Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV.

The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome-positive (Ph(+)) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACAs except -Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P < .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.

Arqueología de la producción agrícola. Aplicación de técnicas de análisis estadístico y geocomputacional a un caso de estudio del IV-II milenio ANE en la Cuenca del Río Grande (Perú)

Muchas investigaciones arqueobotánicas, desde un enfoque cualitativo-descriptivo, limitan el propio campo de estudio a los análisis de presencia/ausencia y/o de frecuencia de taxones a partir de su recuento en los conjuntos vegetales. De esa manera, los datos proporcionados resultan ser inconcluyentes y no fiables para la reconstrucción del paleoambiente, la determinación de la dieta alimenticia y de la práctica económica realizada (recolección VS agricultura), y totalmente insuficientes para determinar los cambios históricos ocurridos en los procesos productivos. Por lo que concierne el Perú, desde los primeros estudios con referencia a restos vegetales recuperados en yacimientos arqueológicos, principalmente de la costa, se documenta el importante papel que han desarrollado las especies vegetales en la vida de las comunidades pre-hispánicas. No obstante la excepcional abundancia y óptima preservación de este tipo de material (botánico) en muchos de los yacimientos arqueológicos de esta región, gracias a las extremas condiciones climáticas y ambientales sobre todo de sus áridas zonas costeras, los estudios arqueobotánicos desarrollados hasta el momento son muy escasos y las limitaciones análiticas que presentan en su mayoría reflejan la poca importancia dada a las investigaciones arqueobotánicas. En el presente trabajo desarrollamos y aplicamos una metodología analítica de tipo cuantitativa para el estudio de los macrorestos vegetales procedentes de un yacimiento de la Costa sur del Perú. Con ello pretendemos obtener datos representativos y objetivos de los conjuntos analizados, cuyo procesado lleve a una exhaustiva y correcta interpretación de la información.

Identificació i caracterització funcional dels complexes proteics dels receptors BRL1 i BRL3 en el teixit vascular d’Arabidopsis Thaliana

Els esteroids juguen papers clau en el creixement I el desenvolupament d’eucariotes multicel•lulars. En plantes, aquestes hormones, anomenades Brassinosteroides (BRs), estan involucrades en una gran varietat de processos biològics essencials per a les plantes. S’han descrit anteriorment dos receptors de BRs del tipus Leucine Rich Repeat Receptor Like Kinase LRR-RLK, BRASSINOSTEROID RECEPTOR LIKE 1 i 3 (BRL1 i BRL3 respectivalemt) que són homòlegs al receptor principal BRI1 i són necessaris pel desenvolupament vascular. Tot i que els principals components de la senyal ja han estat identificats pel seu homòleg més pròxim, el receptor BRI1, els complexes de BRL1 i BRL3 juntament amb els candidats co-receptors així com els components de la ruta de senyalització encara no han sigut identificats. Per tal d’entendre millor la funció molecular d’aquests receptors de BRs en la planta aquesta tesis doctoral planteja dues aproximacions: com a primera aproximació, vaig realitzar un estudi fenotípic del desenvolupament del teixit vascular a la planta model Arabidopsis thaliana (Arabidopsis). Disposant d'una amplia bateria de mutants de síntesis de la hormona i senyalització del receptor BRI1, vam analitzar quantitativament el seu patró vascular a la tija d'Arabidopsis. Vam establir els paràmetres en les plantes silvestres [Col-0 wild type, (WT)] i els vam analitzar a tots i cadascun dels mutants. Això conjuntament amb una col•laboració amb la Dr. Marta Ibañes, física de la Universitat de Barcelona que va construir un model matemàtic per simular la formació del patró vascular ens va permetre el•laborar una hipòtesis que vam demostrar experimentalment i va ser publicada a la revista PNAS. Posteriorment vam observar que les plantes knock-out d'aquests dos receptors BRL1 y BRL3 a diferència de BRI1, no tenien cap fenotip obvi en el teixit vascular de la planta adulta. Així, a continuació, per entendre quina necessitat té la planta de disposar de tres receptors tant altament homòlegs que poden percebre la mateixa hormona, vam utilitzar una aproximació bioquímica en col•laboració amb el Prof. de Vries de la Universitat de Wageningen (Holanda) per tal de purificar els complexes dels receptors in vivo i els seus interactors. Això ens ha permès entendre millor el paper funcional d'aquests receptors en la planta. Els resultats d’aquests experiments estan resumits en un article en preparació que aviat estarà en revisió.

Feuilletages par variétés complexes et problèmes d'uniformisation

Ce texte est une introduction aux feuilletages par variétés complexes et aux problèmes d'uniformisation de tels feuilletages. Nous donnons en introduction une liste fondamentale de questions naturelles sur ces objets ainsi qu'un aperçcu des résultats connus.

Impact of Balanced or Unbalanced Karyotype At Diagnosis On Prognosis of CML: Long-Term Observation From 1346 Patients of the Randomized CML Study IV

Introduction: Acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the translocation t(9;22)(q34;q11) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations and mutations and thereby progression to accelerated phase (AP) and blast crisis (BC). At least 10% of patients in chronic phase (CP) CML show additional alterations at diagnosis. This proportion rises during the course of the disease up to 80% in BC. Acquisition of chromosomal changes during treatment is considered as a poor prognostic indicator, whereas the impact of chromosomal aberrations at diagnosis depends on their type. Patients with major route additional chromosomal alterations (major ACA: +8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11) have a worse outcome whereas patients with minor route ACA show no difference in overall survival (OS) and progression-free survival (PFS) compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome (Fabarius et al., Blood 2011). However, the impact of balanced vs. unbalanced (gains or losses of chromosomes or chromosomal material) karyotypes at diagnosis on prognosis of CML is not clear yet. Patients and methods: Clinical and cytogenetic data of 1346 evaluable out of 1544 patients with Philadelphia and BCR-ABL positive CP CML randomized until December 2011 to the German CML-Study IV, a randomized 5-arm trial to optimize imatinib therapy by combination, or dose escalation and stem cell transplantation were investigated. There were 540 females (40%) and 806 males (60%). Median age was 53 years (range, 16-88). The impact of additional cytogenetic aberrations in combination with an unbalanced or balanced karyotype at diagnosis on time to complete cytogenetic and major molecular remission (CCR, MMR), PFS and OS was investigated. Results: At diagnosis 1174/1346 patients (87%) had the standard t(9;22)(q34;q11) only and 75 patients (6%) had a variant t(v;22). In 64 of 75 patients with t(v;22), only one further chromosome was involved in the translocation; In 8 patients two, in 2 patients three, and in one patient four further chromosomes were involved. Ninety seven patients (7%) had additional cytogenetic aberrations. Of these, 44 patients (3%) lacked the Y chromosome (-Y) and 53 patients (4%) had major or minor ACA. Thirty six of the 53 patients (2.7%) had an unbalanced karyotype (including all patients with major route ACA and patients with other unbalanced alterations like -X, del(1)(q21), del(5)(q11q14), +10, t(15;17)(p10;p10), -21), and 17 (1.3%) a balanced karyotype with reciprocal translocations [e.g. t(1;21); t(2;16); t(3;12); t(4;6); t(5;8); t(15;20)]. After a median observation time of 5.6 years for patients with t(9;22), t(v;22), -Y, balanced and unbalanced karyotype with ACA median times to CCR were 1.05, 1.05, 1.03, 2.58 and 1.51 years, to MMR 1.31, 1.51, 1.65, 2.97 and 2.07 years. Time to CCR and MMR was longer in patients with balanced karyotypes (data statistically not significant). 5-year PFS was 89%, 78%, 87%, 94% and 69% and 5-year OS 91%, 87%, 89%, 100% and 73%, respectively. In CML patients with unbalanced karyotype PFS (p<0.001) and OS (p<0.001) were shorter than in patients with standard translocation (or balanced karyotype; p<0.04 and p<0.07, respectively). Conclusion: We conclude that the prognostic impact of additional cytogenetic alterations at diagnosis of CML is heterogeneous and consideration of their types may be important. Not only patients with major route ACA at diagnosis of CML but also patients with unbalanced karyotypes identify a group of patients with shorter PFS and OS as compared to all other patients. Therefore, different therapeutic options such as intensive therapy with the most potent tyrosine kinase inhibitors or stem cell transplantation are required.

Photoactive sawhorse-type diruthenium tetracarbonyl complexes

Sawhorse-type diruthenium tetracarbonyl complexes incorporating carboxyphenyl porphyrin bridges and pyridine axial ligands have been prepared, characterized and evaluated as potential photosensitizing and chemotherapeutic agents in several human cancer cells (A2780, A549, Me300, HeLa). The mono carboxyphenyl porphyrin derivatives, 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23H-porphyrin (HOOCR1-H2) and 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin-Zn (HOOCR1-Zn), after reaction with Ru-3(CO)(12) and pyridine, give the dinuclear complexes [Ru-2(CO)(4)(OOCR1-H2)(2)(NC5H5)(2)] (1) and [Ru-2(CO)(4)-(OOCR1-Zn)(2)(NC5H5)(2)] (2), respectively. Under the same reaction conditions, the di-carboxyphenyl porphyrin derivatives, 5,10-di(4-carboxyphenyl)-15,20-diphenyl-21,23H-porphyrin (HOOCR2-H2COOH) and 5,10-di(4-carboxyphenyl)-15,20-diphenylporphyrin-Zn (HOOCR2-ZnCOOH), give rise to the tetranuclear complexes, [{Ru-2(CO)(4)(NC5H5)(2)}(2)(OOCR2-H2COO)(2)] (3) and [{Ru-2(CO)(4)(NC5H5)(2! )}(2)(OOCR2-ZnCOO)(2)] (4), in which two sawhorse diruthenium tetracarbonyl units are linked by the di-carboxyphenyl porphyrin ligands. When tested in human cancer cell lines, both Zn(II) metallo-porphyrin derivatives 2 and 4 and the tetranuclear derivative 3 show some degree of cytotoxicity in the dark, but seem to present no phototoxicity upon irradiation at 652 nm. These results demonstrate the effect of the Zn(II) ion insertion into the porphyrin core, resulting in increased cytotoxicity and decreased phototoxicity. On the other hand, complex 1, the less cytotoxic derivative with IC50 > 170 mu M in HeLa cervix and A2780 ovarian cancer cell lines, shows an excellent phototoxicity toward these cancer cell lines with LD50 comprised between 4.5 and 7.5 J/cm(2) (irradiance 30 mW/cm(2)) at 5 mu M concentration (incubation time: 24 h). Overall, an excellent ratio between photo-and cytotoxicity has been found for the metal-free porphyrin derivative [Ru-2(CO)(4)(OOCR1-H2)(2)(! NC5H5)(2)] (1).

Musée de l'histoire du costume, France, Henri IV [32 rue Beaujon, Hôtel de Madrazo, Paris, 8e arrondissement, ouvert au public le 24 janvier 1920] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57824