Mutis por el foro. Artes escénicas y política en tiempos de pandemia

The book Mutis for the forum. Performing arts and politics in times of pandemic is the result of the Colloquium "Catastrophe and paradox: scenes of the pandemic" held virtually by the Latin American Performing Arts Studies Network (REAL), between August 6 and 27, 2020, in which researchers from eight Latin American countries participated. The object of study is the present and future of the performing arts facing the pause imposed by the pandemic and confinement, and the challenge of virtuality. The nineteen essays that make it up offer an interdisciplinary look from a situated theory, while building a memory of the particular historical moment. The publication was not intended exclusively for an academic audience or one specialized in the performing arts, its design allows for interactive reading and it is an essential contribution to questioning the supposed crisis of theater from the pandemic, and undressing the paradoxes that live arts face.Reseña de la publicación digital – Disponible en: https://drive.google.com/file/d/1G6qaehzvAKSqxuLHq6zgncRUgqlHWXXz/vie

Teatro, clandestinidad y resistencia en el Penal de Punta de Rieles

Durante la última dictadura uruguaya las presas políticas desarrollaron en el Penal de Punta de Rieles representaciones teatrales como tácticas de resistencia frente a la fuerte represión de género desplegada allí por el terrorismo de Estado. Se trataba de creaciones colectivas realizadas en medio de un convivio muy particular que condicionó la producción y la recepción de las mencionadas creaciones. Podemos afirmar que las representaciones teatrales en Punta de Rieles constituyeron un discurso subyugado porque se realizaban bajo mecanismos de clandestinidad ya que nunca fueron autorizadas. En ese contexto, la teatralidad escenificada por la Dictadura en el Penal como una estrategia de poder, dialogó con las representaciones teatrales realizadas por las presas políticas. La relación que mantienen con el poder explica la elección del repertorio.During the late Uruguayan dictatorship the women political prisoners developed drama representations at the Prison of Punta Rieles. Such representations constituted tactics of resistance against the strong gender repression practiced by state terrorism. They were collective creations done in the midst of a very particular convivio that conditioned the production and reception of the mentioned work.We can thus claim that such theatrical representations in the prison of Punta Rieles constituted a concealed discourse that took place in a clandestine realm, since the implementation of them was never authorized. In this context, staged theatricality during dictatorship at prison can be regarded as an empowering strategy, establishing a meaningful dialogue with these peculiar drama representations done by the women prisoners, whose relationship with political power explains the choises in the their repertoire

T cell leukemia control via Ras-Raf pathway inhibition with peptides

RATIONALE: RAS-RAF-MEK-ERK pathway has been considered a promising target for anticancer therapy. However, tumor cells may develop resistance against such drugs via hyperactivation of N-Ras, which explains why novel therapeut-ic approaches. In this sense, the Institute Curie- Université Pierre et Marie Curie (Paris 6) designed peptides in order to disturb Ras/Raf interaction which showed pro-apoptotic properties. These peptides were patented as WO2015001045 A2 (PCT/EP2014/064243)5. OBJECTIVE: In order to check the anti-tumoral action of WO2015001045 A2 peptides in a very aggressive BALB/c mice spontaneous leukemia called LB, we performed the present study. METHOD & RESULTS: 50 BALB/c mice inoculated with 106 LB tumor cells were randomly assigned either to control (placebo) or treatment group (that daily received 3 mg of peptide per kg of mice) during 30 days. By day 15 only 24% of the control group was alive vs. 100% of the treatment group. The average survival in treated group was 20,27 days while in control group the mean survival was 15,48 days. Either bone marrow, spleen or axillary nodes demonstrated a higher level of malignant T cell presence compare with treated group (89,78% ; 95,64% & 77,68% versus 72,45%, 80,23% & 63.44% respectively for each organ inspected. DISCUSSION: Our study demonstrated an improvement in survival curves in mice model affected by spontaneous T lymphoid leukemia when peptides WO2015001045 A2 were used. These peptides might be a valid option to become part of the therapeutic armory for malignant lymphoproliferative diseases control.Facultad de Ciencias Médica

T cell leukemia control via Ras-Raf pathway inhibition with peptides

RATIONALE: RAS-RAF-MEK-ERK pathway has been considered a promising target for anticancer therapy. However, tumor cells may develop resistance against such drugs via hyperactivation of N-Ras, which explains why novel therapeut-ic approaches. In this sense, the Institute Curie- Université Pierre et Marie Curie (Paris 6) designed peptides in order to disturb Ras/Raf interaction which showed pro-apoptotic properties. These peptides were patented as WO2015001045 A2 (PCT/EP2014/064243)5. OBJECTIVE: In order to check the anti-tumoral action of WO2015001045 A2 peptides in a very aggressive BALB/c mice spontaneous leukemia called LB, we performed the present study. METHOD & RESULTS: 50 BALB/c mice inoculated with 106 LB tumor cells were randomly assigned either to control (placebo) or treatment group (that daily received 3 mg of peptide per kg of mice) during 30 days. By day 15 only 24% of the control group was alive vs. 100% of the treatment group. The average survival in treated group was 20,27 days while in control group the mean survival was 15,48 days. Either bone marrow, spleen or axillary nodes demonstrated a higher level of malignant T cell presence compare with treated group (89,78% ; 95,64% & 77,68% versus 72,45%, 80,23% & 63.44% respectively for each organ inspected. DISCUSSION: Our study demonstrated an improvement in survival curves in mice model affected by spontaneous T lymphoid leukemia when peptides WO2015001045 A2 were used. These peptides might be a valid option to become part of the therapeutic armory for malignant lymphoproliferative diseases control.Facultad de Ciencias Médica

T cell leukemia control via Ras-Raf pathway inhibition with peptides

RATIONALE: RAS-RAF-MEK-ERK pathway has been considered a promising target for anticancer therapy. However, tumor cells may develop resistance against such drugs via hyperactivation of N-Ras, which explains why novel therapeut-ic approaches. In this sense, the Institute Curie- Université Pierre et Marie Curie (Paris 6) designed peptides in order to disturb Ras/Raf interaction which showed pro-apoptotic properties. These peptides were patented as WO2015001045 A2 (PCT/EP2014/064243)5. OBJECTIVE: In order to check the anti-tumoral action of WO2015001045 A2 peptides in a very aggressive BALB/c mice spontaneous leukemia called LB, we performed the present study. METHOD & RESULTS: 50 BALB/c mice inoculated with 106 LB tumor cells were randomly assigned either to control (placebo) or treatment group (that daily received 3 mg of peptide per kg of mice) during 30 days. By day 15 only 24% of the control group was alive vs. 100% of the treatment group. The average survival in treated group was 20,27 days while in control group the mean survival was 15,48 days. Either bone marrow, spleen or axillary nodes demonstrated a higher level of malignant T cell presence compare with treated group (89,78% ; 95,64% & 77,68% versus 72,45%, 80,23% & 63.44% respectively for each organ inspected. DISCUSSION: Our study demonstrated an improvement in survival curves in mice model affected by spontaneous T lymphoid leukemia when peptides WO2015001045 A2 were used. These peptides might be a valid option to become part of the therapeutic armory for malignant lymphoproliferative diseases control.Facultad de Ciencias Médica

New forms of induction of apoptosis in aggressive lymphoma using peptides that interrupt the RAS / RAF interaction

RAS-RAF-MEK-ERK is a key pathway for apoptosis regulation in cancer cells. B-Raf-inhibitors such as PLX4032 peptide was developed by Institute Curie-Université Pierre et Marie Curie in order to induce apoptosis in cancer cells. Objective: To demonstrate pro-apoptotic properties and survival outcome of EP2014/064243 peptide in murine aggressive lymphoma. Material and methods: BALBc mice with T-lymphoma were randomized assigned either in Group A (peptide+cyclophosphamide-CFM); Group B (peptides), Group C (CFM-control) or Control D (Cl-Na 0.9%-SF control group). Survival probability was calculated by Kaplan-Meier analysis. Apoptosis was detected using TUNEL technique. The protocol was approved by the Institutional Committee for Animal Care (CICUAL: T04-01-2015). Results: The median survival was 24 days (21.6-26.4) for placebo, 33 days (28.0-35.4) for the CFM monotherapy group, 33 (27.1-35.8) for the peptide group and 34 days (24,4-40) for CFM-peptide combined treatment (p < 0.05). In lymph node tissue the mean TUNEL positive cells per field for each treatment group was 2, 12 and 13 and 35 for SF, CFM, peptide and combined therapy (p < 0.05). Conclusion: These findings suggest that in murine aggressive lymphoma treated by an experimental peptide in addition with CFM, had an exponentially pro-apoptotic effect than CFM alone, suggesting that the peptide potentiated the anti-tumoural effect of CFM.Facultad de Ciencias Médica

Anti-tumoral Effect of a Cell Penetrating and Interfering Peptide Targeting PP2A/SET Interaction

Objective: To test cell penetrating and interfering peptide Mut3DPT-PP2A/SET in interaction between serine threonine phosphatase PP2A and its physiological inhibitor, the oncoprotein SET. Materials and methods: Adult male C3H/S-strain mice, 60 days old, were given a graft of breast adenocarcinoma cells (TN60) into subcutaneous tissue. Mut3DPT-PP2A/SET peptide was used to block PP2A and SET oncoprotein interaction. The graft-bearing animals were divided into a control group (injected with saline buffer), and an intervention group injected intraperitoneally with Mut3DPTPP2A/ SET peptide (5 mg/kg) every day from day 5 to day 37. The variables we used to compare the outcome in both groups were tumor size in mm (length×width) and histological changes. In the statistical analysis we used ANOVA and Student-Keuls multiple comparisons test and Tuckey for the post-test analysis. Results: 48 mice were grafted at day 0 with breast UNLP-C3H/S tumor cells, and after randomization, they were assigned to one of the two study groups. At day 5 all mice were injected either with placebo or with the peptide. The treated group showed significant tumor reduction (p<0.07). Histological changes showed presence of apoptosis and necrosis of tumor in treated group. Conclusion: The peptide Mut3DPT-PP2A/SET has demonstrated anti-tumor activity by reduction in vivo of tumor growth becoming a promising future in anticancer therapy.Facultad de Ciencias Médica

Distinct expression patterns of the E3 ligase SIAH-1 and its partner Kid/KIF22 in normal tissues and in the breast tumoral processes

SIAH proteins are the human members of an highly conserved family of E3 ubiquitin ligases. Several data suggest that SIAH proteins may have a role in tumor suppression and apoptosis. Previously, we reported that SIAH-1 induces the degradation of Kid (KIF22), a chromokinesin protein implicated in the normal progression of mitosis and meiosis, by the ubiquitin proteasome pathway. In human breast cancer cells stably transfected with SIAH-1, Kid/KIF22 protein level was markedly reduced whereas, the Kid/KIF22 mRNA level was increased. This interaction has been further elucidated through analyzing SIAH and Kid/KIF22 expression in both paired normal and tumor tissues and cell lines. It was observed that SIAH-1 protein is widely expressed in different normal tissues, and in cells lines but showing some differences in western blotting profiles. Immunofluorescence microscopy shows that the intracellular distribution of SIAH-1 and Kid/KIF22 appears to be modified in human tumor tissues compared to normal controls. When mRNA expression of SIAH-1 and Kid/KIF22 was analyzed by real-time PCR in normal and cancer breast tissues from the same patient, a large variation in the number of mRNA copies was detected between the different samples. In most cases, SIAH-1 mRNA is decreased in tumor tissues compared to their normal counterparts. Interestingly, in all breast tumor tissues analyzed, variations in the Kid/KIF22 mRNA levels mirrored those seen with SIAH-1 mRNAs. This concerted variation of SIAH-1 and Kid/KIF22 messengers suggests the existence of an additional level of control than the previously described protein-protein interaction and protein stability regulation. Our observations also underline the need to re-evaluate the results of gene expression obtained by qRT-PCR and relate it to the protein expression and cellular localization when matched normal and tumoral tissues are analyzed

Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study

BACKGROUND We recently reported that peroxisome proliferator‐activated receptor γ agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add‐on therapy to imatinib would impact CML residual disease, as assessed by BCR‐ABL1 transcript quantification. METHODS CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR4.5) defined by BCR‐ABL1/ABL1 IS RNA levels ≤ 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR4.5 over 12 months. RESULTS Twenty‐four patients were included (age range, 24‐79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR4.5 was 56% (95% confidence interval, 37%‐76%) by 12 months, despite a wide range of therapy duration (1.9‐15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR4.5 by 48 months. The cumulative incidence of MMR to MR4.5 spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients. CONCLUSION Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009‐011675‐79). Cancer 2017;123:1791–1799. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

The disruption of protein-protein interactions as a therapeutic strategy for prostate cancer

This is an accepted manuscript of an article published by Elsevier in Pharmacological Research on 16/08/2020, available online: https://doi.org/10.1016/j.phrs.2020.105145 The accepted version of the publication may differ from the final published version.Prostate cancer (PCa) is one of the most common male-specific cancers worldwide, with high morbidity and mortality rates associated with advanced disease stages. The current treatment options of PCa are prostatectomy, hormonal therapy, chemotherapy or radiotherapy, the selection of which is usually dependent upon the stage of the disease. The development of PCa to a castration-resistant phenotype (CRPC) is associated with a more severe prognosis requiring the development of a new and effective therapy. Protein-protein interactions (PPIs) have been recognised as an emerging drug modality and targeting PPIs is a promising therapeutic approach for several diseases, including cancer. The efficacy of several compounds in which target PPIs and consequently impair disease progression were validated in phase I/II clinical trials for different types of cancer. In PCa, various small molecules and peptides proved successful in inhibiting important PPIs, mainly associated with the androgen receptor (AR), Bcl-2 family proteins, and kinases/phosphatases, thus impairing the growth of PCa cells in vitro. Moreover, a majority of these compounds require further validation in vivo and, preferably, in clinical trials. In addition, several other PPIs associated with PCa progression have been identified and now require experimental validation as potential therapeutic loci. In conclusion, we consider the disruption of PPIs to be a promising though challenging therapeutic strategy for Pca. Agents which modulate PPIs might be employed as a monotherapy or as an adjunct to classical chemotherapeutics to overcome drug resistance and improve efficacy. The discovery of new PPIs with important roles in disease progression, and of novel optimized strategies to target them, are major challenges for the scientific and pharmacological communities.We thank the Portuguese Foundation for Science and Technology(FCT), European Union, QREN, FEDER and COMPETE for funding iBiMED (UIDB/04501/2020, POCI-01-0145-FEDER-23007628 and UID/BIM/04501/2019) and an individual scholarship from BM (SFRH/BD/146032/2019)