Inhibition of alanine-serine-cysteine transporter 2-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between V-9302 and photosensitizer.

The efficiency of reactive oxygen species (ROS)-based photodynamic therapy (PDT) is far from satisfactory, because cancer cells can adapt to PDT by upregulating glutathione (GSH) levels. The GSH levels in tumor cells are determined based on glutamine availability via alanine-serine-cysteine transporter 2 (ASCT2)-mediated entry into cells. Herein, we develop co-assembled nanoparticles (PPa/V-9302 NPs) of the photosensitizer pyropheophorbide a (PPa) and V-9302 (a known inhibitor of ASCT2) in a 1:1 M ratio using a one-step precipitation method to auto-enhance photodynamic therapy. The computational simulations revealed that PPa and V-9302 could self-assemble through different driving forces, such as π-π stacking, hydrophobic interactions, and ionic bonds. Such PPa/V-9302 NPs could disrupt the intracellular redox homeostasis due to enhanced ROS production via PPa-induced PDT and reduced GSH synthesis via inhibition of the ASCT2-mediated glutamine flux by V-9302. The in vivo assays reveal that PPa/V-9302 NPs could increase the drug accumulation in tumor sites and suppress tumor growth in BALB/c mice bearing mouse breast carcinoma (4 T1) tumor. Our findings provide a new paradigm for the rational design of the PDT-based combinational cancer therapy.

Learning Drug-Disease-Target Embedding (DDTE) from knowledge graphs to inform drug repurposing hypotheses.

We aimed to develop and validate a new graph embedding algorithm for embedding drug-disease-target networks to generate novel drug repurposing hypotheses. Our model denotes drugs, diseases and targets as subjects, predicates and objects, respectively. Each entity is represented by a multidimensional vector and the predicate is regarded as a translation vector from a subject to an object vectors. These vectors are optimized so that when a subject-predicate-object triple represents a known drug-disease-target relationship, the summed vector between the subject and the predicate is to be close to that of the object; otherwise, the summed vector is distant from the object. The DTINet dataset was utilized to test this algorithm and discover unknown links between drugs and diseases. In cross-validation experiments, this new algorithm outperformed the original DTINet model. The MRR (Mean Reciprocal Rank) values of our models were around 0.80 while those of the original model were about 0.70. In addition, we have identified and verified several pairs of new therapeutic relations as well as adverse effect relations that were not recorded in the original DTINet dataset. This approach showed excellent performance, and the predicted drug-disease and drug-side-effect relationships were found to be consistent with literature reports. This novel method can be used to analyze diverse types of emerging biomedical and healthcare-related knowledge graphs (KG).

Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: an open-label, non-randomised and controlled trial.

BACKGROUND: There are no effective therapies for patients with coronavirus disease-2019 (COVID-19). METHODS: Forty-one patients with confirmed COVID-19 were enrolled in the study and divided into two groups: artemisinin-piperaquine (AP) (n = 23) and control (n = 18). The primary outcome were the time taken to reach undetectable levels of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the percentage of participants with undetectable SARS-CoV-2 on days 7, 10, 14, and 28. The computed tomography (CT) imaging changes within 10 days, corrected QT interval changes, adverse events, and abnormal laboratory parameters were the secondary outcomes. RESULTS: The mean time to reach undetectable viral RNA (mean ± standard deviation) was 10.6 ± 1.1 days (95% confidence interval [CI] 8.4-12.8) for the AP group and 19.3 ± 2.1 days (95% CI 15.1-23.5) for the control group. The percentages of patients with undetectable viral RNA on days 7, 10, 14, 21, and 28 were 26.1%, 43.5%, 78.3%, 100%, and 100%, respectively, in the AP group and 5.6%, 16.7%, 44.4%, 55.6%, and 72.2%, respectively, in the control group. The CT imaging within 10 days post-treatment showed no significant between-group differences (P > 0.05). Both groups had mild adverse events. CONCLUSIONS: In patients with mild-to-moderate COVID-19, the time to reach undetectable SARS-CoV-2 was significantly shorter in the AP group than that in the control group. However, physicians should consider QT interval changes before using AP.

Literature-Wide Association Studies (LWAS) for a Rare Disease: Drug Repurposing for Inflammatory Breast Cancer.

Drug repurposing is an effective means for rapid drug discovery. The aim of this study was to develop and validate a computational methodology based on Literature-Wide Association Studies (LWAS) of PubMed to repurpose existing drugs for a rare inflammatory breast cancer (IBC). We have developed a methodology that conducted LWAS based on the text mining technology Word2Vec. 3.80 million "cancer"-related PubMed abstracts were processed as the corpus for Word2Vec to derive vector representation of biological concepts. These vectors for drugs and diseases served as the foundation for creating similarity maps of drugs and diseases, respectively, which were then employed to find potential therapy for IBC. Three hundred and thirty-six (336) known drugs and three hundred and seventy (370) diseases were expressed as vectors in this study. Nine hundred and seventy (970) previously known drug-disease association pairs among these drugs and diseases were used as the reference set. Based on the hypothesis that similar drugs can be used against similar diseases, we have identified 18 diseases similar to IBC, with 24 corresponding known drugs proposed to be the repurposing therapy for IBC. The literature search confirmed most known drugs tested for IBC, with four of them being novel candidates. We conclude that LWAS based on the Word2Vec technology is a novel approach to drug repurposing especially useful for rare diseases.

Multidrug-resistant Acinetobacter baumannii strains with NDM-1: Molecular characterization and in vitro efficacy of meropenem-based combinations.

Acinetobacter baumannii is an important cause of hospital-acquired, multidrug-resistant (MDR) infections occurring worldwide. Anti-microbial combination regimens may be the only feasible treatment option for affected patients. In the present study, the efficacy of the combined therapy of meropenem with colistin, ampicillin-sulbactam, tazobactam and vancomycin against clinical strains of MDR A. baumannii was determined. Anti-microbial susceptibility testing was performed and resistance genes were characterized by a multiplex polymerase chain reaction (PCR)-reverse line blot assay. The genetic background of New Delhi metallo-ß-lactamase 1 (NDM-1) was analysed by primer walking. The presence of NDM-1 was detected using the modified Hodge test and the EDTA-combined disk test. To screen for synergistic drug effects, the fractional inhibitory concentration index was calculated using a checkerboard assay. The results of the PCR as well as the sequence analyses suggested that NDM-1 was located downstream of the ISAba125 element. In addition, a synergistic effect was determined for meropenem + vancomycin, meropenem + tazobactam and meropenem + ampicillin + sulbactam in two strains each, and in four strains for meropenem + colistin. A total of five A. baumannii strains with resistance to numerous antibiotics and carrying numerous resistance genes were identified. In the strains of A. baumannii, the NDM-1 gene was integrated in a transposon structure with a copy of the ISAba125 insertion sequence. However, the genetic background was not identical among the different species and strains. The genetic variability of NDM-1 may facilitate the rapid dissemination of this gene. In conclusion, meropenem may enhance the efficacy of antibiotics in A. baumannii strains with NDM-1-associated MDR.

Biomedical applications of carbon-nanotube composites.

The unique physical, chemical and mechanical properties of carbon nanotubes make them attractive for a variety of biomedical applications. Carbon nanotubes have been used to modify conventional biomedical materials to enhance mechanical properties, biocompatibility, or to impart other functionalities. New multifunctional composite materials using carbon nanotubes have been developed by combining them with inorganic, polymeric or biological materials. The biomedical applications for which novel carbon nanotube composites have been investigated include antimicrobial coatings, neural implants, tissue engineering scaffolds and electrochemical biosensors. In this paper, research on development and application of carbon nanotube composites for biomedical applications has been reviewed.

Semipolar r-plane ZnO films on Si(100) substrates: Thin film epitaxy and optical properties.

We report heteroepitaxial growth of (101 2) oriented (r-plane) ZnO films on Si(100) substrates. The films were grown by pulsed laser deposition and integration of ZnO with silicon was achieved using a tetragonal yttria stabilized zirconia (YSZ) buffer layer. It was observed that ZnO films grown at temperatures in the range of 700-750 degrees C with relatively high oxygen pressure ( approximately 70 mTorr) were (101 2) oriented. ZnO films deposited with lower oxygen pressures were found to be purely (0002) orientated. Experiments carried out to elucidate the role of oxygen pressure indicated that the crystallographic orientation of ZnO depends on the nature of atomic termination of YSZ layer. It has been proposed that crystallographic orientation of ZnO is controlled by chemical free energy associated with ZnO-YSZ interface. Detailed x-ray diffraction and transmission electron microscopy studies showed existence of four types of in-plane domains in r-plane ZnO films. Optical characterization demonstrated that photoluminescence of r-plane ZnO films was superior to that of c-plane ZnO films grown under similar conditions.

Atomic layer deposition-based functionalization of materials for medical and environmental health applications.

Nanoporous alumina membranes exhibit high pore densities, well-controlled and uniform pore sizes, as well as straight pores. Owing to these unusual properties, nanoporous alumina membranes are currently being considered for use in implantable sensor membranes and water purification membranes. Atomic layer deposition is a thin-film growth process that may be used to modify the pore size in a nanoporous alumina membrane while retaining a narrow pore distribution. In addition, films deposited by means of atomic layer deposition may impart improved biological functionality to nanoporous alumina membranes. In this study, zinc oxide coatings and platinum coatings were deposited on nanoporous alumina membranes by means of atomic layer deposition. PEGylated nanoporous alumina membranes were prepared by self-assembly of 1-mercaptoundec-11-yl hexa(ethylene glycol) on platinum-coated nanoporous alumina membranes. The pores of the PEGylated nanoporous alumina membranes remained free of fouling after exposure to human platelet-rich plasma; protein adsorption, fibrin networks and platelet aggregation were not observed on the coated membrane surface. Zinc oxide-coated nanoporous alumina membranes demonstrated activity against two waterborne pathogens, Escherichia coli and Staphylococcus aureus. The results of this work indicate that nanoporous alumina membranes may be modified using atomic layer deposition for use in a variety of medical and environmental health applications.

Optical and electrical properties of gallium-doped Mg(x)Zn(1-x)O.

In this study, the optical and electrical properties of epitaxial single crystal gallium-doped Mg(x)Zn(1-x)O thin films grown on c-plane sapphire substrates by pulsed laser deposition were investigated. In these films, the Ga content was varied from 0.05 to 7 at. % and the Mg content was varied from 5 to 15 at. %. X-ray diffraction showed that the solid solubility limit of Ga in Mg(x)Zn(1-x)O is less than 3 at. %. The absorption spectra were fitted to examine Ga doping effects on bandgap and band tail characteristics. Distinctive trends in fitted bandgap and band tail characteristics were determined in films with Ga content below 3 at. % and Ga content above 3 at. %. The effects of bandgap engineering on optical transparency were evaluated using transmission spectra. Carrier concentration and Hall mobility data were obtained as functions of Ga content and Mg content. The electrical properties were significantly degraded when the Ga content exceeded 3 at. %. Correlations between conduction mechanisms and gallium doping of Mg(x)Zn(1-x)O thin films were described. In addition, the effect of bandgap engineering on the electrical properties of epitaxial single crystal gallium-doped Mg(x)Zn(1-x)O thin films was discussed.

Mechanical and biological properties of nanoporous carbon membranes.

Implantable blood glucose sensors have inadequate membrane-tissue interfaces for long term use. Biofouling and inflammation processes restrict biosensor membrane stability. An ideal biosensor membrane material must prevent protein adsorption and exhibit cell compatibility. In addition, a membrane must exhibit high porosity and low thickness in order to allow the biosensor to respond to analyte fluctuations. In this study, the structural, mechanical and biological properties of nanoporous alumina membranes coated with diamond-like carbon thin films were examined using scanning probe microscopy, nanoindentation and MTT viability assay. We anticipate that this novel membrane material could find use in immunoisolation devices, kidney dialysis membranes and other medical devices encountering biocompatibility issues that limit in vivo function.

Pulsed laser deposition of nanoporous cobalt thin films.

Nanoporous cobalt thin films were deposited on anodized aluminum oxide (AAO) membranes at room temperature using pulsed laser deposition. Scanning electron microscopy demonstrated that the nanoporous cobalt thin films retained the monodisperse pore size and high porosity of the anodized aluminum oxide substrates. Temperature- and field-dependent magnetic data obtained between 10 K and 350 K showed large hysteresis behavior in these materials. The increase of coercivity values was larger for nanoporous cobalt thin films than for multilayered cobalt/alumina thin films. The average diameter of the cobalt nanograins in the nanoporous cobalt thin films was estimated to be approsimately 5 nm for blocking temperatures near room temperature. These results suggest that pulsed laser deposition may be used to fabricate nanoporous magnetic materials with unusual properties for biosensing, drug delivery, data storage, and other technological applications.

Compositional and electrochemical characterization of noble metal-diamondlike carbon nanocomposite thin films.

A detailed characterization of platinum- and gold-diamondlike carbon (DLC) nanocomposite films deposited onto silicon substrates is presented. A modified pulsed laser deposition (PLD) technique was used to incorporate noble metal nanoclusters into hydrogen-free DLC films. Several analytical techniques, including transmission electron microscopy, atomic force microscopy, Rutherford backscattering spectroscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and nanoindentation testing, were used to investigate these thin films in an effort to determine their physical and electrochemical properties. Rutherford backscattering spectroscopy indicated that the gold- and platinum-DLC films contain metal concentrations between three and 36 atomic percent. Cross-sectional transmission electron microscopy revealed that metal is present as arrays of noble metal islands embedded within the DLC matrix, while atomic force microscopy provided evidence of target splashing. In addition, due to the inclusion of metal, metal-DLC thin films exhibited greater conductivity than their metal-free counterparts. The electrochemical properties were studied using quasi-reversible redox couples and correlated to the metal concentration. Finally, the influence of the layer's composition on the electron-transfer kinetics and the achievable working potential window is discussed. The results discussed herein suggest that metal-DLC thin films grown by pulsed laser deposition present a promising alternative electrode material for electrochemistry.

Nanoporous hard carbon membranes for medical applications.

Current blood glucose sensors have proven to be inadequate for long term in vivo applications; membrane biofouling and inflammation play significant roles in sensor instability. An ideal biosensor membrane material must prevent protein adsorption and promote integration of the sensor with the surrounding tissue. Furthermore, biosensor membranes must be sufficiently thin and porous in order to allow the sensor to rapidly respond to fluctuations in analyte concentration. In this study, the use of diamondlike carbon-coated anodized aluminum oxide as a potential biosensor membrane is discussed. Diamondlike carbon films and diamondlike carbon-coated anodized aluminum oxide nanoporous membranes were examined using scanning electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and platelet rich plasma testing. The diamondlike carbon-coated anodized aluminum oxide membranes remained free from protein adsorption during in vitro platelet rich plasma testing. We anticipate that this novel membrane could find use in immunoisolation devices, pacemakers, kidney dialysis membranes, microdialysis systems, and other devices facing biocompatibility issues that limit in vivo function.