The ghost of Tom Joad : the development of the character’s mythical aura through literature, cinema and music

Traballo Fin de Grao en Lingua e Literatura Inglesas. Curso 2015-2016In the research area of literature and other artistic expressions, I have not found many instances of analysis of the exchange between literature and music. Being aware of the relevance of this connection in contemporary cultural studies, I will endeavor to focus my attention in these fields and with that purpose in mind I will regard literature, cinema and music as equally fundamental cultural productions throughout the elaboration of this paper. In order to convey the potential of this interrelation for the construction of works that eventually assimilate into culture, I intend to analyze an artistic creation that has undergone a transposition through these three different manifestations and which, in the process, would have acquired the potentiality each of them can provide. John Steinbeck’s masterpiece novel The Grapes of Wrath (1939) seemed a very accurate example. Until the present date, the story has been transposed to the silver screen by John Ford – The Grapes of Wrath (1940) –, to popular music by Woody Guthrie and Bruce Springsteen, and even to the theatre by Frank Galati in 1988. In this dissertation, I will not deal with the latter transposition of the story; instead I have chosen to go deeper into the web of internal influences that has developed among the novel, the film and the songs written out of the story of the Joad family as well as among their different authors

Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer : An Update

Physicians treating patients affected by nonmuscle-invasive bladder cancer (NMIBC) have been in shock during the last six years since manufacturing restrictions on the production of the first-option medicine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), have resulted in worldwide shortages. This shortage of BCG has led to a rethinking of the established treatment guidelines for the rationing of the administration of BCG. Some possible schedule modifications consist of a decrease in the length of maintenance treatment, a reduction in the dose of BCG in intravesical instillations or the use of different BCG substrains. All these strategies have been considered valuable in times of BCG shortage. In addition, the lack of availability of BCG has also led to the general recognition of the need to find new treatment options for these patients so that they are not dependent on a single treatment. Few alternatives are committed to definitively replacing BCG intravesical instillations, but several options are being evaluated to improve its efficacy or to combine it with other chemotherapeutic or immunotherapeutic options that can also improve its effect. In this article, we review the current state of the treatment with BCG in terms of all of the aforementioned aspects

Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers

The arsenal against different types of cancers has increased impressively in the last decade. The detailed knowledge of the tumor microenvironment enables it to be manipulated in order to help the immune system fight against tumor cells by using specific checkpoint inhibitors, cell-based treatments, targeted antibodies, and immune stimulants. In fact, it is widely known that the first immunotherapeutic tools as immune stimulants for cancer treatment were bacteria and still are; specifically, the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG) continues to be the treatment of choice for preventing cancer recurrence and progression in non-invasive bladder cancer. BCG and also other mycobacteria or their components are currently under study for the immunotherapeutic treatment of different malignancies. This review focuses on the preclinical and clinical assays using mycobacteria to treat non-urological cancers, providing a wide knowledge of the beneficial applications of these microorganisms to manipulate the tumor microenvironment aiming at tumor clearance

El medi de cultiu dels micobacteris terapèutics afecta la seva eficàcia en el tractament contra el càncer de bufeta

L'actual tractament per al càncer de bufeta no invasiu consisteix en provocar una resposta antitumoral en l'organisme instil·lant el micobacteri Mycobacterium bovis Calmette-Guérin (BCG) dins la bufeta. Investigadores del Departament de Genètica i de Microbiologia de la UAB han estudiat quins medis de cultiu per al BCG milloren la resposta antitumoral de l'organisme, així com la resposta antitumoral si s'hi instil·la Mycobacterium brumae.El actual tratamiento para el cáncer de vejiga no invasivo consiste en provocar una respuesta antitumoral en el organismo instilando la micobacteria Mycobacterium bovis Calmette-Guérin (BCG) en la vejiga. Investigadoras del Departamento de Genética y Microbiología de la UAB han estudiado qué medios de cultivo para crecer BCG mejoran la respuesta antitumoral del organismo, así como la respuesta si se instila Mycobacterium brumae

Each Mycobacterium Requires a Specific Culture Medium Composition for Triggering an Optimized Immunomodulatory and Antitumoral Effect

Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the first treatment option for non-muscle-invasive bladder cancer (BC) patients. In research laboratories, M. bovis BCG is mainly grown in commercially available media supplemented with animal-derived agents that favor its growth, while biomass production for patient treatment is performed in Sauton medium which lacks animal-derived components. However, there is not a standardized formulation of Sauton medium, which could affect mycobacterial characteristics. Here, the impact of culture composition on the immunomodulatory and antitumor capacity of M. bovis BCG and Mycolicibacterium brumae, recently described as efficacious for BC treatment, has been addressed. Both mycobacteria grown in Middlebrook and different Sauton formulations, differing in the source of nitrogen and amount of carbon source, were studied. Our results indicate the relevance of culture medium composition on the antitumor effect triggered by mycobacteria, indicating that the most productive culture medium is not necessarily the formulation that provides the most favorable immunomodulatory profile and the highest capacity to inhibit BC cell growth. Strikingly, each mycobacterial species requires a specific culture medium composition to provide the best profile as an immunotherapeutic agent for BC treatment. Our results highlight the relevance of meticulousness in mycobacteria production, providing insight into the application of these bacteria in BC research

Remodeling the bladder tumor immune microenvironment by mycobacterial species with changes in their cell envelope composition

Intravesical BCG instillation after bladder tumor resection is the standard treatment for non-muscle invasive bladder cancer; however, it is not always effective and frequently has undesirable side effects. Therefore, new strategies that improve the clinical management of patients are urgently needed. This study aimed to comprehensively evaluate the bladder tumor immune microenvironment profile after intravesical treatment with a panel of mycobacteria with variation in their cell envelope composition and its impact on survival using an orthotopic murine model to identify more effective and safer therapeutic strategies. tumor-bearing mice were intravesically treated with a panel of BCG and M. brumae cultured under different conditions. Untreated tumor-bearing mice and healthy mice were also included as controls. After mycobacterial treatments, the infiltrating immune cell populations in the bladder were analysed by flow cytometry. We provide evidence that mycobacterial treatment triggered a strong immune infiltration into the bladder, with BCG inducing higher global absolute infiltration than M. brumae. The induced global immune microenvironment was strikingly different between the two mycobacterial species, affecting both innate and adaptive immunity. Compared with M. brumae, BCG treated mice exhibited a more robust infiltration of CD4 + and CD8 + T-cells skewed toward an effector memory phenotype, with higher frequencies of NKT cells, neutrophils/gMDSCs and monocytes, especially the inflammatory subset, and higher CD4 + T/CD4 + T and CD8 + T/CD4 + T ratios. Conversely, M. brumae treatment triggered higher proportions of total activated immune cells and activated CD4 + and CD8 + T cells and lower ratios of CD4 + T cells/CD4 + T, CD8 + T cells/CD4 + T and inflammatory/reparative monocytes. Notably, the mycobacterial cell envelope composition in M. brumae had a strong impact on the immune microenvironment, shaping the B and myeloid cell compartment and T-cell maturation profile and thus improving survival. Overall, we demonstrate that the bladder immune microenvironment induced by mycobacterial treatment is species specific and shaped by mycobacterial cell envelope composition. Therefore, the global bladder immune microenvironment can be remodelled, improving the quality of infiltrating immune cells, the balance between inflammatory and regulatory/suppressive responses and increasing survival

Alteration in the Culex pipiens transcriptome reveals diverse mechanisms of the mosquito immune system implicated upon Rift Valley fever phlebovirus exposure

Rift Valley fever phlebovirus (RVFV) causes an emerging zoonotic disease and is mainly transmitted by Culex and Aedes mosquitoes. While Aedes aegypti-dengue virus (DENV) is the most studied model, less is known about the genes involved in infection-responses in other mosquito-arboviruses pairing. The main objective was to investigate the molecular responses of Cx. pipiens to RVFV exposure focusing mainly on genes implicated in innate immune responses. Mosquitoes were fed with blood spiked with RVFV. The fully-engorged females were pooled at 3 different time points: 2 hours post-exposure (hpe), 3- and 14-days post-exposure (dpe). Pools of mosquitoes fed with non-infected blood were also collected for comparisons. Total RNA from each mosquito pool was subjected to RNA-seq analysis and a de novo transcriptome was constructed. A total of 451 differentially expressed genes (DEG) were identified. Most of the transcriptomic alterations were found at an early infection stage after RVFV exposure. Forty-eight DEG related to immune infection-response were characterized. Most of them were related with the RNAi system, Toll and IMD pathways, ubiquitination pathway and apoptosis. Our findings provide for the first time a comprehensive view on Cx. pipiens-RVFV interactions at the molecular level. The early depletion of RNAi pathway genes at the onset of the RVFV infection would allow viral replication in mosquitoes. While genes from the Toll and IMD immune pathways were altered in response to RVFV none of the DEG were related to the JAK/STAT pathway. The fact that most of the DEG involved in the Ubiquitin-proteasome pathway (UPP) or apoptosis were found at an early stage of infection would suggest that apoptosis plays a regulatory role in infected Cx. pipiens midguts. This study provides a number of target genes that could be used to identify new molecular targets for vector control.info:eu-repo/semantics/publishedVersio

Critical role of AMP-activated protein kinase in the balance between mitophagy and mitochondrial biogenesis in MELAS disease

MELAS syndrome is a mitochondrial disorder that is caused mainly by the m.3243A > G mutation in mitochondrial DNA. Here, we report on how the severity of pathophysiological alterations is differently expressed in fibroblasts derived from patients with MELAS disease. We evaluated mitophagy activation and mitochondrial biogenesis which are the main mechanisms regulating the degradation and genesis of mitochondrial mass in MELAS fibroblasts and transmitochondrial cybrids. Our results suggest a critical balance between mitophagy and mitochondrial biogenesis which leads to the expression of different degrees of pathological severity among MELAS fibroblast cell lines according to their heteroplasmy load and the activation of AMP-activated protein kinase (AMPK). AMPK-activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) or coenzyme Q10 (CoQ) increased peroxisome proliferator-activated receptor alpha (PGC-1α) nuclear translocation, mitochondrial biogenesis, antioxidant enzyme system response, autophagic flux and improved pathophysiological alterations in MELAS fibroblasts with the most severe phenotype. Our findings support the hypothesis that mitochondrial biogenesis, increased antioxidant response and autophagy clearance serve as compensatory mechanisms in response to mitophagic degradation of dysfunctional mitochondria and point out that AMPK is an important player in this balance.This work was supported by FIS PI13/00129 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyecto de Investigación de Excelencia de la Junta de AndalucíaCTS-5725, and by AEPMI (Asociación de Enfermos de Patología Mitocondrial).Peer Reviewe

Mycobacteria emulsified in olive oil-in-water trigger a robust immune response in bladder cancer treatment

The hydrophobic composition of mycobacterial cell walls leads to the formation of clumps when attempting to resuspend mycobacteria in aqueous solutions. Such aggregation may interfere in the mycobacteria-host cells interaction and, consequently, influence their antitumor effect. To improve the immunotherapeutic activity of Mycobacterium brumae, we designed different emulsions and demonstrated their efficacy. The best formulation was initially selected based on homogeneity and stability. Both olive oil (OO)- and mineral oil-in-water emulsions better preserved the mycobacteria viability and provided higher disaggregation rates compared to the others. But, among both emulsions, the OO emulsion increased the mycobacteria capacity to induce cytokines' production in bladder tumor cell cultures. The OO-mycobacteria emulsion properties: less hydrophobic, lower pH, more neutralized zeta potential, and increased affinity to fibronectin than non-emulsified mycobacteria, indicated favorable conditions for reaching the bladder epithelium in vivo. Finally, intravesical OO-M. brumae-treated mice showed a significantly higher systemic immune response, together with a trend toward increased tumor-bearing mouse survival rates compared to the rest of the treated mice. The physicochemical characteristics and the induction of a robust immune response in vitro and in vivo highlight the potential of the OO emulsion as a good delivery vehicle for the mycobacterial treatment of bladder cancer