Principales complicaciones asociadas a la administración de quimioterapia intraperitoneal y endovenosa en pacientes con cáncer de ovario / Main complications associated with the administration of intraperitoneal and intravenous chemotherapy in ovarian cancer patients

Antecedentes: El cáncer de ovario causa más muertes que cualquier otro tipo de cáncer ginecológico. La mayoría de casos se diagnostican en una etapa avanzada de la enfermedad y el tratamiento de elección es generalmente la terapia combinada de quimioterapia intraperitoneal (IP) y endovenosa (EV). A pesar de que esta opción farmacológica ha demostrado alargar la supervivencia, se han reportado múltiples efectos adversos asociados a dicho tratamiento. Objetivo: Identificar los efectos adversos y las complicaciones derivadas del tratamiento con quimioterapia IP+EV en pacientes con carcinoma de ovario avanzado a partir de estadio IIIC, durante el periodo 2007-2015. Metodología: Se realizó un estudio descriptivo, longitudinal y retrospectivo. Un grupo de 17 mujeres diagnosticadas con cáncer de ovario a partir de estadio III fueron tratadas con quimioterapia IP+EV en el Hospital Clínic de Barcelona durante el periodo 2007-2015. Resultados: De las 17 pacientes que recibieron tratamiento con quimioterapia IP+EV, sólo 5 (29,41%) finalizaron los 6 ciclos de tratamiento. De forma notable, 12 (70,58%) pacientes no completaron el tratamiento debido a una serie de complicaciones, que fueron frecuentemente asociadas al reservorio IP y a trastornos psicológicos. Los principales efectos adversos reportados fueron astenia, neurotoxicidad y dolor abdominal. Conclusiones: La mayoría de pacientes interrumpieron la terapia debido a complicaciones relacionadas con el reservorio IP y trastornos psicológicos. Creemos que la enfermera juega un papel importante, no sólo en el manejo de los aspectos técnicos de la terapia, sino también en el soporte emocional a dichas pacientes durante esta etapa (AU)

Background: Ovarian cancer displays the highest death rates amongst all gynaecologic cancers. Most cases are diagnosed at an advanced stage of the disease and the treatment of choice is generally the combination therapy of intraperitoneal (IP) and intravenous (IV) chemotherapy. While this approach has been shown to prolong survival, multiple associated toxicities have been reported. Objective: To identify the side effects and complications resulting from IP+IV chemotherapy treatment in stage III and stage IV ovarian cancer patients during the 2007-2015 period. Methods: A descriptive, longitudinal and retrospective study was performed. A group of 17 women diagnosed with stage III and stage IV ovarian cancer were treated with IP+IV chemotherapy in Hospital Clínic de Barcelona during the period 2007-2015. Results: Of the 17 patients who were treated with IP+IV chemotherapy, only 5 (29,41%) completed the 6 cycles of treatment. Notably, 12 (70,58%) patients discontinued the treatment due to a series of complications, which were frequently associated with IP reservoir and psychological disorders. The most commonly reported side effects were asthenia, neurotoxicity and abdominal pain. Conclusions: The majority of patients discontinued their prescribed therapy due to complications associated with IP reservoir and psychological disorders. We believe that the nurse plays a key role, not only in managing the technical aspects of the therapy but also in providing patients with emotional support throughout their journey (AU)

Aspirin induces apoptosis in human leukemia cells independently of NF-kappaB and MAPKs through alteration of the Mcl-1/Noxa balance.

Aspirin and other non-steroidal anti-inflammatory drugs induce apoptosis in most cell types. In this study we examined the mechanism of aspirin-induced apoptosis in human leukemia cells. We analyzed the role of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPKs) pathways. Furthermore, we studied the changes induced by aspirin in some genes involved in the control of apoptosis at mRNA level, by performing reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), and at protein level by Western blot. Our results show that aspirin induced apoptosis in leukemia Jurkat T cells independently of NF-kappaB. Although aspirin induced p38 MAPK and c-Jun N-terminal kinase activation, selective inhibitors of these kinases did not inhibit aspirin-induced apoptosis. We studied the regulation of Bcl-2 family members in aspirin-induced apoptosis. Aspirin increased the mRNA levels of some pro-apoptotic members, such as BIM, NOXA, BMF or PUMA, but their protein levels did not change. In contrast, aspirin decreased the protein levels of Mcl-1. Interestingly, in the presence of aspirin the protein levels of Noxa remained high. This alteration of the Mcl-1/Noxa balance was also found in other leukemia cell lines and primary chronic lymphocytic leukemia cells (CLL). Furthermore, in CLL cells aspirin induced an increase in the protein levels of Noxa. Knockdown of Noxa or Puma significantly attenuated aspirin-induced apoptosis. These results indicate that aspirin induces apoptosis through alteration of the Mcl-1/ Noxa balance.

Sequential waves of polyadenylation and deadenylation define a translation circuit that drives meiotic progression.

The maternal mRNAs that drive meiotic progression in oocytes contain short poly(A) tails and it is only when these tails are elongated that translation takes place. Cytoplasmic polyadenylation requires two elements in the 3'-UTR (3'-untranslated region), the hexanucleotide AAUAAA and the CPE (cytoplasmic polyadenylation element), which also participates in the transport and localization, in a quiescent state, of its targets. However, not all CPE-containing mRNAs are activated at the same time during the cell cycle, and polyadenylation is temporally and spatially regulated during meiosis. We have recently deciphered a combinatorial code that can be used to qualitatively and quantitatively predict the translational behaviour of CPE-containing mRNAs. This code defines positive and negative feedback loops that generate waves of polyadenylation and deadenylation, creating a circuit of mRNA-specific translational regulation that drives meiotic progression.

A combinatorial code for CPE-mediated translational control.

Cytoplasmic polyadenylation plays a key role in the translational control of mRNAs driving biological processes such as gametogenesis, cell-cycle progression, and synaptic plasticity. What determines the distinct time of polyadenylation and extent of translational control of a given mRNA, however, is poorly understood. The polyadenylation-regulated translation is controlled by the cytoplasmic polyadenylation element (CPE) and its binding protein, CPEB, which can assemble both translational repression or activation complexes. Using a combination of mutagenesis and experimental validation of genome-wide computational predictions, we show that the number and relative position of two elements, the CPE and the Pumilio-binding element, with respect to the polyadenylation signal define a combinatorial code that determines whether an mRNA will be translationally repressed by CPEB, as well as the extent and time of cytoplasmic polyadenylation-dependent translational activation.

Cytoplasmic mRNA polyadenylation and translation assays.

Vertebrate development is directed by maternally inherited messenger RNAs that are synthesized during the very long period of oogenesis. These dormant mRNAs usually contain short poly(A) tails and are stored as mRNA ribonucleoproteins that preclude ribosomal recruitment. In Xenopus laevis oocytes treated with the meiosis-inducing hormone progesterone, their poly(A) tails are elongated, and the mRNAs are mobilized into polysomes. This cytoplasmic polyadenylation is directed by cis-acting elements located in the 3' untranslated region of the mRNAs. However, the cytoplasmic polyadenylation of all the maternal mRNAs does not take place at once, but rather the translational activation of specific mRNAs is regulated in a sequential manner during meiosis and early development. This chapter describes the use of microinjected reporter mRNAs and radiolabeled RNAs into Xenopus oocytes to study the mRNA translational control by cytoplasmic polyadenylation. Cyclin B1 mRNA is used to illustrate the methods described.

Synthesis, pharmacology and molecular modeling of N-substituted 2-phenyl-indoles and benzimidazoles as potent GABA(A) agonists.

Among the known non-benzodiazepine hypnotic drugs, Zolpidem (1a), Indiplon (2a) and Zaleplon (2b) have shown high affinity and selectivity for the alpha(1) subunit of the GABA-A receptor. Our group has performed pharmacophoric and ADMET-prediction studies to evaluate a virtual library of new molecules based on privileged structures. Among these, we have synthesized a library of N-substituted indoles and a library of N-substituted benzimidazoles. Afterwards, in vitro screening and in vivo spontaneous motor activity in mice has revealed molecules with good in vitro affinities for the alpha(1) receptor and potent in vivo induction of sedation.

Aspirin-induced apoptosis in jurkat cells is not mediated by peroxisome proliferator-activated receptor delta.

Nonsteroidal antiinflammatory drugs may induce apoptosis via inhibition of peroxisome proliferator-activated receptor delta (PPARdelta) activity. Here we analyze the role of PPARdelta in aspirin-induced apoptosis of Jurkat cells, which, together with other lymphoid cell lines, express PPARdelta mRNA. Aspirin increased PPARdelta mRNA levels in Jurkat cells, but decreased the activity of both PPARdelta and PPARalpha/gamma, assayed using the luciferase reporter constructs DRE and ACO, respectively. The DNA binding of PPARdelta was not affected by 10 mM aspirin, which induces apoptosis in Jurkat cells. Moreover, neither addition of a specific ligand of PPARdelta nor transient transfection of PPARdelta expression vectors protected Jurkat cells from aspirin-induced apoptosis. These results indicate that PPARdelta is not involved in aspirin-induced apoptosis. Therefore, the mechanism by which aspirin mediates cell death in Jurkat cells remains unknown.

Transcriptional and translational control of Mcl-1 during apoptosis.

Mcl-1 is an antiapoptotic member of the Bcl-2 family whose protein and mRNA have a short half-life. In this report, we studied the changes in Mcl-1 protein and mRNA expression induced by staurosporine and aspirin. Both drugs induced apoptosis in Jurkat cells and reduced the levels of Mcl-1 protein. The caspase inhibitor Z-VAD.fmk and the proteasome inhibitor MG132 partially protected Mcl-1 from decay, indicating that both caspase-dependent and proteasome pathways are involved during apoptosis. Staurosporine also reduced Mcl-1 mRNA levels and this reduction was mostly caspase-dependent. In addition, staurosporine reduced the transcriptional activity of the Mcl-1 promoter fused to a luciferase gene reporter more than actinomycin D, a general inhibitor of transcription. Thus, we conclude that staurosporine down-regulates Mcl-1 mRNA levels by inhibiting transcription in a caspase-dependent manner and reduces Mcl-1 protein levels by a caspase-independent post-transcriptional mechanism. In contrast aspirin, at doses and times that induced loss of viability and decay of Mcl-1 protein, had no effect on Mcl-1 mRNA levels. Aspirin rapidly inhibited de novo protein synthesis before caspase activation. Moreover, the translational factor eIF2alpha was transiently phosphorylated and therefore inhibited very soon after aspirin treatment. Aspirin also inhibited the luciferase reporter activity of several attached promoter constructs, but it did not affect the luciferase activity of a construct containing an internal ribosome entry site (IRES) in its mRNA 5(')UTR. We conclude that staurosporine inhibits transcription and translation, whereas aspirin only inhibits cap-dependent translation. Treatment with cycloheximide, at doses that inhibit protein synthesis without affecting cell viability, also induced Mcl-1 protein decay. Mcl-1 disappearance might be necessary but not sufficient for the induction of apoptosis by staurosporine and aspirin. A model for the control of Mcl-1 during drug-induced apoptosis is presented.