Live imaging of neolymphangiogenesis identifies acute antimetastatic roles of dsRNA mimics.

Long-range communication between tumor cells and the lymphatic vasculature defines competency for metastasis in different cancer types, particularly in melanoma. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole-body analyses of tumor progression. Here, we exploit immunocompetent and immunodeficient mouse models for live imaging of Vegfr3-driven neolymphangiogenesis, as a versatile platform for drug screening in vivo. Spatiotemporal analyses of autochthonous melanomas and patient-derived xenografts identified double-stranded RNA mimics (dsRNA nanoplexes) as potent inhibitors of neolymphangiogenesis, metastasis, and post-surgical disease relapse. Mechanistically, dsRNA nanoplexes were found to exert a rapid dual action in tumor cells and in their associated lymphatic vasculature, involving the transcriptional repression of the lymphatic drivers Midkine and Vegfr3, respectively. This suppressive function was mediated by a cell-autonomous type I interferon signaling and was not shared by FDA-approved antimelanoma treatments. These results reveal an alternative strategy for targeting the tumor cell-lymphatic crosstalk and underscore the power of Vegfr3-lymphoreporters for pharmacological testing in otherwise aggressive cancers.The authors thank previous and present colleagues in the CNIO Melanoma Group, particularly Damia Tormo and Lisa Osterloh for help and support at the initial stages of this study; Jose A Esteban (CSIC-UAM) for critical reading of this manuscript; Lionel Larue (INSERM; France) and Martin McMahon (Hunstman Cancer Center, USA) for the Tyr:CreERT2 and BrafCA mouse strains, respectively; and Ignacio Melero at Hospital Clinico, Pamplona, Spain, for Ifnar1-deficient mice. The authors thank Isabel Blanco, Soraya Ruiz, and Virginia Granda (CNIO-Animal Facility Unit), Diego Megias (CNIO-Confocal Unit), and Eduardo Jose Caleiras and Patricia Gonzalez (CNIO-Histopathology Unit) for technical assistance. M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (SAF2017-89533-R), the Asociacion Espanola Contra el Cancer (AECC), Fundacion La Caixa, and an Established Investigator Award by the Melanoma Research Alliance (MRA). D.O. is funded by grants from the Spanish Ministry of Health (AES-PIS PI18/1057) and "Beca Leonardo a Investigadores y Creadores Culturales 2018 de la Fundacion BBVA". The CNIO Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019. S.O. is also supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness (BFU2015-71376-R).S

Oncocytic carcinoma of the parotid gland with late cervical lymph node metastases: a case report

<p>Abstract</p> <p>Introduction</p> <p>Oncocytic carcinoma is a rare proliferation of cytomorphologically malignant oncocytes mainly found in glandular tissue, accounting for 0.5% of all epithelial salivary gland malignancies and 0.18% of all epithelial salivary gland tumors.</p> <p>Case presentation</p> <p>We report a case of oncocytic carcinoma arising in the parotid gland of a 65-year-old Caucasian man. Our patient initially underwent left superficial parotidectomy, including the removal of the mass. A close follow-up was made, and four years after first surgery cervical lymph node metastases were confirmed. Therefore, a complete parotidectomy and radical neck dissections were performed. There were no complications and no sign of recurrence after six months of follow-up.</p> <p>Conclusion</p> <p>Oncocytic carcinoma is an extremely rare malignancy in the salivary glands. Prophylactic neck dissection may be indicated for tumors larger than 2 cm in diameter (our patient's tumor was 2.5 cm at its greatest diameter). The clinical course of our patient, with the appearance of cervical lymph node metastases after four years of follow-up, supports this approach. Further investigation of the prognosis and correct treatment of patients with oncocytic carcinoma are required as more cases are reported.</p

Identification and characterization of a novel non-structural protein of bluetongue virus

Bluetongue virus (BTV) is the causative agent of a major disease of livestock (bluetongue). For over two decades, it has been widely accepted that the 10 segments of the dsRNA genome of BTV encode for 7 structural and 3 non-structural proteins. The non-structural proteins (NS1, NS2, NS3/NS3a) play different key roles during the viral replication cycle. In this study we show that BTV expresses a fourth non-structural protein (that we designated NS4) encoded by an open reading frame in segment 9 overlapping the open reading frame encoding VP6. NS4 is 77–79 amino acid residues in length and highly conserved among several BTV serotypes/strains. NS4 was expressed early post-infection and localized in the nucleoli of BTV infected cells. By reverse genetics, we showed that NS4 is dispensable for BTV replication in vitro, both in mammalian and insect cells, and does not affect viral virulence in murine models of bluetongue infection. Interestingly, NS4 conferred a replication advantage to BTV-8, but not to BTV-1, in cells in an interferon (IFN)-induced antiviral state. However, the BTV-1 NS4 conferred a replication advantage both to a BTV-8 reassortant containing the entire segment 9 of BTV-1 and to a BTV-8 mutant with the NS4 identical to the homologous BTV-1 protein. Collectively, this study suggests that NS4 plays an important role in virus-host interaction and is one of the mechanisms played, at least by BTV-8, to counteract the antiviral response of the host. In addition, the distinct nucleolar localization of NS4, being expressed by a virus that replicates exclusively in the cytoplasm, offers new avenues to investigate the multiple roles played by the nucleolus in the biology of the cell

Nutrient intakes related to osteoporotic fractures in men and women – The Brazilian Osteoporosis Study (BRAZOS)

<p>Abstract</p> <p>Background</p> <p>Adequate nutrition plays an important role in bone mass accrual and maintenance and has been demonstrated as a significant tool for the prevention of fractures in individuals with osteoporosis.</p> <p>Objective</p> <p>The aim of the present study was to evaluate bone health-related nutrients intake and its association with osteoporotic fractures in a representative sample of 2344 individuals aged 40 years or older in Brazil.</p> <p>Methods</p> <p>In a transversal population-based study, a total of 2420 individuals over 40 years old were evaluated from March to April 2006. Participants were men and women from all socio-economic classes and education levels living around the Brazilian territory Individuals responded a questionnaire including self reported fractures as well a 24-hour food recall. Nutrient intakes were evaluated by Nutrition Data System for Research software (NDSR, University of Minnesota, 2007). Low trauma fracture was defined as that resulting of a fall from standing height or less. Nutrient intakes adequacies were performed by using the DRI's proposed values. Statistical analysis comprises Oneway ANCOVA adjusted by age and use of nutritional supplements and multiple logistic regression. SAS software was used for statistical analysis.</p> <p>Results</p> <p>Fractures was reported by 13% of men and 15% of women. Women with fractures presented significantly higher calcium, phosphorus and magnesium intakes. However, in all regions and socio-economical levels mean intakes of bone related nutrients were below the recommended levels. It was demonstrated that for every 100 mg/phosphorus increase the risk of fractures by 9% (OR 1.09; IC95% 1.05–1.13, p < 0.001).</p> <p>Conclusion</p> <p>The results demonstrated inadequacies in bone related nutrients in our population as well that an increase in phosphorus intake is related to bone fractures.</p

A giant adrenal lipoma presenting in a woman with chronic mild postprandial abdominal pain: a case report

<p>Abstract</p> <p>Introduction</p> <p>Adrenal lipomas are rare, small, benign, non-functioning tumors, which must be histopathologically differentiated from other tumors such as myelolipomas or liposarcomas. They are usually identified incidentally during autopsy, imaging, or laparotomy. Occasionally, they may present acutely due to complications such as abdominal pain from retroperitoneal bleeding, or systemic symptoms of infection. We report a giant adrenal lipoma (to the best of our knowledge, the second largest in the literature) clinically presenting with chronic mild postprandial pain.</p> <p>Case presentation</p> <p>A 54-year-old Caucasian woman presented several times over a period of 10 years to various emergency departments complaining of long-term mild postprandial abdominal pain. Although clinical examinations were unrevealing, an abdominal computed tomography scan performed at her most recent presentation led to the identification of a large lipoma of the left adrenal gland, which occupied most of the retroperitoneal space. Myelolipoma was ruled out due to the absence of megakaryocytes, immature leukocytes, or erythrocytes. Liposarcoma was ruled out due to the absence of lipoblasts. The size of the lipoma (16 × 14 × 7 cm) is, to the best of our knowledge, the second largest reported to date. After surgical resection, our patient was relieved of her symptoms and remains healthy six years postoperatively.</p> <p>Conclusion</p> <p>Physicians should be aware that differential diagnosis of mild chronic abdominal pain in patients presenting in emergency rooms may include large adrenal lipomas. When initial diagnostic investigation is not revealing, out-patient specialist evaluation should be planned to enable appropriate further investigations.</p

An insight into the sialome of Simulium guianense (DIPTERA:SIMulIIDAE), the main vector of River Blindness Disease in Brazil

<p>Abstract</p> <p>Background</p> <p>Little is known about the composition and function of the saliva in black flies such as <it>Simulium guianense</it>, the main vector of river blindness disease in Brazil. The complex salivary potion of hematophagous arthropods counteracts their host's hemostasis, inflammation, and immunity.</p> <p>Results</p> <p>Transcriptome analysis revealed ubiquitous salivary protein families--such as the Antigen-5, Yellow, Kunitz domain, and serine proteases--in the <it>S. guianense </it>sialotranscriptome. Insect-specific families were also found. About 63.4% of all secreted products revealed protein families found only in <it>Simulium</it>. Additionally, we found a novel peptide similar to kunitoxin with a structure distantly related to serine protease inhibitors. This study revealed a relative increase of transcripts of the SVEP protein family when compared with <it>Simulium vittatum </it>and <it>S. nigrimanum </it>sialotranscriptomes. We were able to extract coding sequences from 164 proteins associated with blood and sugar feeding, the majority of which were confirmed by proteome analysis.</p> <p>Conclusions</p> <p>Our results contribute to understanding the role of <it>Simulium </it>saliva in transmission of <it>Onchocerca volvulus </it>and evolution of salivary proteins in black flies. It also consists of a platform for mining novel anti-hemostatic compounds, vaccine candidates against filariasis, and immuno-epidemiologic markers of vector exposure.</p

New Forearm Elements Discovered of Holotype Specimen Australovenator wintonensis from Winton, Queensland, Australia

New skeletal elements are reported of the holotype specimen Australovenator wintonensis, from the type locality, near Winton, central western Queensland. New elements include left and right humeri, right radius, right radiale, right distal carpal 1, near complete right metacarpal I, left manual phalanx II-1, left manual phalanx II-2, near complete left manual phalanx II-3 and a left manual phalanx III-3. These new elements combined with those previously described are compared against other neovenatorids

Classifications for Cesarean Section: A Systematic Review

Background: Rising cesarean section (CS) rates are a major public health concern and cause worldwide debates. To propose and implement effective measures to reduce or increase CS rates where necessary requires an appropriate classification. Despite several existing CS classifications, there has not yet been a systematic review of these. This study aimed to 1) identify the main CS classifications used worldwide, 2) analyze advantages and deficiencies of each system.Methods and Findings: Three electronic databases were searched for classifications published 1968-2008. Two reviewers independently assessed classifications using a form created based on items rated as important by international experts. Seven domains (ease, clarity, mutually exclusive categories, totally inclusive classification, prospective identification of categories, reproducibility, implementability) were assessed and graded. Classifications were tested in 12 hypothetical clinical case-scenarios. From a total of 2948 citations, 60 were selected for full-text evaluation and 27 classifications identified. Indications classifications present important limitations and their overall score ranged from 2-9 (maximum grade = 14). Degree of urgency classifications also had several drawbacks (overall scores 6-9). Woman-based classifications performed best (scores 5-14). Other types of classifications require data not routinely collected and may not be relevant in all settings (scores 3-8).Conclusions: This review and critical appraisal of CS classifications is a methodologically sound contribution to establish the basis for the appropriate monitoring and rational use of CS. Results suggest that women-based classifications in general, and Robson's classification, in particular, would be in the best position to fulfill current international and local needs and that efforts to develop an internationally applicable CS classification would be most appropriately placed in building upon this classification. the use of a single CS classification will facilitate auditing, analyzing and comparing CS rates across different settings and help to create and implement effective strategies specifically targeted to optimize CS rates where necessary.Universidade Federal de São Paulo, Dept Obstet, São Paulo, BrazilBrazilian Cochrane Ctr, São Paulo, BrazilWorld Hlth Org, Dept Reprod Hlth & Res, Geneva, SwitzerlandWorld Hlth Org, Dept Knowledge Management & Sharing, Geneva, SwitzerlandUniversidade Federal de São Paulo, Dept Obstet, São Paulo, BrazilWeb of Scienc

High-resolution genetic mapping with pooled sequencing

Background: Modern genetics has been transformed by high-throughput sequencing. New experimental designs in model organisms involve analyzing many individuals, pooled and sequenced in groups for increased efficiency. However, the uncertainty from pooling and the challenge of noisy sequencing data demand advanced computational methods. Results: We present MULTIPOOL, a computational method for genetic mapping in model organism crosses that are analyzed by pooled genotyping. Unlike other methods for the analysis of pooled sequence data, we simultaneously consider information from all linked chromosomal markers when estimating the location of a causal variant. Our use of informative sequencing reads is formulated as a discrete dynamic Bayesian network, which we extend with a continuous approximation that allows for rapid inference without a dependence on the pool size. MULTIPOOL generalizes to include biological replicates and case-only or case-control designs for binary and quantitative traits. Conclusions: Our increased information sharing and principled inclusion of relevant error sources improve resolution and accuracy when compared to existing methods, localizing associations to single genes in several cases. MULTIPOOL is freely available at http://cgs.csail.mit.edu/multipool/ webcite.National Science Foundation (U.S.) (Graduate Research Fellowship Grant 0645960