Programmatic human papillomavirus testing in cervical cancer prevention in the Jujuy Demonstration Project in Argentina: a population-based, before-and-after retrospective cohort study

Background: Human papillomavirus (HPV) testing for cervical cancer prevention was introduced in Argentina through the Jujuy Demonstration Project (2011-14). The programme tested women aged 30 years and older attending the public health system with clinician-collected HPV tests. HPV self-collection was introduced as a programmatic strategy in 2014. We aimed to evaluate the effectiveness of programmatic HPV testing to detect cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+) in comparison with cytology-based screening. Methods: We did a population-based, before-and-after retrospective cohort study using data from the National Cervical Cancer Prevention Program for the Jujuy province in northwest Argentina. We obtained data for the cytology-based screening period from Jan 1, 2010, until Dec 31, 2011, and for the HPV-based screening period from Jan 1, 2012, until Dec 31, 2014. The primary outcome was detection of histologically diagnosed CIN2+ among women aged 30 years and older. To assess the outcomes in all individuals included in the study, we used multivariable logistic regression and propensity score matching. The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework was used for the before-and-after analysis of programmatic dimensions. Findings: Of the 29 631 women who underwent cytology-based screening in 2010?11, CIN2+ was detected in 236 (0·8%) individuals. Of the 49 565 women HPV tested in 2012?14 (clinician-collected tests, n=44 700; self-collection tests, n=4865), 693 (1·4%; 658 clinician-collected tests; 35 self-collection tests) were found to have CIN2+ after the first round of screening. Compared with cytology-based screening, the odds ratio of being diagnosed with a CIN2+ lesion was 2·34 (95% CI 2·01?2·73; p<0·0010) with clinician-collected tests, and 1·08 (0·74?1·52; p=0·68) when screened with self-collection tests, after controlling for age and health insurance status. Screening coverage was similar in both periods (52·7% vs 53·2%); improvements of programmatic indicators were observed in the HPV testing period in relation to laboratory centralisation, lower overscreening (6·6% vs 0·0%), higher adherance to age recommendations (79·3% vs 98·8%), and a decrease of inadequate samples (3·6% vs 0·2%). Interpretation: HPV testing in middle-income settings increases detection of CIN2+ lesions and allows for improvement of programmatic indicators. Evidence suggests that the introduction of HPV testing will accelerate the reduction of cervical cancer burden. Funding: Argentinian National Cancer Institute and National Council of Scientific and Technologic Research.Fil: Arrossi, Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Estudios de Estado y Sociedad; ArgentinaFil: Paolino, Melisa Delia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Estudios de Estado y Sociedad; ArgentinaFil: Laudi, Rosa. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Gago, Juan Ezequiel. Centro de Estudios de Estado y Sociedad; Argentina. Ministerio de Salud. Instituto Nacional del Cáncer; ArgentinaFil: Campanera, Alicia. Ministerio de Salud de la Provincia de Jujuy; ArgentinaFil: Marín, Oscar. Hospital Pablo Soria; ArgentinaFil: Falcón, Cristina. Hospital Pablo Soria; ArgentinaFil: Serra, Verónica. Ministerio de Salud de la Provincia de Jujuy; ArgentinaFil: Herrero, Rolando. No especifíca;Fil: Thouyaret, Laura. Ministerio de Salud. Instituto Nacional del Cáncer; Argentin

Immunomodulatory role of histamine H4 receptor in breast cancer

Background: Although the role of histamine H4 receptor (H4R) in immune cells is being extensively investigated, its immunomodulatory function in cancer is completely unknown. This study aimed to investigate the role of H4R in antitumour immunity in a model of triple-negative breast cancer. Methods: We evaluated growth parameters, histological characteristics and the composition of tumour, splenic and tumour draining lymph node (TDLN) immune subsets, in a syngeneic model, developed orthotopically with 4T1 cells in H4R knockout (H4R-KO) and wild-type mice. Results: Mice lacking H4R show reduced tumour size and weight, decreased number of lung metastases and percentage of CD4 + tumour-infiltrating T cells, while exhibiting increased infiltration of NK cells and CD19 + lymphocytes. Likewise, TDLN of H4R-KO mice show decreased CD4 + T cells and T regulatory cells (CD4 + CD25 + FoxP3 + ), and increased percentages of NK cells. Finally, H4R-deficient mice show decreased Tregs in spleens and non-draining lymph nodes, and a negative correlation between tumour weight and the percentages of CD4 + , CD19 + and NK splenic cells, suggesting that H4R also regulates antitumour immunity at a systemic level. Conclusions: This is the first report that demonstrates the participation of H4R in antitumour immunity, suggesting that H4R could be a target for cancer treatment.Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Nicoud, Melisa Beatriz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Massari, Noelia Andrea. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Comodoro; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Herrero Ducloux, María Verónica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Comodoro; ArgentinaFil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

Study of the antitumour effects and the modulation of immune response by histamine in breast cancer

Background: The aim of this work was to improve the knowledge of the role of histamine in breast cancer by assessing the therapeutic efficacy of histamine and histamine H4 receptor (H4R) ligands in a triple-negative breast cancer (TNBC) model developed in immunocompetent hosts. By using publicly available genomic data, we further investigated whether histidine decarboxylase (HDC) could be a potential biomarker. Methods: Tumours of 4T1 TNBC cells were orthotopically established in BALB/c mice. Treatments employed (mg kg−1): histamine (1 and 5), JNJ28610244 (H4R agonist, 1 and 5) and JNJ7777120 (H4R antagonist, 10). Results: Increased HDC gene expression is associated with better relapse-free and overall survival in breast cancer patients. Histamine treatment (5 mg kg−1) of 4T1 tumour-bearing mice reduced tumour growth and increased apoptosis. Although no immunomodulatory effects were observed in wild-type mice, significant correlations between tumour weight and cytotoxic lymphocyte infiltration were detected in H4R knockout mice. H4R agonist or antagonist differentially modulated tumour growth and immunity in 4T1 tumour-bearing mice. Conclusions: Histamine plays a complex role and stands out as a promising drug for TNBC treatment, which deserves to be tested in clinical settings. HDC expression level is associated with clinicopathological characteristics, suggesting a prognostic value in breast cancer.Fil: Nicoud, Melisa Beatriz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Massari, Noelia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Formoso, Karina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Herrero Ducloux, María Verónica. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Martinel Lamas, Diego José. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

Drug Screening Identifies Sigma-1-Receptor as a Target for the Therapy of VWM Leukodystrophy

Vanishing white matter (VWM) disease is an autosomal genetic leukodystrophy caused by mutations in subunits of eukaryotic translation initiation factor 2B (eIF2B). The clinical symptoms exhibit progressive loss of white matter in both hemispheres of the brain, accompanied by motor functions deterioration, neurological deficits, and early death. To date there is no treatment for VWM disease. The aim of this work was to expedite rational development of a therapeutic opportunity. Our approach was to design a computer-aided strategy for an efficient and reliable screening of drug-like molecules; and to use primary cultures of fibroblasts isolated from the Eif2b5R132H/R132H VWM mouse model for screening. The abnormal mitochondria content phenotype of the mutant cells was chosen as a read-out for a simple cell-based fluorescent assay to assess the effect of the tested compounds. We obtained a hit rate of 0.04% (20 hits out of 50,000 compounds from the selected library). All primary hits decreased mitochondria content and brought it closer to WT levels. Structural similarities between our primary hits and other compounds with known targets allowed the identification of three putative cellular pathways/targets: 11β-hydroxysteroid dehydrogenase type 1, Sonic hedgehog (Shh), and Sigma-1-Receptor (S1R). In addition to initial experimental indication of Shh pathway impairment in VWM mouse brains, the current study provides evidence that S1R is a relevant target for pharmaceutical intervention for potential treatment of the disease. Specifically, we found lower expression level of S1R protein in fibroblasts, astrocytes, and whole brains isolated from Eif2b5R132H/R132H compared to WT mice, and confirmed that one of the hits is a direct binder of S1R, acting as agonist. Furthermore, we provide evidence that treatment of mutant mouse fibroblasts and astrocytes with various S1R agonists corrects the functional impairments of their mitochondria and prevents their need to increase their mitochondria content for compensation purposes. Moreover, S1R activation enhances the survival rate of mutant cells under ER stress conditions, bringing it to WT levels. This study marks S1R as a target for drug development toward treatment of VWM disease. Moreover, it further establishes the important connection between white matter well-being and S1R-mediated proper mitochondria/ER function

Los mosaicos de vegetación y roca maximizan los servicios hídricos en las zonas altas de montaña del centro de la Argentina

En sistemas con lluvias estacionales, el rendimiento hídrico (caudal de salida del curso de agua relativo al área de la cuenca) en la estación seca depende de las lluvias previas y de la infiltración y la evapotranspiración, procesos que, a su vez, están afectados por las características del paisaje. Nuestro objetivo fue evaluar el efecto de distintas variables de paisaje sobre el rendimiento hídrico y la tasa de recesión (tasa a la que disminuye el caudal) durante la estación seca, en cuencas de alta montaña del centro de la Argentina. Seleccionamos 33 cuencas de 9-61 ha, y durante el final de la estación seca de 2017 medimos semanalmente el caudal en sus puntos de cierre durante siete semanas consecutivas. Para cada cuenca calculamos el rendimiento hídrico (mm/mes) promedio y un índice de recesión (adimensional) como la diferencia normalizada del rendimiento entre las últimas y las primeras fechas. Los paisajes extensamente ocupados por un mosaico de pajonal y roca, con pendiente y rugosidad intermedias, tuvieron los rendimientos hídricos máximos (>5 mm/mes). Por lo contrario, el rendimiento hídrico fue más bajo tanto en los paisajes suaves y cubiertos por vegetación, como en los muy ásperos (muy rugosos, escarpados y rocosos). Por su parte, la recesión fue lenta en los paisajes más ásperos y muy abrupta en los paisajes más suaves. Posiblemente, en los paisajes suaves y vegetados se pierde mucha agua por evapotranspiración, mientras que en los paisajes muy ásperos se pierde mucha agua por escorrentía después de las lluvias. Los paisajes con aspereza intermedia y un mosaico de vegetación y roca serían los que optimizan el almacenamiento, minimizando las pérdidas por evapotranspiración. Por lo tanto, para sostener el rendimiento hídrico es prioritario conservar este tipo de paisajes, evitando la erosión del suelo que genera un aumento de áreas rocosas.Fil: Cingolani, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Poca, María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Whitworth Hulse, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Giorgis, Melisa Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Vaieretti, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Herrero, María Lucrecia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Navarro Ramos, Silvia Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Renison, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentin

The Energy Status of Astrocytes Is the Achilles’ Heel of eIF2B-Leukodystrophy

Translation initiation factor 2B (eIF2B) is a master regulator of global protein synthesis in all cell types. The mild genetic Eif2b5(R132H) mutation causes a slight reduction in eIF2B enzymatic activity which leads to abnormal composition of mitochondrial electron transfer chain complexes and impaired oxidative phosphorylation. Previous work using primary fibroblasts isolated from Eif2b5(R132H/R132H) mice revealed that owing to increased mitochondrial biogenesis they exhibit normal cellular ATP level. In contrast to fibroblasts, here we show that primary astrocytes isolated from Eif2b5(R132H/R132H) mice are unable to compensate for their metabolic impairment and exhibit chronic state of low ATP level regardless of extensive adaptation efforts. Mutant astrocytes are hypersensitive to oxidative stress and to further energy stress. Moreover, they show migration deficit upon exposure to glucose starvation. The mutation in Eif2b5 prompts reactive oxygen species (ROS)-mediated inferior ability to stimulate the AMP-activated protein kinase (AMPK) axis, due to a requirement to increase the mammalian target of rapamycin complex-1 (mTORC1) signalling in order to enable oxidative glycolysis and generation of specific subclass of ROS-regulating proteins, similar to cancer cells. The data disclose the robust impact of eIF2B on metabolic and redox homeostasis programs in astrocytes and point at their hyper-sensitivity to mutated eIF2B. Thereby, it illuminates the central involvement of astrocytes in Vanishing White Matter Disease (VWMD), a genetic neurodegenerative leukodystrophy caused by homozygous hypomorphic mutations in genes encoding any of the 5 subunits of eIF2B

Psycho-social impact of positive human papillomavirus testing in Jujuy, Argentina results from the Psycho-Estampa study

Fil: Arrossi, Silvina. Centro de Estudios de Estado y Sociedad; Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, ArgentinaHuman papillomavirus (HPV) testing can have a negative impact on women’s lives which might also result in abandoning the follow-up and treatment process. This study measured the psycho-social impact of HPV-positivity among HPV-tested women from Jujuy, Argentina, a middle-low income setting. In this cross-sectional study (2015–2016), the psycho-social impact of HPV-positivity was measured using the Psycho-Estampa Scale, specifically designed and validated to be used in screening contexts. We measured mean scores for each of the five scale domains, and the Overall Impact score (Values from 1: No impact to 4: Heavy impact). We compared scores according to cytology triage diagnosis using ordinal logistic regression. A total of 163 HPV-positive women were recruited at the Centro Carlos Alvarado hospital and included in the study sample; of these, 124 (76.1%) had normal triage cytologies. The overall Impact score was between low and moderate (mean:2.56, SD:0.65). The highest psycho-social impact was measured in the Worries about cancer and treatment domain (mean score:3.60, SD:0.60), followed by Sexuality domain (mean:2.50; SD:1.00). The Uncertainty about information provided by health providers domain had the lowest mean score (mean:2.14, SD:0.73). Compared to women with normal cytologies (n = 124), women with abnormal cytologies (n = 39) had a higher likelihood of greater overall Psycho-social Impact (OR: 2.91; p = 0.0036). No statistically significant differences were found in scores of specific domains according to cytology results. It is important to devise specific counseling interventions to reduce the psycho-social impact of HPV-Testing as primary screening and its potential effect on completion of the diagnosis/ treatment process

Fire reduces dry season low flows in a subtropical highland of central Argentina

Wildfires are recurrent in seasonally-dry ecosystems; however, their effects on streamflows at the end of the dry season (low flows) are not well understood. The infiltration-evapotranspiration trade-off hypothesis postulates that when vegetation cover is lost or degraded, low flows in the following dry season are reduced due to impaired water infiltration and storage in soils during the wet season, which surpass gains due to diminished evapotranspiration. We tested this hypothesis in the context of vegetation loss produced by fire. For this purpose, we seized a wildfire in a subtropical highland of central Argentina and selected 12 burnt and 12 unburnt catchments of 15–60 ha. We measured low flows at the outlet point of each catchment in two opportunities: one year after the fire (post-fire dry season) and in a dry season not affected by previous fire (control dry season). Using the 12 unburnt catchments, we built linear regression models to estimate the expected low flows for the post-fire dry season under a no-fire scenario. The predictor variables were low flows in the control dry season. We applied the models to burnt catchments and compared the expected with the observed low flows. We also evaluated vegetation activity through satellite images. Burnt catchments showed significant low flow reductions of 31–48% compared with expectations under a no-fire scenario, supporting the infiltration-evapotranspiration trade-off hypothesis. Vegetation activity was lower in burnt than in unburnt catchments only for the first three months after the fire, while it was more active since then for one year. Together our results suggest that post-fire reduced low flows can be explained by a reduced infiltration, as well as by higher evapotranspiration due to increased vegetation activity. Given the extent of seasonally dry ecosystems worldwide, we highlight the importance of controlling wildfires to improve streamflow in the dry-season.Fil: Cingolani, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Poca, María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Whitworth Hulse, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Giorgis, Melisa Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Vaieretti, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Herrero, María Lucrecia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Navarro Ramos, Silvia Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Renison, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentin

Antitumoral ans inmunomodulatory role for histamine in breast cancer

It is well known that histamine is a key regulator of inmune cell functions and it also modulates cancer cell proliferation. The aim of this work was to investigate the effect of histamine and its H4 receptor (H4R) agonist (JNJ28610244) on tumour growth and in the inmune tumour microenvironment as a whole, in a triple negative breast cancer (TNBC) syngeneic model developed in inmunocompetent mice. Tumours of tne TNBC cell line 4T1 were established in Balb/c mice. Treatments employed: histamine (1 or 5mg/kg) and JNJ28610244 (1 or 5mg kg). Results show that histamine treatment (5mg/kg) reduces tumour growth more effectively that JNJ28610244. Histamine but the agonist increases tumour apoptosis and it reduces the number of intratumoural vessels. Histamine also reduces immunosuppression throught the modulation of the tumour microenvironment, as it increasesthe tumour secretion of IFN gamma and reduces the number of T regulatory (Treg) lymphocytes in lymph nodes and spleen. A lower concretation (1mg/kg) of JNJ28610244 reduces tumour size while no inmunomodulatory effects are observed in the immune cell subsets studied. In contrast, a higher concentration (5mg/kg) is not able to decrease tumour growth probably because of the immunosuppressive effect produced in the tumour microenvironment, showing increased levels of interleukin (IL)-10 and decreased levels of IFNy in tumours and increased infiltrating Treg cells in tumour draining lymph nodes. These results highlight the critical interplay between tumour cells and host immune response that determine the clinical therapeutic outcomes and suggest that histamine is a key pleiotropic mediator with therapeutic benefits in TNBC.Fil: Nicoud, Melisa Beatriz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Massari, Noelia Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Formoso, Karina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Herrero Ducloux, María Verónica. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Martinel Lamas, Diego José. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaLXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVI Reunión Anual de la Sociedad Argentina de Inmunología; Reunión Anual de la Sociedad Argentina de FisiologíaMar del PlataArgentinaSociedad Argentina de Investigacion ClinicaSociedad Argentina de InmunologíaSociedad Argentina de FisiologíaSociedad Argentina de VirologíaSociedad Argentina de Nanomedicina

Histamine therapeutic efficacy in metastatic melanoma : role of histamine H4 receptor agonists and opportunity for combination with radiation

Abstract: The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells. Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma