Encapsulation of gold nanostructures and oil-in-water nanocarriers in microgels with biomedical potential

Indexación: Scopus.Funding: This research was funded by FONDECYT 1161450, 1150744, 11130494 and 1170929, FONDEQUIP EQM160157, EQM170111, CONICYT-FONDAP 15130011, and CONICYT PhD Scholarship 21141137.Here we report the incorporation of gold nanostructures (nanospheres or nanorods, functionalized with carboxylate-end PEG) and curcumin oil-in-water (O/W) nanoemulsions (CurNem) into alginate microgels using the dripping technique. While gold nanostructures are promising nanomaterials for photothermal therapy applications, CurNem possess important pharmacological activities as reported here. In this sense, we evaluated the effect of CurNem on cell viability of both cancerous and non-cancerous cell lines (AGS and HEK293T, respectively), demonstrating preferential toxicity in cancer cells and safety for the non-cancerous cells. After incorporating gold nanostructures and CurNem together into the microgels, microstructures with diameters of 220 and 540 µm were obtained. When stimulating microgels with a laser, the plasmon effect promoted a significant rise in the temperature of the medium; the temperature increase was higher for those containing gold nanorods (11–12 ◦ C) than nanospheres (1–2 ◦ C). Interestingly, the incorporation of both nanosystems in the microgels maintains the photothermal properties of the gold nanostructures unmodified and retains with high efficiency the curcumin nanocarriers. We conclude that these results will be of interest to design hydrogel formulations with therapeutic applications. © 2018 by the authors.https://www.mdpi.com/1420-3049/23/5/120

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial

Background The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. Patients and methods Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF) ≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. Results Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C → T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H → T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). Conclusion PLD+C+H → T+H is feasible and results in lower early cardiotoxicity rates compared with A+C → T+

Paracrine met signaling triggers epithelial mesenchymal transition in mammary luminal progenitors, affecting their fate

HGF/Met signaling has recently been associated with basal-type breast cancers, which are thought to originate from progenitor cells residing in the luminal compartment of the mammary epithelium. We found that ICAM-1 efficiently marks mammary luminal progenitors comprising hormone receptor-positive and receptor-negative cells, presumably ductal and alveolar progenitors. Both cell populations strongly express Met, while HGF is produced by stromal and basal myoepithelial cells. We show that persistent HGF treatment stimulates the clonogenic activity of ICAM1-positive luminal progenitors, controlling their survival and proliferation, and leads to the expression of basal cell characteristics, including stem cell potential. This is accompanied by the induction of Snai1 and Snai2, two major transcription factors triggering epithelial–mesenchymal transition, the repression of the luminal-regulatory genes Elf5 and Hey1, and claudin downregulation. Our data strongly indicate that paracrine Met signaling can control the function of luminal progenitors and modulate their fate during mammary development and tumorigenesis

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Search based software engineering: Trends, techniques and applications

© ACM, 2012. This is the author's version of the work. It is posted here by permission of ACM for your personal use. Not for redistribution. The definitive version is available from the link below.In the past five years there has been a dramatic increase in work on Search-Based Software Engineering (SBSE), an approach to Software Engineering (SE) in which Search-Based Optimization (SBO) algorithms are used to address problems in SE. SBSE has been applied to problems throughout the SE lifecycle, from requirements and project planning to maintenance and reengineering. The approach is attractive because it offers a suite of adaptive automated and semiautomated solutions in situations typified by large complex problem spaces with multiple competing and conflicting objectives. This article provides a review and classification of literature on SBSE. The work identifies research trends and relationships between the techniques applied and the applications to which they have been applied and highlights gaps in the literature and avenues for further research.EPSRC and E

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment

Expression of Activated PIK3CA in Ovarian Surface Epithelium Results in Hyperplasia but Not Tumor Formation

activation is one of the early genetic events in ovarian cancer. However, its role in malignant transformation of ovarian surface epithelium (OSE) is largely unclear..