Updates on Anticancer Therapy-Mediated Vascular Toxicity and New Horizons in Therapeutic Strategies.

Vascular toxicity is a frequent adverse effect of current anticancer chemotherapies and often results from endothelial dysfunction. Vascular endothelial growth factor inhibitors (VEGFi), anthracyclines, plant alkaloids, alkylating agents, antimetabolites, and radiation therapy evoke vascular toxicity. These anticancer treatments not only affect tumor vascularization in a beneficial manner, they also damage ECs in the heart. Cardiac ECs have a vital role in cardiovascular functions including hemostasis, inflammatory and coagulation responses, vasculogenesis, and angiogenesis. EC damage can be resulted from capturing angiogenic factors, inhibiting EC proliferation, survival and signal transduction, or altering vascular tone. EC dysfunction accounts for the pathogenesis of myocardial infarction, atherothrombosis, microangiopathies, and hypertension. In this review, we provide a comprehensive overview of the effects of chemotherapeutic agents on vascular toxicity leading to hypertension, microvascular rarefaction thrombosis and atherosclerosis, and affecting drug delivery. We also describe the potential therapeutic approaches such as vascular endothelial growth factor (VEGF)-B and prokineticin receptor-1 agonists to maintain endothelial function during or following treatments with chemotherapeutic agents, without affecting anti-tumor effectiveness.

Methylomic analysis identifies C11orf87 as a novel epigenetic biomarker for GI cancers.

Gastric cancer is one of the leading causes of cancer death worldwide. Previous studies demonstrated that activation of STAT3 is crucial for the development and progression of gastric cancer. However, the role of STAT3 in neuronal related gene methylation in gastric cancer has never been explored. In this study, by using DNA methylation microarray, we identified a potential STAT3 target, C11orf87, showing promoter hypomethylation in gastric cancer patients with lower STAT3 activation and AGS gastric cancer cell lines depleted with STAT3 activation. Although C11orf87 methylation is independent of its expression, ectopic expression of a constitutive activated STAT3 mutant upregulated its expression in gastric cancer cell line. Further bisulfite pyrosequencing demonstrated a progressive increase in DNA methylation of this target in patient tissues from gastritis, intestinal metaplasia, to gastric cancer. Intriguingly, patients with higher C11orf87 methylation was associated with better survival. Furthermore, hypermethylation of C11orf87 was also frequently observed in other GI cancers, as compared to their adjacent normal tissues. These results suggested that C11orf87 methylation may serve as a biomarker for diagnosis and prognosis of GI cancers, including gastric cancer. We further postulated that constitutive activation of STAT3 might be able to epigenetically silence C11orf87 as a possible negative feedback mechanism to protect the cells from the overactivation of STAT3. Targeted inhibition of STAT3 may not be appropriate in gastric cancer patients with promoter hypermethylation of C11orf87.

Tight regulation of a timed nuclear import wave of EKLF by PKCθ and FOE during Pro-E to Baso-E transition.

Erythropoiesis is a highly regulated process during which BFU-E are differentiated into RBCs through CFU-E, Pro-E, PolyCh-E, OrthoCh-E, and reticulocyte stages. Uniquely, most erythroid-specific genes are activated during the Pro-E to Baso-E transition. We show that a wave of nuclear import of the erythroid-specific transcription factor EKLF occurs during the Pro-E to Baso-E transition. We further demonstrate that this wave results from a series of finely tuned events, including timed activation of PKCθ, phosphorylation of EKLF at S68 by P-PKCθ(S676), and sumoylation of EKLF at K74. The latter EKLF modifications modulate its interactions with a cytoplasmic ankyrin-repeat-protein FOE and importinß1, respectively. The role of FOE in the control of EKLF nuclear import is further supported by analysis of the subcellular distribution patterns of EKLF in FOE-knockout mice. This study reveals the regulatory mechanisms of the nuclear import of EKLF, which may also be utilized in the nuclear import of other factors.

Detecting the effect of targeted anti-cancer medicines on single cancer cells using a poly-silicon wire ion sensor integrated with a confined sensitive window.

A mold-cast polydimethylsiloxane (PDMS) confined window was integrated with a poly-silicon wire (PSW) ion sensor. The PSW sensor surface inside the confined window was coated with a 3-aminopropyltriethoxysilane (γ-APTES) sensitive layer which allowed a single living cell to be cultivated. The change in the microenvironment due to the extracellular acidification of the single cell could then be determined by measuring the current flowing through the PSW channel. Based on this, the PSW sensor integrated with a confined sensitive window was used to detect the apoptosis as well as the effect of anti-cancer medicines on the single living non-small-lung-cancer (NSLC) cells including lung adenocarcinoma cancer cells A549 and H1299, and lung squamous-cell carcinoma CH27 cultivated inside the confined window. Single human normal cells including lung fibroblast cells WI38, lung fibroblast cells MRC5, and bronchial epithelium cell Beas-2B were tested for comparison. Two targeted anti-NSCLC cancer medicines, Iressa and Staurosporine, were used in the present study. It was found that the PSW sensor can be used to accurately detect the apoptosis of single cancer cells after the anti-cancer medicines were added. It was also found that Staurosporine is more effective than Iressa in activating the apoptosis of cancer cells.

Characteristics of polysilicon wire glucose sensors with a surface modified by silica nanoparticles/γ-APTES nanocomposite.

This report investigates the sensing characteristics of polysilicon wire (PSW) glucose biosensors, including thickness characteristics and line-width effects on detection limits, linear range and interference immunity with membranes coated by micropipette/spin-coating and focus-ion-beam (FIB) processed capillary atomic-force-microscopy (C-AFM) tip scan/coating methods. The PSW surface was modified with a mixture of 3-aminopropyl-triethoxysilane (γ-APTES) and polydimethylsiloxane (PDMS)-treated hydrophobic fumed silica nanoparticles (NPs). We found that the thickness of the γ-APTES+NPs nonocomposite could be controlled well at about 22 nm with small relative standard deviation (RSD) with repeated C-AFM tip scan/coatings. The detection limit increased and linear range decreased with the line width of the PSW through the tip-coating process. Interestingly, the interference immunity ability improves as the line width increases. For a 500 nm-wide PSW, the percentage changes of the channel current density changes (ΔJ) caused by acetaminophen (AP) can be kept below 3.5% at an ultra-high AP-to-glucose concentration ratio of 600:1. Simulation results showed that the line width dependence of interference immunity was strongly correlated with the channel electrical field of the PSW biosensor.

Gamma-ray sterilization effects in silica nanoparticles/γ-APTES nanocomposite-based pH-sensitive polysilicon wire sensors.

In this paper, we report the γ-ray sterilization effects in pH-sensitive polysilicon wire (PSW) sensors using a mixture of 3-aminopropyltriethoxysilane (γ-APTES) and polydimethylsiloxane (PDMS)-treated hydrophobic fumed silica nanoparticles (NPs) as a sensing membrane. pH analyses showed that the γ-ray irradiation-induced sensitivity degradation of the PSW pH sensor covered with γ-APTES/silica NPs nanocomposite (γ-APTES+NPs) could be restored to a condition even better than prior to γ-ray irradiation by 40-min of post-sterilization room-temperature UV annealing. We found that the trapping charges caused by γ-ray sterilization primarily concentrated in the native oxide layer for the pH sensor covered with γ-APTES, but accumulated in the γ-APTES+NPs layer for the γ-APTES+NPs-covered sensor. It is believed that mixing the PDMS-treated silica NPs into γ-APTES provides many γ-APTES/SiO(2) interfaces for the accumulation of trapping charges and for post-sterilization UV oxidation, thus restoring γ-ray-induced sensor degradation. The PDMS-treated silica NPs not only enhance the sensitivity of the pH-sensitive PSW sensors but are also able to withstand the two-step sterilization resulting from γ-ray and UV irradiations. This investigation suggests γ-ray irradiation could be used as a highly-efficient sterilization method for γ-APTES-based pH-sensitive biosensors.

Electrical characterization of single cells using polysilicon wire ion sensor in an isolation window.

A polysilicon wire (PSW) sensor can detect the H(+) ion density (pH value) of the medium coated on its surface, and different cells produce different extracellular acidification and hence different H(+) ion densities. Based on this, we used a PSW sensor in combination with a mold-cast polydimethylsiloxane (PDMS) isolation window to detect the adhesion, apoptosis and extracellular acidification of single normal cells and single cancer cells. Single living human normal cells WI38, MRC5, and BEAS-2B as well as non-small-cell lung cancer (NSCLC) cells A549, H1299, and CH27 were cultivated separately inside the isolation window. The current flowing through the PSW channel was measured. From the PSW channel current change as a function of time, we determined the cell adhesion time by observing the time required for the current change to saturate, since a stable extracellular ion density was established after the cells were completely adhered to the PSW surface. The apoptosis of cells can also be determined when the channel current change drops to zero. We found that all the NSCLC cells had a higher channel current change and hence a lower pH value than the normal cells anytime after they were seeded. The corresponding average pH values were 5.86 for A549, 6.00 for H1299, 6.20 for CH27, 6.90 for BEAS-2B, 6.96for MRC5, and 7.02 for WI38, respectively, after the cells were completely adhered to the PSW surface. Our results show that NSCLC cells have a stronger cell-substrate adhesion and a higher extracellular acidification rate than normal cells.

Polysilicon wire glucose sensor highly immune to interference.

This study investigated the interference elimination ability of a glucose sensor made of polysilicon wire (PSW) with a surface modified by 3-aminopropyltriethoxysilane mixed with polydimethylsiloxane-treated hydrophobic fumed silica nanoparticles plus ultra-violet illumination (γ-APTES+NPs+UV). Glucose sensing of the PSW sensor in the presence of five common interferences such as ascorbic acid (AA), uric acid (UA), acetaminophen (AP), L-cysteine (Lys), and citric acid (CA) was performed. We found that the disturbance caused by the interferences was low for interference-to-glucose concentration ratios up to 600:1 if the PSW surface is modified with γ-APTES+NPs+UV. The outstanding interference immunity of this PSW glucose sensor is believed to be mainly due to the fact that it is a dry-type sensor and the extremely low leakage of the γ-APTES+NPs membrane which allows the PSW to show three orders of magnitude lower leakage current than with the γ-APTES membrane only. In addition to its excellent interference immunity, the PSW glucose sensor with a line width of 100 nm also exhibits a wide linear detection range, an ultra-high sensitivity, an ultra low detection limit, and it can be reused more than a thousand times without much sensitivity degradation.

Molecular population genetics and gene expression analysis of duplicated CBF genes of Arabidopsis thaliana.

BACKGROUND: CBF/DREB duplicate genes are widely distributed in higher plants and encode transcriptional factors, or CBFs, which bind a DNA regulatory element and impart responsiveness to low temperatures and dehydration. RESULTS: We explored patterns of genetic variations of CBF1, -2, and -3 from 34 accessions of Arabidopsis thaliana. Molecular population genetic analyses of these genes indicated that CBF2 has much reduced nucleotide diversity in the transcriptional unit and promoter, suggesting that CBF2 has been subjected to a recent adaptive sweep, which agrees with reports of a regulatory protein of CBF2. Investigating the ratios of Ka/Ks between all paired CBF paralogus genes, high conservation of the AP2 domain was observed, and the major divergence of proteins was the result of relaxation in two regions within the transcriptional activation domain which was under positive selection after CBF duplication. With respect to the level of CBF gene expression, several mutated nucleotides in the promoters of CBF3 and -1 of specific ecotypes might be responsible for its consistently low expression. CONCLUSION: We concluded from our data that important evolutionary changes in CBF1, -2, and -3 may have primarily occurred at the level of gene regulation as well as in protein function.