Background: Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets. Methods: We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N = 279) and invasive ductal carcinoma (IDC, N = 1301) using METABRIC, TCGA, and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade, and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines.
Cardiovascular disease is one of the leading causes of death worldwide, and evidence
indicates a correlation between the inflammatory process and cardiac dysfunction.
Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for
long-term use because of potentially severe side effects to the heart. Considering
this and the frequent prescribing of commercial celecoxib, the present study analyzed
cellular and molecular effects of 1 and 10 µM celecoxib in a cell culture model.
After a 24-h incubation, celecoxib reduced cell viability in a dose-dependent manner
as also demonstrated in MTT assays. Furthermore, reverse transcription-polymerase
chain reaction analysis showed that the drug modulated the expression level of genes
related to death pathways, and Western blot analyses demonstrated a modulatory effect
of the drug on COX-2 protein levels in cardiac cells. In addition, the results
demonstrated a downregulation of prostaglandin E2 production by the cardiac cells
incubated with celecoxib, in a dose-specific manner. These results are consistent
with the decrease in cell viability and the presence of necrotic processes shown by
Fourier transform infrared analysis, suggesting a direct correlation of prostanoids
in cellular homeostasis and survival.
Pulmonary delivery is increasingly seen as an attractive, non-invasive route for the delivery of forthcoming protein therapeutics. In this context, here we describe protein complexes with a new 'complexing excipient'vitamin B 12 -targeted poly(ethylene glycol)-block-poly(glutamic acid) copolymers. These form complexes in sub-200 nm size with a model protein, suitable for cellular targeting and intracellular delivery. Initially we confirmed expression of vitamin B 12 -internalization receptor (CD320) by Calu-3 cells of the in vitro lung epithelial model used, and demonstrated enhanced B 12 receptor-mediated cellular internalization of B 12 -targeted complexes, relative to non-targeted counterparts or protein alone. To develop an inhalation formulation, the protein complexes were spray dried adopting a standard protocol into powders with aerodynamic diameter within the suitable range for lower airway deposition. The cellular internalization of targeted complexes from dry powders applied directly to Calu-3 model was found to be 2-3 fold higher compared to non-targeted complexes. The copolymer complexes show no complement activation, and in vivo lung tolerance studies demonstrated that repeated administration of formulated dry powders over a 3 week period in healthy BALB/c mice induced no significant toxicity or indications of lung inflammation, as assessed by cell population count and quantification of IL-1β, IL-6, and TNF-α pro-inflammatory markers. Importantly, the in vivo data appear to suggest that B 12targeted polymer complexes administered as dry powder enhance lung retention of their protein payload, relative to protein alone and non-targeted counterparts. Taken together, our data illustrate the potential developability of novel B 12 -targeted poly(ethylene glycol)-poly(glutamic acid) copolymers as excipients suitable to be formulated into a dry powder product for the inhalation delivery of proteins, with no significant lung toxicity, and with enhanced protein retention at their in vivo target tissue.
Chagas disease, which is caused by the intracellular protozoanTrypanosoma
cruzi, is a serious health problem in Latin America. The heart is one of
the major organs affected by this parasitic infection. The pathogenesis of tissue
remodelling, particularly regarding cardiomyocyte behaviour after parasite infection,
and the molecular mechanisms that occur immediately following parasite entry into
host cells are not yet completely understood. Previous studies have reported that the
establishment of parasitism is connected to the activation of the
phosphatidylinositol-3 kinase (PI3K), which controls important steps in cellular
metabolism by regulating the production of the second messenger
phosphatidylinositol-3,4,5-trisphosphate. Particularly, the tumour suppressor PTEN is
a negative regulator of PI3K signalling. However, mechanistic details of the
modulatory activity of PTEN on Chagas disease have not been elucidated. To address
this question, H9c2 cells were infected with T. cruzi Berenice 62
strain and the expression of a specific set of microRNAs (miRNAs) were investigated.
Our cellular model demonstrated that miRNA-190b is correlated to the decrease of
cellular viability rates by negatively modulating PTEN protein expression in
T. cruzi-infected cells.
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