Induction of Therapeutic Protection in an HPV16-Associated Mouse Tumor Model Through Targeting the Human Papillomavirus-16 E5 Protein to Dendritic Cells.

HPV E5 is an oncoprotein mainly expressed in premalignant lesions, which makes it an important target for a vaccine to prevent or cure cervical cancer (CC). In this study, we evaluated whether E5 targeted to DEC-205, present in dendritic cells (DCs), could induce a therapeutic protection against HPV16-induced tumor cells in a mouse model. The HPV-16 E5 (16E5) protein was cross-linked to a monoclonal antibody (mAb) specific to mouse DEC-205 (anti-DEC-205:16E5) or to an isotype control mAb (isotype:16E5). Rotavirus VP6 was cross-linked to the mouse anti-DEC-205 mAb (anti-DEC-205:VP6) as a non-specific antigen control. BALB/c mice were inoculated subcutaneously (s.c.) with the 16E5-expressing BMK-16/myc tumor cells, and 7 and 14 days later the mice were immunized s.c. with the conjugates, free 16E5 or PBS in the presence of adjuvant. Tumor growth was monitored to evaluate protection. A strong protective immune response against the tumor cells was induced when the mice were inoculated with the anti-DEC-205:16E5 conjugate, since 70% of the mice controlled the tumor growth and survived, whereas the remaining 30% developed tumors and died by day 72. In contrast, 100% of the mice in the control groups died by day 30. The anti-DEC-205:16E5 conjugate was found to induce 16E5-specific memory T cells, with a Th1/Th17 profile. Both CD4+ and CD8+ T cells contributed to the observed protection. Finally, treating mice that had developed tumors with an anti-PD-1 mAb, delayed the tumor growth for more than 20 days. These results show that targeting 16E5 to DEC-205, alone or combined with an immune checkpoint blockade, could be a promising protocol for the treatment of the early stages of HPV-associated cancer.

Dengue virus infection induces chromatin remodeling at locus AAEL006536 in the midgut of Aedes aegypti.

OBJECTIVE: To identify and characterize Aedes aegypti's AAEL006536 gene proximal upstream cis-regulatory sequences activated by dengue virus infection. MATERIALS AND METHODS: A. aegypti Rockefeller strain mosquitoes were blood fed or infected with dengue virus 2. Open chromatinprofiling was then carried out in pools of midguts from each group of mosquitoes. RESULTS: The proximal upstream region does not contain open chromatin sites in the midguts of blood-fed mosquitoes as detected by FAIRE-qPCR. In contrast, two cis-regulatory sites were identified in the same upstream region of dengue virus-infected mosquito midguts. The distal sequence contains STAT-, REL- and C/EBP-type transcription factor binding sites. CONCLUSIONS: The activation of two proximal cis-regulatory sequences, induced by dengue virus infection, is mediated by chromatin remodeling mechanisms. Binding sites suggest a dengue virus infectioninduced participation of immunity transcription factors in the up-regulation of this gene. This suggests the participation of the AAEL006536 gene in the mosquito's antiviral innate immune response.

Dengue virus infection induces chromatin remodeling at locus AAEL006536 in the midgut of Aedes aegypti / La infección por virus dengue induce remodelación de la cromatina en el locus AAEL006536 en el intestino medio de Aedes aegypti

Abstract: Objective: To identify and characterize Aedes aegypti's AAEL006536 gene proximal upstream cis-regulatory sequences activated by dengue virus infection. Materials and methods: A. aegypti Rockefeller strain mosquitoes were blood fed or infected with dengue virus 2. Open chromatin profiling was then carried out in pools of midguts from each group of mosquitoes. Results: The proximal upstream region does not contain open chromatin sites in the midguts of blood-fed mosquitoes as detected by FAIRE-qPCR. In contrast, two cis-regulatory sites were identified in the same upstream region of dengue virus-infected mosquito midguts. The distal sequence contains STAT-, REL- and C/EBP-type transcription factor binding sites. Conclusion: The activation of two proximal cis-regulatory sequences, induced by dengue virus infection, is mediated by chromatin remodeling mechanisms. Binding sites suggest a dengue virus infection-induced participation of immunity transcription factors in the up-regulation of this gene. This suggests the participation of the AAEL006536 gene in the mosquito's antiviral innate immune response.

Resumen: Objetivo: Identificar y caracterizar las secuencias reguladoras activadas por la infección por virus dengue en la región proximal del gen AAEL006536 de Aedes aegypti. Material y métodos: Mosquitos de la cepa Rockefeller de A. aegypti se infectaron con virus dengue o se alimentaron con sangre. Se obtuvieron los perfiles de cromatina abierta del locus en los intestinos de cada uno de los grupos. Resultados: Se identificaron dos sitios reguladores solo en los intestinos de mosquitos infectados por virus dengue. El sitio distal contiene sitios de unión a factores de transcripción tipo REL, STAT y C/EBP. Conclusiones: La activación de dos sitios reguladores proximales está mediada por la remodelación de la cromatina. Los sitios de unión a factores de transcripción en el sitio regulador distal sugieren la participación de las vías de inmunidad en la regulación del gen. Esto sugiere la participación de este gen en la respuesta inmune del mosquito frente a la infección viral.

Antibiotic-Resistant Acinetobacter baumannii Increasing Success Remains a Challenge as a Nosocomial Pathogen.

Antibiotic-resistant infectious bacteria currently imply a high risk and therefore constitute a strong challenge when treating patients in hospital settings. Characterization of these species and of particular strains is a priority for the establishment of diagnostic tests and preventive procedures. The relevance of Acinetobacter baumannii as a problematic microorganism in inpatient facilities, particularly intensive care units, has increased over time. This review aims to draw attention to (i) the historical emergence of carbapenem-resistant Acinetobacter baumannii, (ii) the current status of surveillance needs in Latin America, and (iii) recent data suggesting that A. baumannii continues to spread and evolve in hospital settings. First, we present synopsis of the series of events leading to the discovery and precise identification of this microorganism in hospital settings. Then key events in the acquisition of antibiotic-resistant genes by this microorganism are summarized, highlighting the race between new antibiotic generation and emergence of A. baumannii resistant strains. Here we review the historical development of this species as an infectious threat, the current state of its distribution, and antibiotic resistance characteristics, and we discuss future prospects for its control.

[Polymorphisms in gene regulatory regions and their role in the physiopathology of complex disease in the post-genomic era]. / Polimorfismos reguladores y su participación en la patogenia de enfermedades complejas en la era posgenómica.

The genomic era is imparting a new impulse to the study of the role of genetic variation in susceptibility to disease. The most common type of genetic variation between individuals is single nucleotide polymorphisms (SNP). The association of SNPs with susceptibility to disease is the current focus of intense research. Recently, the study of SNPs that alter the regulatory mechanisms of gene expression (rSNP) has emerged as a promising field for understanding disease, since this type of variation can have a profound effect on human traits related to susceptibility to disease. The finding and functional characterization of biologically significant rSNPs is advancing our knowledge of genetic determinants for multifactorial disease.

Polimorfismos reguladores y su participación en la patogenia de enfermedades complejas en la era posgenómica / Polymorphisms in gene regulatory regions and their role in the physiopathology of complex disease in the post-genomic era

El estudio de la participación de la variación genética en la predisposición a las enfermedades complejas ha cobrado nuevas dimensiones en la era genómica. Los polimorfismos de un solo nucleótido (SNP) son el tipo de variación más común entre individuos y su vinculación con enfermedades es motivo de investigación intensa. En fecha reciente, el estudio de los SNP que afectan la expresión genética (rSNP) ha suscitado mayor interés, ya que las diferencias de la expresión genética entre un sujeto y otro pueden modificar el fenotipo. El descubrimiento y caracterización funcional de los rSNP y el estudio de su frecuencia alélica representan un nuevo campo en la búsqueda de determinantes genéticos de enfermedades multifactoriales.

The genomic era is imparting a new impulse to the study of the role of genetic variation in susceptibility to disease. The most common type of genetic variation between individuals is single nucleotide polymorphisms (SNP). The association of SNPs with susceptibility to disease is the current focus of intense research. Recently, the study of SNPs that alter the regulatory mechanisms of gene expression (rSNP) has emerged as a promising field for understanding disease, since this type of variation can have a profound effect on human traits related to susceptibility to disease. The finding and functional characterization of biologically significant rSNPs is advancing our knowledge of genetic determinants for multifactorial disease.