Nanoparticle-facilitated functional and molecular imaging for the early detection of cancer

Cancer detection in its early stages is imperative for effective cancer treatment and patient survival. In recent years, biomedical imaging techniques, such as magnetic resonance imaging, computed tomography and ultrasound have been greatly developed and have served pivotal roles in clinical cancer management. Molecular imaging (MI) is a non-invasive imaging technique that monitors biological processes at the cellular and sub-cellular levels. To achieve these goals, MI uses targeted imaging agents that can bind targets of interest with high specificity and report on associated abnormalities, a task that cannot be performed by conventional imaging techniques. In this respect, MI holds great promise as a potential therapeutic tool for the early diagnosis of cancer. Nevertheless, the clinical applications of targeted imaging agents are limited due to their inability to overcome biological barriers inside the body. The use of nanoparticles has made it possible to overcome these limitations. Hence, nanoparticles have been the subject of a great deal of recent studies. Therefore, developing nanoparticle-based imaging agents that can target tumors via active or passive targeting mechanisms is desirable. This review focuses on the applications of various functionalized nanoparticle-based imaging agents used in MI for the early detection of cancer

Tinzaparin Provides Lower Lipid Profiles in Maintenance Hemodialysis Patients: A Cross-Sectional Observational Study

As a low-molecular-weight heparin, tinzaparin has effectively been used as an anticoagulant during hemodialysis sessions. However, the impact of different heparin types on dyslipidemia is still controversial. In our study, 434 chronic hemodialysis patients were evaluated. The mean age was 65 ± 13. Forty-eight patients (11%) and 386 patients (89%) were in the tinzaparin and unfractionated heparin (UFH) groups, respectively. Triglyceride had significant difference between the two groups (P=0.001) but total cholesterol, HDL, or LDL did not. In the univariate analysis, the triglyceride level was significantly associated with tinzaparin use [β: −39.9, 95% confidence interval (CI): −76.7 to −3.0], and this association remained following the multivariate analysis (β: −40.8, 95% CI: −75.1 to −6.5). The difference in serum total cholesterol level between tinzaparin and UFH became significant (β: −13, 95% CI: −24.5 to −1.56) after adjustment in the multivariate analysis. Moreover, in a subgroup analysis, male diabetic patients showed lower serum triglyceride levels with the use of tinzaparin, while older, nondiabetic, male patients showed significant advantages in total cholesterol levels with the use of tinzaparin. Based on our findings, tinzaparin shows a significant association with a lower lipid profile in patients with chronic hemodialysis when compared to UFH

Clinical Study Tinzaparin Provides Lower Lipid Profiles in Maintenance Hemodialysis Patients: A Cross-Sectional Observational Study

As a low-molecular-weight heparin, tinzaparin has effectively been used as an anticoagulant during hemodialysis sessions. However, the impact of different heparin types on dyslipidemia is still controversial. In our study, 434 chronic hemodialysis patients were evaluated. The mean age was 65 ± 13. Forty-eight patients (11%) and 386 patients (89%) were in the tinzaparin and unfractionated heparin (UFH) groups, respectively. Triglyceride had significant difference between the two groups ( = 0.001) but total cholesterol, HDL, or LDL did not. In the univariate analysis, the triglyceride level was significantly associated with tinzaparin use [ : −39.9, 95% confidence interval (CI): −76.7 to −3.0], and this association remained following the multivariate analysis ( : −40.8, 95% CI: −75.1 to −6.5). The difference in serum total cholesterol level between tinzaparin and UFH became significant ( : −13, 95% CI: −24.5 to −1.56) after adjustment in the multivariate analysis. Moreover, in a subgroup analysis, male diabetic patients showed lower serum triglyceride levels with the use of tinzaparin, while older, nondiabetic, male patients showed significant advantages in total cholesterol levels with the use of tinzaparin. Based on our findings, tinzaparin shows a significant association with a lower lipid profile in patients with chronic hemodialysis when compared to UFH

Effects of methyl terminal and carbon bridging groups ratio on critical properties of porous organosilicate-glass films

Organosilicate glass-based porous low dielectic constant films with different ratios of terminal methyl to bridging organic (methylene, ethylene and 1,4-phenylene) groups are spin-on deposited by using a mixture of alkylenesiloxane with organic bridges and methyltrimethoxysilane, followed by soft baking at 120–200◦ C and curing at 430◦ C. The films’ porosity was controlled by using sacrificial template Brij® L4. Changes of the films’ refractive indices, mechanical properties, k-values, porosity and pore structure versus chemical composition of the film’s matrix are evaluated and compared with methyl-terminated low-k materials. The chemical resistance of the films to annealing in oxygen-containing atmosphere is evaluated by using density functional theory (DFT). It is found that the introduction of bridging groups changes their porosity and pore structure, increases Young’s modulus, but the improvement of mechanical properties happens simultaneously with the increase in the refractive index and k-value. The 1,4-phenylene bridging groups have the strongest impact on the films’ properties. Mechanisms of oxidative degradation of carbon bridges are studied and it is shown that 1,4-phenylene-bridged films have the highest stability. Methylene-and ethylene-bridged films are less stable but methylene-bridged films show slightly higher stability than ethylene-bridged films. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Directed Evolution of a Lysosomal Enzyme with Enhanced Activity at Neutral pH by Mammalian Cell-Surface Display

SummaryHuman β-glucuronidase, due to low intrinsic immunogenicity in humans, is an attractive enzyme for tumor-specific prodrug activation, but its utility is hindered by low activity at physiological pH. Here we describe the development of a high-throughput screening procedure for enzymatic activity based on the stable retention of fluorescent reaction product in mammalian cells expressing properly folded glycoproteins on their surface. We utilized this procedure on error-prone PCR and saturation mutagenesis libraries to isolate β-glucuronidase tetramers that were up to 60-fold more active (kcat/Km) at pH 7.0 and were up to an order of magnitude more effective at catalyzing the conversion of two structurally disparate glucuronide prodrugs to anticancer agents. The screening procedure described here can facilitate investigation of eukaryotic enzymes requiring posttranslational modifications for biological activity

The iNOS/Src/FAK axis is critical in Toll-like receptor-mediated cell motility in macrophages

AbstractThe Toll-like receptors (TLRs) play a pivotal role in innate immunity for the detection of highly conserved, pathogen-expressed molecules. Previously, we demonstrated that lipopolysaccharide (LPS, TLR4 ligand)-increased macrophage motility required the participation of Src and FAK, which was inducible nitric oxide synthase (iNOS)-dependent. To investigate whether this iNOS/Src/FAK pathway is a general mechanism for macrophages to mobilize in response to engagement of TLRs other than TLR4, peptidoglycan (PGN, TLR2 ligand), polyinosinic–polycytidylic acid (polyI:C, TLR3 ligand) and CpG-oligodeoxynucleotides (CpG, TLR9 ligand) were used to treat macrophages in this study. Like LPS stimulation, simultaneous increase of cell motility and Src (but not Fgr, Hck, and Lyn) was detected in RAW264.7, peritoneal macrophages, and bone marrow-derived macrophages exposed to PGN, polyI:C and CpG. Attenuation of Src suppressed PGN-, polyI:C-, and CpG-elicited movement and the level of FAK Pi-Tyr861, which could be reversed by the reintroduction of siRNA-resistant Src. Besides, knockdown of FAK reduced the mobility of macrophages stimulated with anyone of these TLR ligands. Remarkably, PGN-, polyI:C-, and CpG-induced Src expression, FAK Pi-Tyr861, and cell mobility were inhibited in macrophages devoid of iNOS, indicating the importance of iNOS. These findings corroborate that iNOS/Src/FAK axis occupies a central role in macrophage locomotion in response to engagement of TLRs

Identification of novel DNA methylation inhibitors via a two-component reporter gene system

<p>Abstract</p> <p>Background</p> <p>Targeting abnormal DNA methylation represents a therapeutically relevant strategy for cancer treatment as demonstrated by the US Food and Drug Administration approval of the DNA methyltransferase inhibitors azacytidine and 5-aza-2'-deoxycytidine for the treatment of myelodysplastic syndromes. But their use is associated with increased incidences of bone marrow suppression. Alternatively, procainamide has emerged as a potential DNA demethylating agent for clinical translation. While procainamide is much safer than 5-aza-2'-deoxycytidine, it requires high concentrations to be effective in DNA demethylation in suppressing cancer cell growth. Thus, our laboratories have embarked on the pharmacological exploitation of procainamide to develop potent DNA methylation inhibitors through lead optimization.</p> <p>Methods</p> <p>We report the use of a DNA methylation two-component enhanced green fluorescent protein reporter system as a screening platform to identify novel DNA methylation inhibitors from a compound library containing procainamide derivatives.</p> <p>Results</p> <p>A lead agent IM25, which exhibits substantially higher potency in <it>GSTp1 </it>DNA demethylation with lower cytotoxicity in MCF7 cells relative to procainamide and 5-aza-2'-deoxycytidine, was identified by the screening platform.</p> <p>Conclusions</p> <p>Our data provide a proof-of-concept that procainamide could be pharmacologically exploited to develop novel DNA methylation inhibitors, of which the translational potential in cancer therapy/prevention is currently under investigation.</p

NOXA-Induced Alterations in the Bax/Smac Axis Enhance Sensitivity of Ovarian Cancer Cells to Cisplatin

Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy

Fosmid library end sequencing reveals a rarely known genome structure of marine shrimp Penaeus monodon

<p>Abstract</p> <p>Background</p> <p>The black tiger shrimp (<it>Penaeus monodon</it>) is one of the most important aquaculture species in the world, representing the crustacean lineage which possesses the greatest species diversity among marine invertebrates. Yet, we barely know anything about their genomic structure. To understand the organization and evolution of the <it>P. monodon </it>genome, a fosmid library consisting of 288,000 colonies and was constructed, equivalent to 5.3-fold coverage of the 2.17 Gb genome. Approximately 11.1 Mb of fosmid end sequences (FESs) from 20,926 non-redundant reads representing 0.45% of the <it>P. monodon </it>genome were obtained for repetitive and protein-coding sequence analyses.</p> <p>Results</p> <p>We found that microsatellite sequences were highly abundant in the <it>P. monodon </it>genome, comprising 8.3% of the total length. The density and the average length of microsatellites were evidently higher in comparison to those of other taxa. AT-rich microsatellite motifs, especially poly (AT) and poly (AAT), were the most abundant. High abundance of microsatellite sequences were also found in the transcribed regions. Furthermore, <it>via </it>self-BlastN analysis we identified 103 novel repetitive element families which were categorized into four groups, <it>i.e</it>., 33 WSSV-like repeats, 14 retrotransposons, 5 gene-like repeats, and 51 unannotated repeats. Overall, various types of repeats comprise 51.18% of the <it>P. monodon </it>genome in length. Approximately 7.4% of the FESs contained protein-coding sequences, and the Inhibitor of Apoptosis Protein (IAP) gene and the Innexin 3 gene homologues appear to be present in high abundance in the <it>P. monodon </it>genome.</p> <p>Conclusions</p> <p>The redundancy of various repeat types in the <it>P. monodon </it>genome illustrates its highly repetitive nature. In particular, long and dense microsatellite sequences as well as abundant WSSV-like sequences highlight the uniqueness of genome organization of penaeid shrimp from those of other taxa. These results provide substantial improvement to our current knowledge not only for shrimp but also for marine crustaceans of large genome size.</p