Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

The low-density lipoprotein receptor-related protein (LRP1B), encoding an endocytic LDL-family receptor, is among the 10 most significantly deleted genes across 3312 human cancer specimens. However, currently the apparently crucial role of this lipoprotein receptor in carcinogenesis is not clear. Here we show that LRP1B inactivation (by chromosomal, epigenetic and microRNA (miR)-mediated mechanisms) results in changes to the tumor environment that confer cancer cells an increased growth and invasive capacity. LRP1B displays frequent DNA copy number loss and CpG island methylation, resulting in mRNA underexpression. By using CpG island reporters methylated in vitro, we found that DNA methylation disrupts a functional binding site for the histone-acetyltransferase p300 located at intron 1. We identified and validated an miR targeting LRP1B (miR-548a-5p), which is overexpressed in cancer cell lines as a result of 8q22 DNA gains. Restoration of LRP1B impaired in vitro and in vivo tumor growth, inhibited cell invasion and led to a reduction of matrix metalloproteinase 2 in the extracellular medium. We emphasized the role of an endocytic receptor acting as a tumor suppressor by modulating the extracellular environment composition in a way that constrains the invasive behavior of the cancer cells

Vav proteins are key regulators of Card9 signaling for innate antifungal immunity

Fungal infections are major causes of morbidity and mortality, especially in immunocompromised individuals. The innate immune system senses fungal pathogens through Syk-coupled C-type lectin receptors (CLRs), which signal through the conserved immune adaptor Card9. Although Card9 is essential for antifungal defense, the mechanisms that couple CLR-proximal events to Card9 control are not well defined. Here, we identify Vav proteins as key activators of the Card9 pathway. Vav1, Vav2, and Vav3 cooperate downstream of Dectin-1, Dectin-2, and Mincle to engage Card9 for NF-κB control and proinflammatory gene transcription. Although Vav family members show functional redundancy, Vav1/2/3(-/-) mice phenocopy Card9(-/-) animals with extreme susceptibility to fungi. In this context, Vav3 is the single most important Vav in mice, and a polymorphism in human VAV3 is associated with susceptibility to candidemia in patients. Our results reveal a molecular mechanism for CLR-mediated Card9 regulation that controls innate immunity to fungal infections

On the Peripheries of Planetary Urbanization: Globalizing Manaus and its Expanding Impact

In this paper I argue that global urbanism produces peripherality in ways that cannot be adequately problematized without taking into account its actual extent and geographically uneven development. Therefore, planetary urbanization needs to engage scholarly traditions attuned to regional urbanization if the discourse is to move past limitations in the urban globalization canon and its narrow focus on cities. To that end, I examine research on extensive urbanization in the Amazon region. Illustrative case studies show how attempts to globalize Manaus precipitated territorial restructuring and sociospatial change far beyond the city's boundaries. Manaus is now a more unequal city. Selective metropolitan expansion to the Rio Negro's south bank has led to the simultaneous upgrading and peripheralization of Iranduba. Yet, the building of a city-centric regional network of roadways also shaped Roraima State's transformation from isolated borderland to bypassed periphery. Moreover, financial and symbolic appropriations of standing rainforests by metropolitan conservationism marginalize remote communities even in the absence of exploitative deforestation and resource extraction. Final remarks emphasize the need for further research on the hybrid (urban—rural) conditions and functional articulations of distant-yet-impacted peripheries. Such efforts may broaden the political horizons of planetary urbanization by informing extensive contestations of entrepreneurial urbanism

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70–75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.This study was supported by FCT (“Portuguese Foundation for Science and Technology”) through a PhD grant to RB (SFRH/ BD/111321/2015). Further funding was obtained from the project “Advancing cancer research: from basic knowledge to application” NORTE-01-0145-FEDER-000029: “Projetos Estruturados de I & D & I,” funded by Norte 2020—Programa Operacional Regional do Norte. This article is a result of the project PTDC/MED-ONC/31438/2017 (The Other Faces of Telomerase: Looking beyond Tumor Immortalization), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI) and by Portuguese funds through FCT. Further funding by the European Regional Development Fund (ERDF) through the Operational Programme for Competitiveness and Internationalisation— COMPETE 2020, and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-016390:CANCEL STEM

Abundance and Species Richness of Leafhoppers and Planthoppers (Hemiptera: Cicadellidae and Delphacidae) in Brazilian Maize Crops

Fil: De Oliveira, Charles Martins. Embrapa Cerrados. Planaltina. Brasília/DF; BrazilFil: De Oliveira, Elizabeth. Embrapa Milho e Sorgo. Sete Lagoas/MG; BrazilFil: Prazeres De Souza, Isabel Regina. Embrapa Milho e Sorgo. Sete Lagoas/MG; BrazilFil: Alves, Elcio. DuPont do Brazil S.A. DivisÆo Pioneer Sementes. Itumbiara/GO; BrazilFil: Dolezal, William. Pioneer Hi-Bred International. Itumbiara/GO; BrazilFil: Paradell, Susana Liria. División Entomología. Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Marino de Remes Lenicov, Ana María. División Entomología. Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Frizzas, Marina Regina. Universidade de Brasília. Departamento de Zoologia. Instituto de Ciências Biológicas. Brasília/DF; Brazi

Alexithymia, emotional awareness and perceived dysfunctional parental behaviors in heroin dependents

© Springer Science+Business Media New York 2013The original publication is available at www.springerlink.com © Springer Science+Business MediaThe aim of this study was to analyse alexithymia and deficits in emotional awareness, in heroin addicts, and their relationship with perceptions of early parental interactions. The sample included 99 opiate dependent outpatients and 43 healthy controls. Assessment was performed using the Toronto Alexithymia Scale, the Levels of Emotional Awareness Scale, the Inventory for Assessing Memories of Parental Rearing Behavior, the Mini-Mental State Examination and the Hospital Anxiety and Depression Scale. Findings suggest parental representations, which were mostly characterized by emotional unavailability and a rejection interaction pattern, significantly related to alexithymia. Emotional awareness was associated with the number of years of drug use and methadone level. Negative affect was associated with alexithymia but not to emotional awareness. Regression analyses emphasized the influence of perceived dysfunctional parenting behaviors in alexithymia and difficulties in identifying feelings, particularly an interaction with paternal rejection, moderated by self-reported anxiety. These results are discussed addressing comprehensive issues of emotion regulation and treatment strategies in heroin dependence