Ultrastructure of the lung in a murine model of malaria-associated acute lung injury/acute respiratory distress syndrome

Background: the mechanisms through which infection with Plasmodium spp. result in lung disease are largely unknown. Recently a number of mouse models have been developed to research malaria-associated lung injury but no detailed ultrastructure studies of the disease in its terminal stages in a murine model have yet been published. the goal was to perform an ultrastructural analysis of the lungs of mice that died with malaria-associated acute lung injury/acute respiratory distress syndrome to better determine the relevancy of the murine models and investigate the mechanism of disease.Methods: DBA/2 mice were infected with Plasmodium berghei strain ANKA. Mice had their lungs removed immediately after death, processed using standard methods and viewed by transmission electron microscopy (TEM).Results: Infected red blood cell: endothelium contact, swollen endothelium with distended cytoplasmic extensions and thickening of endothelium basement membrane were observed. Septa were thick and filled with congested capillaries and leukocytes and the alveolar spaces contained blood cells, oedema and cell debris.Conclusion: Results show that the lung ultrastructure of P. berghei ANKA-infected mice has similar features to what has been described in post-mortem TEM studies of lungs from individuals infected with Plasmodium falciparum. These data support the use of murine models to study malaria-associated acute lung injury.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Dept Immunol, São Paulo, BrazilUniv São Paulo, Fac Med, Lab Med Invest 59, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Phys & Earth Sci, Diadema, BrazilUniv São Paulo, Dept Parasitol, São Paulo, BrazilUniv São Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Phys & Earth Sci, Diadema, BrazilFAPESP: 2009/53256-7FAPESP: 2009/53889-0CNPq: 306668/2012-2FAPESP: 2011/195252-0Web of Scienc

Primary resistance of HIV to antiretrovirals among individuals recently diagnosed at voluntary counselling and testing centres in the metropolitan region of Recife, Pernambuco

Determining the prevalence and type of antiretroviral (ARV) resistance among ARV-naïve individuals is important to assess the potential responses of these individuals to first-line regimens. The prevalence of primary resistance and the occurrence of recent infections among individuals with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) were identified among recently diagnosed patients at five sexually transmitted disease/AIDS testing and counselling centres in the metropolitan region of Recife (RMR), Pernambuco, Brazil, between 2007-2009. One-hundred and eight samples were analysed using the Calypte® BED assay. Males predominated (56%), as did patients aged 31-50 years. Twenty-three percent presented evidence of a recent HIV infection. The median CD4+ T lymphocyte count was 408 cells/mm³ and the median viral load was 3.683 copies/mL. The prevalence of primary resistance was 4.6% (confidence interval 95% = 1-8.2%) based on criteria that excluded common polymorphisms in accordance with the surveillance drug resistance mutation criteria. The prevalence of resistance to non-nucleoside reverse transcriptase, nucleoside/nucleotide reverse transcriptase and protease inhibitors were 3.8%, 1.5% and 0.8%, respectively. Fifty-seven percent of strains were from clade B, 37.7% were clade F and 3.1% were clade C; there were no statistically significant differences with respect to resistance between clades. Recent infection tended to be more common in men (p = 0.06) and in municipalities in the south of the RMR (Jaboatão dos Guararapes and Cabo de Santo Agostinho) (p = 0.046). The high prevalence of recent infection and the high prevalence of non-B strains in this poor Brazilian region merit further attention.Laboratório Central de Saúde Pública de Pernambuco Setor de VirologiaUniversidade Federal de Pernambuco Programa de Pós-Graduação em Medicina TropicalFiocruz Centro de Pesquisa Aggeu MagalhãesCentro de Testagem e Aconselhamento Herbert de SouzaUniversidade Federal de São Paulo (UNIFESP) Laboratório de RetrovirologiaUNIFESP, Laboratório de RetrovirologiaSciEL

Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model

<p>Abstract</p> <p>Background</p> <p>There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed <it>in vitro</it>. <it>In vivo </it>experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out.</p> <p>Results</p> <p>Lapatinib dramatically reduced cell proliferation (<it>P </it>< 0.0001), DNA synthesis (<it>P </it>< 0.006), and colony formation capacity (<it>P </it>< 0.0001) in A549 cells <it>in vitro</it>. Furthermore, lapatinib induced G1 cell cycle arrest (<it>P </it>< 0.0001) and apoptotic cell death (<it>P </it>< 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. <it>In vivo </it>experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (<it>P </it>< 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (<it>P </it>< 0.0001).</p> <p>Conclusion</p> <p>Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.</p

Search for the pair production of light top squarks in the e(+/-)mu(-/+) final state in proton-proton collisions at root s=13 TeV

A search for the production of a pair of top squarks at the LHC is presented. This search targets a region of parameter space where the kinematics of top squark pair production and top quark pair production are very similar, because of the mass difference between the top squark and the neutralino being close to the top quark mass. The search is performed with 35.9 fb(-1) of proton-proton collisions at a centre-of-mass energy of root s = 13 TeV, collected by the CMS detector in 2016, using events containing one electron-muon pair with opposite charge. The search is based on a precise estimate of the top quark pair background, and the use of the M-T2 variable, which combines the transverse mass of each lepton and the missing transverse momentum. No excess of events is found over the standard model predictions. Exclusion limits are placed at 95% confidence level on the production of top squarks up to masses of 208 GeV for models with a mass difference between the top squark and the lightest neutralino close to that of the top quark.Peer reviewe

Search for Higgs boson pair production in the gamma gamma b(b)over-bar final state in pp collisions at root s=13 TeV

A search is presented for the production of a pair of Higgs bosons, where one decays into two photons and the other one into a bottom quark-antiquark pair. The analysis is performed using proton-proton collision data at root s = 13 TeV recorded in 2016 by the CMS detector at the LHC, corresponding to an integrated luminosity of 35.9 fb(-1) . The results are in agreement with standard model (SM) predictions. In a search for resonant production, upper limits are set on the cross section for new spin-0 or spin-2 particles. For the SM-like nonresonant production hypothesis, the data exclude a product of cross section and branching fraction larger than 2.0 fb at 95% confidence level (CL), corresponding to about 24 times the SM prediction. Values of the effective Higgs boson self-coupling K X are constrained to be within the range -11 < K-lambda < 17 at 95% CL, assuming all other Higgs boson couplings are at their SM value. The constraints on K-lambda, are the most restrictive to date. (C) 2018 The Author(s). Published by Elsevier B.V.Peer reviewe