Mechanisms of growth inhibition of primary prostate epithelial cells following gamma irradiation or photodynamic therapy including senscence, necrosis, and autophagy, but not apoptosis

In comparison to more differentiated cells, prostate cancer stem-like cells are radioresistant, which could explain radio-recurrent prostate cancer. Improvement of radiotherapeutic efficacy may therefore require combination therapy. We have investigated the consequences of treating primary prostate epithelial cells with gamma irradiation and photodynamic therapy (PDT), both of which act through production of reactive oxygen species (ROS). Primary prostate epithelial cells were cultured from patient samples of benign prostatic hyperplasia and prostate cancer prior to treatment with PDT or gamma irradiation. Cell viability was measured using MTT and alamar blue assay, and cell recovery by colony-forming assays. Immunofluorescence of gamma-H2AX foci was used to quantify DNA damage, and autophagy and apoptosis were assessed using Western blots. Necrosis and senescence were measured by propidium iodide staining and beta-galactosidase staining, respectively. Both PDT and gamma irradiation reduced the colony-forming ability of primary prostate epithelial cells. PDT reduced the viability of all types of cells in the cultures, including stem-like cells and more differentiated cells. PDT induced necrosis and autophagy, whereas gamma irradiation induced senescence, but neither treatment induced apoptosis. PDT and gamma irradiation therefore inhibit cell growth by different mechanisms. We suggest these treatments would be suitable for use in combination as sequential treatments against prostate cancer

Arrival of Paleo-Indians to the Southern Cone of South America: New Clues from Mitogenomes

With analyses of entire mitogenomes, studies of Native American mitochondrial DNA (mtDNA) variation have entered the final phase of phylogenetic refinement: the dissection of the founding haplogroups into clades that arose in America during and after human arrival and spread. Ages and geographic distributions of these clades could provide novel clues on the colonization processes of the different regions of the double continent. As for the Southern Cone of South America, this approach has recently allowed the identification of two local clades (D1g and D1j) whose age estimates agree with the dating of the earliest archaeological sites in South America, indicating that Paleo-Indians might have reached that region from Beringia in less than 2000 years. In this study, we sequenced 46 mitogenomes belonging to two additional clades, termed B2i2 (former B2l) and C1b13, which were recently identified on the basis of mtDNA control-region data and whose geographical distributions appear to be restricted to Chile and Argentina. We confirm that their mutational motifs most likely arose in the Southern Cone region. However, the age estimate for B2i2 and C1b13 (11–13,000 years) appears to be younger than those of other local clades. The difference could reflect the different evolutionary origins of the distinct South American-specific sub-haplogroups, with some being already present, at different times and locations, at the very front of the expansion wave in South America, and others originating later in situ, when the tribalization process had already begun. A delayed origin of a few thousand years in one of the locally derived populations, possibly in the central part of Chile, would have limited the geographical and ethnic diffusion of B2i2 and explain the present-day occurrence that appears to be mainly confined to the Tehuelche and Araucanian-speaking grou

Infectious Diseases and Globalization: insights from a National Tropical Medicine Referral Unit

Las enfermedades infecciosas importadas están cambiando en aspectos importantes como la incidencia, la epidemiología (con riesgo de transmisión local de algunas en zonas no-endémicas) y su gravedad, especialmente en poblaciones vulnerables como migrantes y personas inmunodeprimidas. La tesis se presenta como un compendio de artículos publicados en la línea de investigación de las enfermedades importadas. Se realizó una descripción de casos importados de arbovirosis, malaria y otras infecciones, registrados en una red nacional de patología importada por viajeros e inmigrantes. Las arbovirosis importadas y la malaria importada estaban entre los 10 diagnósticos más frecuentes en la red nacional de patología importada, siendo la infección por arbovirus el segundo diagnóstico más frecuente en el grupo de viajeros convencionales. Las tendencias temporales de las infecciones importadas reflejaron la situación epidemiológica global del momento, y en algunas ocasiones los viajeros actuaron como centinelas de epidemias que ocurrieron en otras zonas geográficas. Una porporción importante de las arbovirosis se registraron en mujeres de edad fértil, resaltando la necesidad de mejorar el consejo pre-viaje y las medidas de prevención por el posible riesgo de transmisión vertical de estas infecciones. No se demostró una asociación entre la infección por arbovirus y la inmunosupresión, y ninguno de los casos graves (todos por virus dengue) ocurrieron en personas inmunocomprometidas. La pandemia de COVID-19 se asoció con un aumento en el número de casos de malaria grave registrados en la red nacional de patología importada durante el periodo 2020-2021. Los migrantes, y otras poblaciones vulnerables, podrían padecer infecciones graves y complicaciones por enfermedades como la COVID-19, la infección por HTLV-1 y algunas enfermedades inmunoprevenibles. El consejo pre-viaje fue subóptimo en los estudios y se identificó la necesidad de mejorar las estrategias de prevención de las enfermedades infecciosas en poblaciones como viajeros e inmigrantes. Los datos aportados por el estudio de la patología importada pueden contribuir a la mejora del conocimiento de las enfermedades infecciosas

The eukaryotic linear motif resource ELM: 10 years and counting

The eukaryotic linear motif (ELM http://elm.eu.org) resource is a hub for collecting, classifying and curating information about short linear motifs (SLiMs). For >10 years, this resource has provided the scientific community with a freely accessible guide to the biology and function of linear motifs. The current version of ELM contains ∼200 different motif classes with over 2400 experimentally validated instances manually curated from >2000 scientific publications. Furthermore, detailed information about motif-mediated interactions has been annotated and made available in standard exchange formats. Where appropriate, links are provided to resources such as switches.elm.eu.org and KEGG pathways.Fil: Dinkel, Holder. European Molecular Biology Laboratory; AlemaniaFil: Van Roey, Kim. European Molecular Biology Laboratory; AlemaniaFil: Michael, Sushama. European Molecular Biology Laboratory; AlemaniaFil: Davey, Norman E.. University Of California ; Estados UnidosFil: Weatheritt, Robert J.. MRC. Laboratory of Molecular Biology; Estados UnidosFil: Born, Diana. Ruprecht-Karls-Universität; AlemaniaFil: Speck, Tobias. Ruprecht-Karls-Universität; AlemaniaFil: Kruger, Daniel. Ruprecht-Karls-Universität; AlemaniaFil: Grebnev, Gleb. University College Dublin; IrlandaFil: Kuban, Marta. Maria Sklodowska-Curie Memorial Cancer Center. Laboratory of Bioinformatics and Biostatistics; PoloniaFil: Strumillo, Marta. Maria Sklodowska-Curie Memorial Cancer Center. Laboratory of Bioinformatics and Biostatistics; PoloniaFil: Uyar, Bora. European Molecular Biology Laboratory; AlemaniaFil: Budd, Aidan. European Molecular Biology Laboratory; AlemaniaFil: Altenberg, Brigitte. European Molecular Biology Laboratory; AlemaniaFil: Seiler, Markus. European Molecular Biology Laboratory; AlemaniaFil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Glavina, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Diella, Francesca. European Molecular Biology Laboratory; AlemaniaFil: Gibson, Toby J. European Molecular Biology Laboratory; Alemani

ELM—the database of eukaryotic linear motifs

Linear motifs are short, evolutionarily plastic components of regulatory proteins and provide low-affinity interaction interfaces. These compact modules play central roles in mediating every aspect of the regulatory functionality of the cell. They are particularly prominent in mediating cell signaling, controlling protein turnover and directing protein localization. Given their importance, our understanding of motifs is surprisingly limited, largely as a result of the difficulty of discovery, both experimentally and computationally. The Eukaryotic Linear Motif (ELM) resource at http://elm.eu.org provides the biological community with a comprehensive database of known experimentally validated motifs, and an exploratory tool to discover putative linear motifs in user-submitted protein sequences. The current update of the ELM database comprises 1800 annotated motif instances representing 170 distinct functional classes, including approximately 500 novel instances and 24 novel classes. Several older motif class entries have been also revisited, improving annotation and adding novel instances. Furthermore, addition of full-text search capabilities, an enhanced interface and simplified batch download has improved the overall accessibility of the ELM data. The motif discovery portion of the ELM resource has added conservation, and structural attributes have been incorporated to aid users to discriminate biologically relevant motifs from stochastically occurring non-functional instance

Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: TropNet data from the DengueTools Research Initiative.

We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012-13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent

Visceral leishmaniasis and HIV coinfection in the Mediterranean region

Visceral leishmaniasis is hypoendemic in Mediterranean countries, where it is caused by the flagellate protozoan Leishmania infantum. VL cases in this area account for 5%-6% of the global burden. Cases of Leishmania/HIV coinfection have been reported in the Mediterranean region, mainly in France, Italy, Portugal, and Spain. Since highly active antiretroviral therapy was introduced in 1997, a marked decrease in the number of coinfected cases in this region has been reported. The development of new diagnostic methods to accurately identify level of parasitemia and the risk of relapse is one of the main challenges in improving the treatment of coinfected patients. Clinical trials in the Mediterranean region are needed to determine the most adequate therapeutic options for Leishmania/HIV patients as well as the indications and regimes for secondary prophylaxis. This article reviews the epidemiological, diagnostic, clinical, and therapeutic aspects of Leishmania/HIV coinfection in the Mediterranean region.S

A power law global error model for the identification of differentially expressed genes in microarray data

BACKGROUND: High-density oligonucleotide microarray technology enables the discovery of genes that are transcriptionally modulated in different biological samples due to physiology, disease or intervention. Methods for the identification of these so-called "differentially expressed genes" (DEG) would largely benefit from a deeper knowledge of the intrinsic measurement variability. Though it is clear that variance of repeated measures is highly dependent on the average expression level of a given gene, there is still a lack of consensus on how signal reproducibility is linked to signal intensity. The aim of this study was to empirically model the variance versus mean dependence in microarray data to improve the performance of existing methods for identifying DEG. RESULTS: In the present work we used data generated by our lab as well as publicly available data sets to show that dispersion of repeated measures depends on location of the measures themselves following a power law. This enables us to construct a power law global error model (PLGEM) that is applicable to various Affymetrix GeneChip data sets. A new DEG identification method is therefore proposed, consisting of a statistic designed to make explicit use of model-derived measurement spread estimates and a resampling-based hypothesis testing algorithm. CONCLUSIONS: The new method provides a control of the false positive rate, a good sensitivity vs. specificity trade-off and consistent results with varying number of replicates and even using single samples

Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) randomized controlled trial:A systematic review of published responses

OBJECTIVES: The objective of this review was to assess the nature and tone of the published responses to the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) randomized controlled trial. METHODS: Published articles that cited the PulMiCC trial were identified from Clarivate Web of Science (</p