Prolonged Cerebral Circulation Time Is the Best Parameter for Predicting Vasospasm during Initial CT Perfusion in Subarachnoid Hemorrhagic Patients

Purpose

We sought to imitate angiographic cerebral circulation time (CCT) and create a similar index from baseline CT perfusion (CTP) to better predict vasospasm in patients with subarachnoid hemorrhage (SAH).

Methods

Forty-one SAH patients with available DSA and CTP were retrospectively included. The vasospasm group was comprised of patients with deterioration in conscious functioning and newly developed luminal narrowing; remaining cases were classified as the control group. The angiography CCT (XA-CCT) was defined as the difference in TTP (time to peak) between the selected arterial ROIs and the superior sagittal sinus (SSS). Four arterial ROIs were selected to generate four corresponding XA-CCTs: the right and left anterior cerebral arteries (XA-CCT_RA2 and XA-CCT_LA2) and right- and left-middle cerebral arteries (XA-CCT_RM2 and XA-CCT_LM2). The CCTs from CTP (CT-CCT) were defined as the differences in TTP from the corresponding arterial ROIs and the SSS. Correlations of the different CCTs were calculated and diagnostic accuracy in predicting vasospasm was evaluated.

Results

Intra-class correlations ranged from 0.96 to 0.98. The correlations of XA-CCT_RA2, XA-CCT_RM2, XA-CCT_LA2, and XA-CCT_LM2 with the corresponding CT-CCTs were 0.64, 0.65, 0.53, and 0.68, respectively. All CCTs were significantly prolonged in the vasospasm group (5.8–6.4 s) except for XA-CCT_LA2. CT-CCT_A2 of 5.62 was the optimal cut-off value for detecting vasospasm with a sensitivity of 84.2% and specificity 82.4%

Conclusion

CT-CCTs can be used to interpret cerebral flow without deconvolution algorithms, and outperform both MTT and TTP in predicting vasospasm risk. This finding may help facilitate management of patients with SAH.     

Isolation and Identification of a Novel Antioxidant with Antitumour Activity from <Emphasis Type="Italic">Serratia ureilytica</Emphasis> Using Squid Pen as Fermentation Substrate

The antioxidant activity of the culture supernatant of Serratia ureilytica TKU013 with squid pen as the sole carbon/nitrogen source was assessed by three methods, and the phenolic contents were assayed. The supernatant with the highest antioxidant activity was further purified by liquid–liquid partition, revealing the ethyl acetate extract exhibited the strongest antioxidant activity and the highest total phenolic content. Eight fractions were retrieved from silica gel column chromatography of this extract, designated F1–F8. F4 was found to possess the strong antioxidative activity and the highest total phenolic content and also exhibited strong cytotoxic activities against two different tumoural cell lines. A new compound (Serranticin) with antioxidant and antitumor activity was obtained from F4. The structure of Serranticin is analogous to that of siderophores (hexacoordinated catecholamine), which are iron chelators. As such, Serranticin has the potential for use as a deferration agent in various iron overload diseases.     

Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells

Background

The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive.

Methodology/Principal Findings

Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib.

Conclusions/Significance

Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.     

BPR1K653, a novel Aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells

Background

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.

Principal Findings

BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.

Conclusions and Significance

BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.     

536. Saruma Henryi

Summary.  Saruma henryi Oliver is described and illustrated. The distribution, ecology, taxonomy and cultural requirements of this unusual member of the Aristolochiaceae are discussed.     

Damage formation and repair efficiency in the p53 gene of cell lines and blood lymphocytes assayed by multiplex long quantitative polymerase chain reaction

We examined ultraviolet (UV) irradiation and cisplatin treatment damage formation and repair efficiency in the p53 tumor suppressor gene of various cultured cell lines and lymphocytes using a nonradioactive multiplex long quantitative polymerase chain reaction (QPCR) assay, which amplified a 7-kb fragment of the target gene and a 500-bp fragment of the template control to successfully increase the sensitivity and reliability of the assay. The multiplex long QPCR detected a lesion frequency of 0.63 lesions/10kb/10J/m(2) in the p53 gene of fibroblast cells. In addition, the multiplex long QPCR assay detected pronounced differences in the repair of UV damage in the p53 gene among repair-proficient CRL-1475 cells and repair-deficient XP-A and XP-C cells. The multiplex long QPCR assay was also evaluated as a sensitive assay for the detection of DNA damage induced by cisplatin. The data indicated that the lesion frequency in the p53 gene was 1.27-1.75 times higher in the H23 cisplatin-sensitive cell than in the H1435 cisplatin-resistant cell at the IC(70) dose. After 8-h and 24-h repair periods, only 13 and 75% of cisplatin-induced damage had been removed in the H23 cells, whereas these values were 92 and 100% in the H1435 cells. In addition, our data indicate that multiplex long QPCR is a sensitive method for validly estimating repair in freshly isolated lymphocytes. The results suggest that the current protocol of the multiplex long QPCR method can be used to assess the damage formation and repair efficiency of various agents at biologically relevant doses and to allow a more precise determination of gene-specific repair in disease susceptibility and drug resistance in epidemiological studies.     

Using fluorochemical as oxygen carrier to enhance the growth of marine microalga Nannochloropsis oculata

The commercial value of marine Nannochloropsis oculata has been recognized due to its high content of eicosapentaenoic acid (>50 % w/w). To make it as a profitable bioresource, one of the most desirable goals is to develop a quality-controlled, cost-effective, and large-scale photobioreactor for N. oculata growth. Generally, closed culture system can offer many advantages over open system such as small space requirement, controllable process and low risk of contamination. However, oxygen accumulation is often a detrimental factor for enclosed microalgal culture that has seriously hampered the development of microalga-related industries. In this study, we proposed to use fluorochemical as oxygen carrier to overcome the challenge where four liquid fluorochemicals namely perfluorooctyl bromide, perfluorodecalin, methoxynonafluorobutane, and ethoxynonafluorobutane were investigated separately. Our results showed that the microalgal proliferation with different fluorinated liquids was similar and comparable to the culture without a fluorochemical. When cultured in the photobioreactor with 60 % oxygen atmosphere, the N. oculata can grow up in all the fluorochemical photobioreactors, but completely inhibited in the chamber without a fluorochemical. Moreover, the perfluorooctyl bromide system exhibited the most robust efficacy of oxygen removal in the culture media (perfluorooctyl bromide > perfluorodecalin > methoxynonafluorobutane > ethoxynonafluorobutane), and yielded a >3-fold increase of biomass production after 5 days. In summary, the developed fluorochemical photobioreactors offer a feasible means for N. oculata growth in closed and large-scale setting without effect of oxygen inhibition.     

Cloning and expression of a putative cytochrome P450 gene that influences the colour of Phalaenopsis flowers

Anthocyanins are responsible for reds through blues in flowers. Blue and violet flowers generally contain derivatives of delphinidin, whereas red and pink flowers contain derivatives of cyanidin or pelargonidin. Differences in hydroxylation patterns of these three major classes of anthocyanidins are controlled by the cytochrome P450 enzymes. Flavonoid-3',5'-hydroxylase, a member of the cytochrome P450 family, is the key enzyme in the synthesis of 3',5'-hydroxylated anthocyanins, generally required for blue or purple flowers. Here we report on the isolation of a cDNA clone of a putative flavonoid-3',5'-hydroxylase gene from Phalaenopsis that was then cloned into a plant expression vector. Transient transformation was achieved by particle bombardment of Phalaenopsis petals. The transgenic petals changed from pink to magenta, indicating that the product of the putative flavonoid-3',5'-hydroxylase gene influences anthocyanin pigment synthesis.