3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation

AbstractAn appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies.From the Clinical EditorExisting in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities

Radiation-Enhanced Therapeutic Targeting of Galectin-1 Enriched Malignant Stroma in Triple Negative Breast Cancer

Currently there are no FDA approved targeted therapies for Triple Negative Breast Cancer (TNBC). Ongoing clinical trials for TNBC have focused primarily on targeting the epithelial cancer cells. However, targeted delivery of cytotoxic payloads to the non-transformed tumor associated-endothelium can prove to be an alternate approach that is currently unexplored. The present study is supported by recent findings on elevated expression of stromal galectin-1 in clinical samples of TNBC and our ongoing findings on stromal targeting of radiation induced galectin-1 by the anginex-conjugated arsenic-cisplatin loaded liposomes using a novel murine tumor model. We demonstrate inhibition of tumor growth and metastasis in response to the multimodal nanotherapeutic strategy using a TNBC model with orthotopic tumors originating from 3D tumor tissue analogs (TTA) comprised of tumor cells, endothelial cells and fibroblasts. The ‘rigorous’ combined treatment regimen of radiation and targeted liposomes is also shown to be well tolerated. More importantly, the results presented provide a means to exploit clinically relevant radiation dose for concurrent receptor mediated enhanced delivery of chemotherapy while limiting overall toxicity. The proposed study is significant as it falls in line with developing combinatorial therapeutic approaches for stroma-directed tumor targeting using tumor models that have an appropriate representation of the TNBC microenvironment

Poor Clinical Sensitivity of Rapid Antigen Test for Influenza A Pandemic (H1N1) 2009 Virus

Influenza A pandemic (H1N1) 2009 virus RNA was detected by reverse transcription–PCR in 144 clinical samples from Bonn, Germany. A common rapid antigen–based test detected the virus in only 11.1% of these samples. The paramount feature of rapid test–positive samples was high virus concentration. Antigen-based rapid tests appear unsuitable for virologic diagnostics in the current pandemic

Swabbing for respiratory viral infections in older patients: a comparison of rayon and nylon flocked swabs

The purpose of this study was to compare the sampling efficacy of rayon swabs and nylon flocked swabs, and of oropharyngeal and nasopharyngeal specimens for the detection of respiratory viruses in elderly patients. Samples were obtained from patients 60 years of age or above who were newly admitted to Sorlandet Hospital Arendal, Norway. The patients were interviewed for current symptoms of a respiratory tract infection. Using rayon swabs and nylon flocked swabs, comparable sets of mucosal samples were harvested from the nasopharynx and the oropharynx. The samples were analysed using real-time polymerase chain reaction (PCR) methods. A total of 223 patients (mean age 74.9 years, standard deviation [SD] 9.0 years) were swabbed and a virus was recovered from 11% of the symptomatic patients. Regardless of the sampling site, a calculated 4.8 times higher viral load (95% confidence interval [CI] 1.3–17, p = 0.017) was obtained using the nylon flocked swabs as compared to the rayon swabs. Also, regardless of the type of swab, a calculated 19 times higher viral load was found in the samples from the nasopharynx as compared to the oropharynx (95% CI 5.4–67.4, p < 0.001). When swabbing for respiratory viruses in elderly patients, nasopharyngeal rather than oropharyngeal samples should be obtained. Nylon flocked swabs appear to be more efficient than rayon swabs

Between Big City and Authentic Village: Branding the Small Chinese City

While recent academic research has already produced an impressive corpus on big cities such as Shanghai and Beijing, the small Chinese city has been mostly ignored. In this article, I suggest that consideration of the small city can bring a new perspective on the wider urban fabric of which it is an element. Although small city governments have embraced urban entrepreneurialism with the same enthusiasm as China’s big cities, different configurations of space, branding and the everyday have nevertheless resulted. My case study of Kaili in Guizhou province indicates that the small city exists in a complex relationship with the big city and the village; it is pulled towards large-scale urbanization while simultaneously attempting to construct a unique city image based upon the evocation of rural cultural practices. The perspective from the small city thus suggests the need to consider the rural-urban divide – long a dominant geographical imagination of China – alongside other geographies, including a triad of the small city, the village and the big city

Influenza Virus in Human Exhaled Breath: An Observational Study

Background: Recent studies suggest that humans exhale fine particles during tidal breathing but little is known of their composition, particularly during infection. Methodology/Principal Findings: We conducted a study of influenza infected patients to characterize influenza virus and particle concentrations in their exhaled breath. Patients presenting with influenza-like-illness, confirmed influenza A or B virus by rapid test, and onset within 3 days were recruited at three clinics in Hong Kong, China. We collected exhaled breath from each subject onto Teflon filters and measured exhaled particle concentrations using an optical particle counter. Filters were analyzed for influenza A and B viruses by quantitative polymerase chain reaction (qPCR). Twelve out of thirteen rapid test positive patients provided exhaled breath filter samples (7 subjects infected with influenza B virus and 5 subjects infected with influenza A virus). We detected influenza virus RNA in the exhaled breath of 4 (33%) subjects-three (60%) of the five patients infected with influenza A virus and one (14%) of the seven infected with influenza B virus. Exhaled influenza virus RNA generation rates ranged from <3.2 to 20 influenza virus RNA particles per minute. Over 87% of particles exhaled were under 1 μm in diameter. Conclusions: These findings regarding influenza virus RNA suggest that influenza virus may be contained in fine particles generated during tidal breathing, and add to the body of literature suggesting that fine particle aerosols may play a role in influenza transmission. © 2008 Fabian et al.published_or_final_versio

Electroless copper deposition as a seed layer on TiSiN barrier

Electroless deposition of copper as a seeding technology has received considerable attention in back-end-of-line device fabrication. This work explores the effects of plasma processing parameters such as argon gas flow rate and nitrogen plasma treatment time on the properties of electrolessly plated Cu on TiSiN barrier layers. The barrier film was produced by a low-frequency inductively coupled plasma process. The properties of deposited electroless copper are characterized by x-ray diffraction, four-point resistivity probe, atomic force microscopy, and field emission scanning electron microscope. The required palladium activation time is greatly reduced on TiSiN compared to TiN. In both cases there exists a preferred (111) crystal orientation in Cu film and the intensity ratio of I(111)/I(200) is very close. The Cu grain size is within the range of 23–34 nm for 84 nm thick film. It is found that argon gas flow rate does not have a significant effect on the resistivity of electroless copper film on TiSiN. However, increasing nitrogen plasma treatment time reduces the resistivity of copper film. The roughness of plated Cu layer largely follows the one of the underlying TiSiN. Good surface coverage of electroless Cu seed layer on TiSiN has been achieved in our experiment.Published versio

Effect of processing parameters on electroless Cu seed layer properties

Electroless Cu seed layer is essential for subsequent copper metallization by electroplating for sub-micron wafer technology. This layer is required to provide good step coverage and high uniformity. In the current work, electroless copper was deposited on a TiN surface activated by palladium. The effect of deposition time on the properties of electroless Cu films was reported. It shows that as the deposition time increases, the surface coverage of Cu film on activated TiN is improved and there is a significant reduction in sheet resistance and an increase in grain size of deposited copper film. Of particular interest is that there exists a preferred Cu (111) crystal orientation in the samples subjected to more than as short as 3 min of deposition. A surface roughness (Rrms) of ∼17 nm has been achieved. The results obtained in current study points out a promising process for laying down thin Cu seed layer.Accepted versio