecânico LS 2638 da Mercedes-Benz. A marcha lenta foi responsável pelo maior desperdiço de combustível; as transportadoras A e B consumiram 20.122,33 e 18.321,72 L/mês, respectivamente. Ela induziu a um consumo mensal de combustível na ordem de R$ 19.164,50 (91,32%) e R$ 17.449,61 (99,09%), pois, em média, os motores dos veículos funcionaram 24,47 e 25,79% do tempo de operação para as transportadoras A e B, respectivamente. O excesso de rotação do motor dos veículos também induziu ao consumo mensal de combustível de R$ 69,45 (0,33%) para a transportadora A e de R$155,62 (0,88%) para a transportadora B. O ponto neutro contribuiu com o consumo de combustível em R$ 1.751,73 (8,35%) e R$ 4,80 (0,03%), respectivamente, para as transportadoras A e B. Não foi calculado o consumo relativo ao excesso de velocidade, por não serem conhecidos a faixa de potência, a rotação e o consumo específico associado a cada velocidade. A metodologia usada é específica para o motor OM 457 LA, podendo ser adotada em outros estudos, desde que adaptada às especificações dos motores utilizados; a marcha lenta foi responsável pelo maior consumo de combustível no transporte de madeira, seguida do ponto neutro e do excesso de rotação. No transporte de madeira é possível reduzir significativamente o consumo de combustível em relação à marcha lenta, em virtude do elevado tempo de espera (carregamento, descarregamento, filas e paradas obrigatórias). O uso do ponto neutro e o excesso de velocidade não economizam combustível e comprometem a segurança. As rotações superiores a 2.000 rpm implicam desperdício de combustível. O ponto de rotação máxima ideal para o motor dos veículos nas condições estudadas está na faixa de 1.700 rpm. Um pequeno número de equipes foi responsável pelo elevado número de infrações cometidas. A falta de treinamento dos motoristas contribui para o aumento de consumo de combustível. O cumprimento das normas sobre condução econômica ajuda a reduzir os custos com combustível.