213 research outputs found
The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer
Lung cancer is the leading cause of cancer deaths in the
United States. Current therapies are inadequate. Histone
deacetylase inhibitors (HDACi) are a recently developed
class of anticancer agents that cause increased acetylation
of core histones and nonhistone proteins leading to
modulation of gene expression and protein activityin -
volved in cancer cell growth and survival pathways.
We examined the efficacyof the HDACi panobinostat
(LBH589) in a wide range of lung cancers and mesotheliomas.
Panobinostat was cytotoxic in almost all 37 cancer
cell lines tested. IC50 and LD50 values were in the
low nmol/L range (4–470 nmol/L; median, 20 nmol/L).
Small cell lung cancer (SCLC) cell lines were among
the most sensitive lines, with LD50 values consistently
<25 nmol/L. In lung cancer and mesothelioma animal
models, panobinostat significantlyde creased tumor
growth byan average of 62% when compared with vehicle
control. Panobinostat was equallye ffective in
immunocompetent and severe combined immunodeficiencymic
e, indicating that the inhibition of tumor growth by
panobinostat was not due to direct immunologic effects.Panobinostat was, however, particularlyeffective in SCLC
xenografts, and the addition of the chemotherapyag ent
etoposide augmented antitumor effects. Protein analysis
of treated tumor biopsies revealed elevated amounts of cell
cycle regulators such as p21 and proapoptosis factors,
such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase,
coupled with decreased levels of antiapoptotic
factors such as Bcl-2 and Bcl-XL. These studies together
suggest that panobinostat maybe a useful adjunct in the
treatment of thoracic malignancies, especiallySCLC
Afro-Derived Amazonian Populations: Inferring Continental Ancestry and Population Substructure
Dificuldades enfrentadas pelos indígenas durante a permanência em uma Casa de Saúde Indígena na região Amazônica/Brasil
Decoding Brain Activity Associated with Literal and Metaphoric Sentence Comprehension Using Distributional Semantic Models
Recent years have seen a growing interest within the natural language processing (NLP)community in evaluating the ability of semantic models to capture human meaning representation in the brain. Existing research has mainly focused on applying semantic models to de-code brain activity patterns associated with the meaning of individual words, and, more recently, this approach has been extended to sentences and larger text fragments. Our work is the first to investigate metaphor process-ing in the brain in this context. We evaluate a range of semantic models (word embeddings, compositional, and visual models) in their ability to decode brain activity associated with reading of both literal and metaphoric sentences. Our results suggest that compositional models and word embeddings are able to capture differences in the processing of literal and metaphoric sentences, providing sup-port for the idea that the literal meaning is not fully accessible during familiar metaphor comprehension
Litter fall production and decomposition in a fragment of secondary Atlantic Forest of São Paulo, sp, southeastern Brazil
Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease
Machado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeuticsPM received funding from Ataxia UK Grant (Project: Pharmacologic therapy for Machado-Joseph disease: from a C. elegans drug screen to a mouse model validation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio
Enteric parasites in HIV-1/AIDS-infected patients from a Northwestern São Paulo reference unit in the highly active antiretroviral therapy era
Stability-indicating RP-HPLC method for determination of beclomethasone dipropionate in nanocapsule suspensions
SARS-CoV-2 uses CD4 to infect T helper lymphocytes
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS-CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.</p
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