Post-Franco Theatre

In the multiple realms and layers that comprise the contemporary Spanish theatrical landscape, “crisis” would seem to be the word that most often lingers in the air, as though it were a common mantra, ready to roll off the tongue of so many theatre professionals with such enormous ease, and even enthusiasm, that one is prompted to wonder whether it might indeed be a miracle that the contemporary technological revolution – coupled with perpetual quandaries concerning public and private funding for the arts – had not by now brought an end to the evolution of the oldest of live arts, or, at the very least, an end to drama as we know it

ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report

© The Author(s) 2021.[Background]: Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression. This is the first case report in lung adenocarcinoma of ARID1A gene alterations leading to sporadic MSI, through somatic mutL homolog 1 (MLH1) promoter methylation, with an MLH1 gene mutation as the second somatic hit. [Case presentation]: A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in ARID1A gene, rearranged during transfection (RET) gene fusions, epidermal growth factor receptor (EGFR) gene R776H mutation, breast cancer (BRCA) genes 1/2, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled MLH1 gene promoter methylation. The MLH1 gene mutation and the MLH1 gene methylation were not present at the germline setting. [Conclusions]: In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms

Application of liquid biopsies in metastatic gastrointestinal cancer to identify candidate therapeutic targets

Producción CientíficaBackground:Next-generation sequencing (NGS) of cell-free tumor DNA (ctDNA) hasgreat potential for liquid biopsy in cancer diagnostics and to identify patients withactionable genomic alteration. This study, a prospective longitudinal study, focused ina cohort of metastatic cancer patients without standard effective active antineoplasticmedical treatment options to establish the rate of patients with actionable genomicalteration and the rate of patients accessing medical treatment. The final objective wasto determine the clinical performance based on non-invasive tumor sequencing.Methods:We collected plasma of 10 metastatic gastrointestinal patients with knownstatus of the RAS genes and microsatellites instability in tumor tissue. CtDNA wasextracted from plasma and genomic alterations were analyzed by Guardant 360(Guardant Health, Biosequence, OncoDNA), a next generation sequencing panel. Thispanel consists of 73 cancer related genes and is able to identify different types ofgenomic alterations. Informed consent was obtained from all patients.Results:We were able to identify 78 somatic mutations in total resulting in a mediannumber of eight somatic mutations per patient. The most common altered genes arewell known tumor suppressor and oncogenes like TP53, APC, KRAS, MYC andEGFR.At least one actionable alteration in plasma cfDNA were detected in eight from the 10patients (80%) but the proportion of patients for which a genomic identified recom-mended therapy was available to effectively initiate the treatment were only 37,5%(3/8). In these patients, the identification of alterations like c-MET amplification,FGFR1 amplification or PIK3CA c.1633G>A (p.E545K) mutation, involved inclinically actionable pathways, allowed the selection of a specific therapy. For the rest ofcases the main causes of non-access to medical treatment associated with a specificmutation were, among others, the advanced pre-treated patient and clinical triallogistical access difficulties.Conclusions:Our findings confirm the percentage of cases with potentially druggableaberrations is similar to other studies using this strategy and emphasizes their clinicalvalue to identify candidate therapeutic target

Application of liquid biopsies in metastatic gastrointestinal cancer to identify candidate therapeutic targets

[Background]: Next-generation sequencing (NGS) of cell-free tumor DNA (ctDNA) has great potential for liquid biopsy in cancer diagnostics and to identify patients with actionable genomic alteration. This study, a prospective longitudinal study, focused in a cohort of metastatic cancer patients without standard effective active antineoplastic medical treatment options to establish the rate of patients with actionable genomic alteration and the rate of patients accessing medical treatment. The final objective was to determine the clinical performance based on non-invasive tumor sequencing.[Methods]: We collected plasma of 10 metastatic gastrointestinal patients with known status of the RAS genes and microsatellites instability in tumor tissue. CtDNA was extracted from plasma and genomic alterations were analyzed by Guardant 360 (Guardant Health, Biosequence, OncoDNA), a next generation sequencing panel. This panel consists of 73 cancer related genes and is able to identify different types of genomic alterations. Informed consent was obtained from all patients.[Results]: We were able to identify 78 somatic mutations in total resulting in a median number of eight somatic mutations per patient. The most common altered genes are well known tumor suppressor and oncogenes like TP53, APC, KRAS, MYC andEGFR. At least one actionable alteration in plasma cfDNA were detected in eight from the 10 patients (80%) but the proportion of patients for which a genomic identified recommended therapy was available to effectively initiate the treatment were only 37,5% (3/8). In these patients, the identification of alterations like c-MET amplification, FGFR1 amplification or PIK3CA c.1633G>A (p.E545K) mutation, involved in clinically actionable pathways, allowed the selection of a specific therapy. For the rest of cases the main causes of non-access to medical treatment associated with a specific mutation were, among others, the advanced pre-treated patient and clinical trial logistical access difficulties.[Conclusions]: Our findings confirm the percentage of cases with potentially druggable aberrations is similar to other studies using this strategy and emphasizes their clinical value to identify candidate therapeutic targets

La alternativa local: Descentralización y desarrollo económico

América Latina se está descentralizando. Cada vez más recursos y un mayor poder de decisión están pasando desde los gobiernos centrales hacia el nivel local. Este naciente panorama político, administrativo y fiscal genera nuevos retos y oportunidades para los gobiernos subnacionales, y para el desarrollo económico local de la región. La alternativa local presenta varias experiencias, lecciones y perspectivas sobre la descentralización y los diversos canales por medio de los cuales este proceso puede afectar al desarrollo económico. Los capítulos del libro han sido elaborados por una variedad de actores, tanto expertos de organismos internacionales como encargados de formular y aplicar políticas en los niveles nacional y subnacional, que examinan el fenómeno y evalúan cómo se podría aprovechar el nuevo marco institucional descentralizado de América Latina en favor del desarrollo económico

La alternativa local: Descentralización y desarrollo económico

América Latina se está descentralizando. Cada vez más recursos y un mayor poder de decisión están pasando desde los gobiernos centrales hacia el nivel local. Este naciente panorama político, administrativo y fiscal genera nuevos retos y oportunidades para los gobiernos subnacionales, y para el desarrollo económico local de la región. La alternativa local presenta varias experiencias, lecciones y perspectivas sobre la descentralización y los diversos canales por medio de los cuales este proceso puede afectar al desarrollo económico. Los capítulos del libro han sido elaborados por una variedad de actores, tanto expertos de organismos internacionales como encargados de formular y aplicar políticas en los niveles nacional y subnacional, que examinan el fenómeno y evalúan cómo se podría aprovechar el nuevo marco institucional descentralizado de América Latina en favor del desarrollo económico

Benito Pérez Galdós

In Galdós\u27 time, the tensions between such diverse phenomena as coins and credit, free trade and protectionist tariffs, factory work and domestic economy, masculine and feminine, and private and public exacerbated friction among peoples—those of pueblo and rural origins, whose voices rasped and whose bright colors raked the eye, and a nascent, insecure bourgeosie who, fearful of the masses, strove to imitate the aristocracy. Old and new converged also with the question of suffrage and citizenship to aggravate social malaise and political upheavals—Carlist wars, palace intrigues, the Revolution of 1868 and overthrow of Queen Isabel, the brief reign of Amadeo of Savoy, the aborted First Republic and the Bourbon Restoration (1875-1885), which reached Spain from England in the imported person of Alfonso XII. These turbulent events undergird the cultural, historical, and political events of the novels by Benito Pérez Galdós (1843–1920) to be discussed in this chapter. Galdós is the author of seventy-seven novels, twenty-six original plays, and numerous occasional pieces, written between 1867 and 1920. These divide into two main categories: the historical and the contemporary social novels, now more appropriately described as novels of modernity The forty-six historical novels, called Episodios nacionales, make up five series, each consisting of ten interconnected novels, except the fifth series, left unfinished. The thirty-one novels of modernity, published between 1870 and 1915, also divide into two groups: Novelas de la primera época ( Novels of the Early Period, 1870–1879) and Las novelas de la serie contemporánea ( The Contemporary Social Novels, 1881–1915). The novels of the early period comprise Galdós\u27 first attempts at novel writing, as well as four so-called thesis novels : Doña Perfecta (1876), the sequel Gloria (1876–1877), Marianela (1878), and La familia de León Roch ( The Family of León Roch, 1878–1879). The next group of novels represents what Galdós called his segunda manera —his second style, a different kind of writing ... a more sophisticated and varied mode of narrative presentation