EFECTO DE UN TRATAMIENTO EXPERIMENTAL EN PROCESOS CELULARES ALTERADOS EN MODELOS ANIMALES DE ELA

La Esclerosis Lateral Amiotrófica es una enfermedad neurodegenerativa devastadora y sin tratamiento. Por ello, es de vital importancia el desarrollo de terapias que permitan, por lo menos, mejorar la calidad de vida de los pacientes. Resultados previos de nuestro laboratorio han demostrado el efecto beneficioso del tratamiento con el quimioterápico 5-Fluorouracilo (5-FU) en el modelo murino de ELA SOD1G93A. En este contexto, el objetivo de este Trabajo de Fin de Grado fue determinar si el efecto del tratamiento con dicho fármaco modificaba la expresión de genes implicados en alguno de los procesos patológicos de la enfermedad: autofagia, apoptosis e inflamación. Los resultados obtenidos indican que el tratamiento con 5-FU no modula los procesos de autofagia ni apoptosis en el músculo esquelético de los animales modelos; y sugieren que la vía inflamatoria CCL2/CCR2 podría estar implicada en el mecanismo de acción del tratamiento con 5-FU

Complementing the cancer-immunity cycle

Reactivation of cytotoxic CD8+ T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been particularly successful for tumor types with limited therapeutic options such as melanoma and lung cancer. However, reactivation of T cells is only one step toward tumor elimination, and a substantial fraction of patients fails to respond to these therapies. In this context, combination therapies targeting more than one of the steps of the cancer-immune cycle may provide significant benefits. To find the best combinations, it is of upmost importance to understand the interplay between cancer cells and all the components of the immune response. This review focuses on the elements of the complement system that come into play in the cancer-immunity cycle. The complement system, an essential part of innate immunity, has emerged as a major regulator of cancer immunity. Complement effectors such as C1q, anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1, have been associated with tolerogenic cell death and inhibition of antitumor T-cell responses through the recruitment and/or activation of immunosuppressive cell subpopulations such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), or M2 tumor-associated macrophages (TAMs). Evidence is provided to support the idea that complement blocks many of the effector routes associated with the cancer-immunity cycle, providing the rationale for new therapeutic combinations aimed to enhance the antitumor efficacy of anti-PD-1/PD-L1 checkpoint inhibitors

Complement in Metastasis: A Comp in the Camp

The complement system represents a pillar of the innate immune response. This system, critical for host defense against pathogens, encompasses more than 50 soluble, and membrane-bound proteins. Emerging evidence underscores its clinical relevance in tumor progression and its role in metastasis, one of the hallmarks of cancer. The multistep process of metastasis entails the acquisition of advantageous functions required for the formation of secondary tumors. Thus, targeting components of the complement system could impact not only on tumor initiation but also on several crucial steps along tumor dissemination. This novel vulnerability could be concomitantly exploited with current strategies overcoming tumor-mediated immunosuppression to provide a substantial clinical benefit in the treatment of metastatic disease. In this review, we offer a tour d'horizon on recent advances in this area and their prospective potential for cancer treatment

Complementing the Cancer-Immunity Cycle

Reactivation of cytotoxic CD8+ T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been particularly successful for tumor types with limited therapeutic options such as melanoma and lung cancer. However, reactivation of T cells is only one step toward tumor elimination, and a substantial fraction of patients fails to respond to these therapies. In this context, combination therapies targeting more than one of the steps of the cancer-immune cycle may provide significant benefits. To find the best combinations, it is of upmost importance to understand the interplay between cancer cells and all the components of the immune response. This review focuses on the elements of the complement system that come into play in the cancer-immunity cycle. The complement system, an essential part of innate immunity, has emerged as a major regulator of cancer immunity. Complement effectors such as C1q, anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1, have been associated with tolerogenic cell death and inhibition of antitumor T-cell responses through the recruitment and/or activation of immunosuppressive cell subpopulations such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), or M2 tumor-associated macrophages (TAMs). Evidence is provided to support the idea that complement blocks many of the effector routes associated with the cancer-immunity cycle, providing the rationale for new therapeutic combinations aimed to enhance the antitumor efficacy of anti-PD-1/PD-L1 checkpoint inhibitors

Persistent antiphospholipid antibodies are not associated with worse clinical outcomes in a prospective cohort of hospitalised patients with SARS-CoV-2 infection.

Objective: Patients with COVID-19 presented with an elevated prevalence of antiphospholipid antibodies (aPL) but the relationship with thrombosis is controversial. We analysed the persistence of aPL and their association with the clinical outcomes during hospitalisation in a cohort of COVID-19 patients. Patients and methods: We conducted a prospective study including consecutive hospitalised patients with COVID-19 from Hospital Clínic of Barcelona between March 28th and April 22nd, 2020. Clinical outcomes during hospitalisation were thrombosis, intensive care unit (ICU) admission, and severe ventilatory failure. We determined both criteria and non-criteria aPL. Of note, in those patients with a positive result in the first determination, a second sample separated by at least 12 weeks was drawn to test the persistence of aPL. Results: One hundred and fifty-eight patients (59.5% men) with a mean age of 61.4 ± 14.9 years old were included. Thrombosis was present in 28 (17.7%) patients, severe respiratory failure in 47 (30.5%), and 30 (18.9%) patients were admitted to ICU. Sixteen (28.6%) patients were positive for the criteria aPL at both determinations and only two (3.6%) of them suffered from thrombosis during hospitalisations (both had aCL IgG). However, they presented with low titers of aCL. Of note, aPL were not related to thrombosis, ICU admission or severe respiratory failure. Conclusion: Although aPL were prevalent in our cohort of hospitalised COVID-19 patients and they were persistent in half of tested patients, most determinations were at low titers and they were not related to worse clinical outcomes

Prevalencia de sífilis y características del comportamiento de los jóvenes indígenas del Paraguay, 2016

El objetivo fue determinar la prevalencia de sífilis y características de comportamiento de los jóvenes indígenas del Paraguay en el 2016. Se realizó un estudio observacional, descriptivo de corte transversal con muestro probabilístico estratificado bietapico, que incluyó a jóvenes indígenas de 15 a 18 años de cinco familias lingüísticas de Paraguay. Se utilizó un cuestionario estructurado y para el tamizaje de sífilis se utilizó una test rápido treponémico y para confirmar los resultados reactivos se realizó VDRL, considerando como resultado positivo si el test rápido era positivo + VDRL positivo a una dilución de 1:4 o mayor y si la VDRL era menor a 1:4 con TPHA positivo. Los resultados se expresan como medidas de tendencia central, dispersión y proporciones. Ingresaron al estudio 546 jóvenes de 15 a 18 años, el 67,03% era del sexo femenino. Se identificaron 36 casos de sífilis, que representa una prevalencia de 6,6% [IC95%: 4,7-9,0]. Mayor prevalencia de sífilis se observó en los jóvenes que consumieron alcohol en la última relación sexual 20,6% (14/68) (p<0,001), sexo transaccional 40% (2/5) (p=0,010) y no utilización de condón 20,6% (14/68) (p<0,001). Se encontró una alta prevalencia de sífilis en la población juvenil indígena, relacionada al consumo de alcohol en la última relación, práctica de sexo transaccional y no utilización de preservativos. Se recomienda la implementación de estrategias específicas con abordaje intercultural apropiadas para una población joven, orientadas a disminuir las prácticas de riesgo y promocionar la utilización de preservativos

FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

[EN] Background & Aims: Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. Methods: FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Followup RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. Results: An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. Conclusions: Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. Lay summary: Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.A.V. was supported by ADA of the University of Navarra, Spain, O.E. by FSE; MINECO; FJCI-2017-34233, Spain, R.E. by a donation from Mauge Burgos de la Iglesia’s family, Spain, and P. Olaizola by the Basque Government (PRE_2016_1_0269), Basque Country, Spain. M.J.P. was funded by ISCIII [FIS PI14; 00399, PI17; 00022] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER), Spain; Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Program RYC-2015-17755), Spain. M.A.A was funded by La Caixa Foundation, HEPACARE project, Spain, ISCIII FIS PI16/01126 cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER), Spain, and “Fundación Científica de la Asociación Española Contra el Cáncer’’ (AECC Scientific Foundation) Rare Cancers 2017, Spain. J.M.B. was funded by the Spanish Carlos III Health Institute (ISCIII) (FIS PI15; 01132, PI18; 01075 and Miguel Servet Program CON14; 00129 and CPII19; 00008), Spain, co-financed by “Fondo Europeo de Desarrollo Regional” (FEDER), Spain; “Euskadi RIS3” (2019222054) and BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15; CA; 016; BD), Basque Country, Spain; “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation) Rare Cancers 2017, Spain. S.V. was supported by FEDER; MINECO (SAF2017-89944-R), Spain, by the Government of Navarra-Health Research Department (58; 2018), Navarra, Spain, by La Caixa and Caja Navarra Foundation-CIMA agreement, Spain. None of the funding sources were involved in the decision to submit the article for publication. This article is based upon work from COST Action CA18122 European Cholangiocarcinoma Network, supported by COST (European Cooperation in Science and Technology). COST (European Cooperation in Science and Technology) is a funding agency for research and innovation networks (www.cost.eu)

FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention

A Molecular Characterization of the Allelic Expression of the BRCA1 Founder Δ9–12 Pathogenic Variant and Its Potential Clinical Relevance in Hereditary Cancer:International Journal of Molecular Sciences

Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9–12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9–12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT–qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9–12 alleles using nanopore long-sequencing. Using the Kruskal–Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9–12 and identifying which of them has developed cancer