The HPV cellular transactivator Brn-3a can be used to predict cervical adenocarcinoma and squamous carcinoma precancer lesions in the developed and developing worlds

The cellular transactivator Brn-3a has previously been shown to be expressed at elevated levels in the cervix of women with squamous cell carcinoma of the cervix (SCC) and to activate the expression of HPV E6 mRNA. In this study, we show that common and rare cervical precancer lesions, including those of adenocarcinoma (AC), which are usually difficult to diagnose using classical procedures, also expressed high levels of Brn-3a and can be diagnosed by measuring the levels of Brn-3a and E6 mRNAs

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Extracellular vesicles in human preterm colostrum inhibit infection by human cytomegalovirus in vitro

Breast milk is a complex biofluid that nourishes infants, supports their growth and protects them from diseases. However, at the same time, breastfeeding is a transmission route for human cytomegalovirus (HCMV), with preterm infants being at a great risk of congenital disease. The discrepancy between high HCMV transmission rates and the few reported cases of infants with severe clinical illness is likely due to the protective effect of breast milk. The aim of this study was to investigate the anti-HCMV activity of human preterm colostrum and clarify the role of colostrum-derived extracellular vesicles (EVs). Preterm colostrum samples were collected and the EVs were purified and characterized. The in vitro anti-HCMV activity of both colostrum and EVs was tested against HCMV, and the viral replication step inhibited by colostrum-purified EVs was examined. We investigated the putative role EV surface proteins play in impairing HCMV infection using shaving experiments and proteomic analysis. The obtained results confirmed the antiviral action of colostrum against HCMV and demonstrated a remarkable antiviral activity of colostrum-derived EVs. Furthermore, we demonstrated that EVs impair the attachment of HCMV to cells, with EV surface proteins playing a role in mediating this action. These findings contribute to clarifying the mechanisms that underlie the protective role of human colostrum against HCMV infection

New national and regional Annex I Habitat records: from #123 to #138

New Italian data on the distribution of some of the Annex I Habitats are reported in this contribution. Specifically, 16 records are presented including 9 new occurrences in Natura 2000 sites, and 27 new cells are added in the EEA 10 km × 10 km reference grid. The new data refer to the Italian administrative regions of Abruzzo, Apulia, Latium, Marche, Lombardy, Piedmont, Sardinia, Sicily, Tuscany, and Veneto

The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency

Background: Fumarate hydratase (HGNC approved gene symbol – FH), also known as fumarase, is an enzyme of the tricarboxylic acid (TCA) cycle, involved in fundamental cellular energy production. First described by Zinn et al in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of FH in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800). In some families renal cell cancer also forms a component of the complex and as such has been described as hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839). The identification of FH as a tumor suppressor was an unexpected finding and following the identification of subunits of succinate dehydrogenase in 2000 and 2001, was only the second description of the involvement of an enzyme of intermediary metabolism in tumorigenesis. Description: The FH mutation database is a part of the TCA cycle gene mutation database (formerly the succinate dehydrogenase gene mutation database) and is based on the Leiden Open (source) Variation Database (LOVD) system. The variants included in the database were derived from the published literature and annotated to conform to current mutation nomenclature. The FH database applies HGVS nomenclature guidelines, and will assist researchers in applying these guidelines when directly submitting new sequence variants online. Since the first molecular characterization of an FH mutation by Bourgeron et al in 1994, a series of reports of both FH deficiency patients and patients with MCUL/HLRRC have described 107 variants, of which 93 are thought to be pathogenic. The most common type of mutation is missense (57%), followed by frameshifts and nonsense (27%), and diverse deletions, insertions and duplications. Here we introduce an online database detailing all reported FH sequence variants. Conclusion: The FH mutation database strives to systematically unify all current genetic knowledge of FH variants. We believe that this knowledge will assist clinical geneticists and treating physicians when advising patients and their families, will provide a rapid and convenient resource for research scientists, and may eventually assist in gaining novel insights into FH and its related clinical syndromes. </p

Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies

Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant subclones bearing heterogeneous (epi)genetic changes. We used colorectal cancer (CRC) to test the hypothesis that interfering with an ancestral oncogenic event shared by all the malignant cells (such as WNT pathway alterations) could override heterogeneous mechanisms of acquired drug resistance. Here, we report that in CRC-resistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution of multiple independent cellular lineages. Functional and pharmacological modulation of WNT signalling induces cell death in CRC preclinical models from patients that relapsed during the treatment, regardless of the drug type or resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrains the emergence of drug-resistant clones. Reliance upon the WNT-APC pathway is preserved throughout the branched genomic drift associated with emergence of treatment relapse, thus offering the possibility of a common therapeutic strategy to overcome secondary drug resistance

Tolerância de diferentes cultivares de cana-de-açúcar (Saccharum spp.) A herbicidas

Este trabalho objetivou avaliar a tolerância de cultivares de cana-de-açúcar aos herbicidas sulfentrazone, imazapic, isoxaflutole, clomazone e ametryn+trifloxysulfuronsodium. O delineamento experimental foi em blocos ao acaso, em esquema de parcelas subdivididas com quatro repetições. Os cultivares foram alocados nas parcelas, e os herbicidas, nas subparcelas, constituídas por cinco linhas de 8 m, espaçadas de 1,5 m. Os cultivares utilizados foram: IACSP94-2094, IACSP94-2101, IACSP93-3046, IACSP94-4004, IAC86-2480 e RB72454. Os tratamentos herbicidas foram constituídos por sulfentrazone (0,8 kg ha-1), imazapic (0,147 kg ha-1), isoxaflutole (0,1125 kg ha-1), clomazone (1,1 kg ha-1) e ametryn (1,463 kg ha-1) + trifloxysulfuron-sodium (0,037 kg ha-1), aplicados em pós-emergência sobre as socas da cana de ano no seu terceiro corte. Avaliaram-se, nas três linhas centrais de cada subparcela, os sintomas visuais de toxicidade nas folhas; teor de clorofila total e eficiência fotoquímica (Fv/Fm) aos 15, 30 e 60 dias após aplicação (DAA); altura (cm) aos 30 e 270 DAA; e estande de plantas (colmos m-1) aos 30 e 180 DAA. Aos 270 DAA foram avaliados o diâmetro (cm), a estimativa de produtividade (t ha-1) e os demais parâmetros qualitativos. Os cultivares de cana-de-açúcar IACSP94-2094, IACSP93-3046, IACSP94-4004, IAC86-2480 e RB72454, especialmente IACSP94-2101, foram suscetíveis ao herbicida clomazone até os 30 dias após aplicação, por apresentarem manchas cloróticas nas folhas e menor teor de clorofila, porém com posterior recuperação, sem que houvesse comprometimento da produtividade e das características tecnológicas. Os cultivares também apresentaram elevado grau de tolerância aos herbicidas estudados.This work aimed to evaluate the tolerance of sugarcane cultivars to sulfentrazone, imazapic, isoxaflutole, clomazone and ametryn + trifloxysulfuron-sodium. The experiment was arranged in a randomized block design in a split-plot scheme. The cultivars were allocated to the plots and the herbicides to the sub-plots (five 8.0 m long rows and 1.5 m spacing, with 4 repetitions. The herbicides sulfentrazone (0.8 kg ha-1), imazapic (0.147 kg ha-1), isoxaflutole (0.1125 kg ha-1), clomazone (1.1 kg ha-1), ametryn (1.463 kg ha-1) + trifloxysulfuron sodium (0.037 kg ha-1) and control were evaluated on 3-yr-old ratoons of the cultivars IACSP94-2094, IACSP94-2101, IACSP93-3046, IACSP94-4004, IAC86-2480 and RB72454 in post emergence. The traits evaluated were: plant toxicity symptoms in the plant leaves; total chlorophyll content and photochemical efficiency (Fv/Fm) at 15, 30 and 60 days after application (DAA); height (cm) at 30 and 270 DAA, and plant stand (stalk m-1) at 30 and 180 DAA. Diameter (cm), estimated productivity (t ha-1) and quality analysis were evaluated at 270 DAA. The sugarcane cultivars IACSP94-2094, IACSP93-3046, IACSP94-4004, IAC86-2480, RB72454, and IACSP94-2101 especially, were susceptible to clomazone up to 30 DAA, due to leaf chlorosis and lower chlorophyll content, but had no effect on quality characteristics and productivity. The cultivars were also tolerant to other herbicides