[Corrigendum] Enhanced antitumor activity by the combination of dasatinib and combretastatin A­4 in vitro and in vivo.

Following the publication of this article, an interested reader drew to the authors' attention that the flow cytometric (FCM) plots in Fig. 2A on p. 2278 showing the 'Dasatinib' and 'CA­4' experiments were duplicates of each other. After having re­examined their original data, and due to the overall similarity of the data, the authors have realized that these data were inadvertently assembled incorrectly in the figure. They realize that they also made a further mistake regarding the writing of the ratios of mitochondrial membrane­depolarized HO­8910 cells for these FCM plots (essentially, these were written the wrong way around): The percentage of mitochondrial membrane­depolarized HO­8910 cells should have been written as 22.50% for the dasatinib­treated cells (the centre­left FCM plot) and 15.71% for the CA­4­treated cells (centre­right plot). A revised version of Fig. 2 now showing alternative data for the FCM experiments shown in Fig. 2A, is shown on the next page. Note that the errors made in terms of assembling the data in Fig. 2A did not greatly affect either the results or the conclusions reported in this paper, and all the authors agree with the publication of this corrigendum. The authors regret that these errors went unnoticed prior to the publication of their article, and are grateful to the Editor of Oncology Reports for granting them this opportunity to publish a corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [Oncology Reports 29: 2275­2282, 2013; DOI: 10.3892/or.2013.2405].

Acetylation-dependent glutamate receptor GluR signalosome formation for STAT3 activation in both transcriptional and metabolism regulation.

Besides their original regulating roles in the brain, spinal cord, retina, and peripheral nervous system for mediating fast excitatory synaptic transmission, glutamate receptors consisting of metabotropic glutamate receptors (GluRs) and ionotropic glutamate receptors (iGluRs) have emerged to have a critical role in the biology of cancer initiation, progression, and metastasis. However, the precise mechanism underpinning the signal transduction mediated by ligand-bound GluRs is not clearly elucidated. Here, we show that iGluRs, GluR1 and GluR2, are acetylated by acetyltransferase CREB-binding protein upon glutamate stimulation of cells, and are targeted by lysyl oxidase-like 2 for deacetylation. Acetylated GluR1/2 recruit ß-arrestin1/2 and signal transducer and activator of transcription 3 (STAT3) to form a protein complex. Both ß-arrestin1/2 and STAT3 are subsequently acetylated and activated. Simultaneously, activated STAT3 acetylated at lysine 685 translocates to mitochondria to upregulate energy metabolism-related gene transcription. Our results reveal that acetylation-dependent formation of GluR1/2-ß-arrestin1/2-STAT3 signalosome is critical for glutamate-induced cell proliferation.

The role of iron in Parkinson's disease monkeys assessed by susceptibility weighted imaging and inductively coupled plasma mass spectrometry.

Mounting evidences indicated that elevated iron levels in the substantia nigra (SN) have been concerned as the underlying mechanisms of neurodegenerative diseases, including Parkinson's disease (PD). The present study used the 1-Methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP)-treated cynomolgus monkeys for PD to evaluate the usability of SWI for assessing iron deposition in the cerebral nuclei of PD. The results showed that susceptibility-weighted imaging (SWI) phase values of the ipsilateral (MPTP-lesion side) SN of MPTP-treated monkeys were lower than those in the contralateral SN of MPTP-treated monkeys and the same side of Control monkeys, suggesting that iron deposition were elevated in the affected side SN of MPTP-treated monkeys. Whereas MPTP has not effects on the SWI phase values in other detected brain regions of monkeys, including red nucleus (RN), putamen (PUT) and caudate nucleus (CA). Furthermore, ICP-MS results showed that MPTP increased the iron levels in MPTP injection side, but no in the ipsilateral striatum. Additionally, MPTP treatment did not affect the calcium and manganese levels in the detected brain regions of monkeys. However, Pearson correlation analysis results indicated that there were not relationship between SWI phase values in MPTP-lesion side of SN with the behavioral score, tyrosine hydroxylase (TH)-positive cells number and iron levels in the MPTP-lesion side of midbrain. Taken together, the results confirm the involvement of SN iron accumulations in the MPTP-treated monkey models for PD, and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of PD.

New homoisoflavonoid analogues protect cells by regulating autophagy.

As a special group of naturally occurring flavonoids, homoisoflavonoids have been discovered as active components of several traditional Chinese medicines for nourishing heart and mind. In this study, twenty homoisoflavonoid analogues, including different substitution groups on rings A and B, as well as heteroaromatic B ring, were synthesized and evaluated for their cardioprotective and neuroprotective activities. In a H2O2-induced H9c2 cardiomyocytes injury assay, nine homoisoflavonoid analogues showed promising activities in the same level as the positive control, diazoxide. Six cardioprotective compounds with representative structure diversities were then evaluated for their neuroprotective effects on MPP+ induced SH-SY5Y cell injury model. Furthermore, autophagy inducing monodansylcadaverine (MDC) fluorescence staining methods and molecular docking studies indicated the action mechanism of these compounds may involve autophagy regulating via class I PI3K signaling pathway.

Are Benign and Borderline Brain Tumors Underreported?

BACKGROUND: Primary benign and borderline (BB) brain tumors have been reportable since 2004 by population-based cancer registries in the United States. Because these tumors often are diagnosed clinically at nonhospital settings, underreporting is a big concern. Despite this, the magnitude and geographic variations in underreporting are unknown. The objectives of this study are to assess variations in BB brain tumor incidence rate by registry and trend in comparison to malignant brain tumors, as well as to identify the factors associated with the completeness of BB brain tumor reporting. METHODS: North American Association of Central Cancer Registries (NAACCR) Cancer in North America (CINA) Deluxe 1995­2012 Analytic File, which included data from 47 US population-based cancer registries, was used. Age-adjusted incidence rate and average annual percent change (APC) were calculated. Correlation coefficients were used to assess the relationships between incidence rates and clinical factors. RESULTS: The overall age-adjusted incidence rate was 14.2 per 100,000 for BB brain tumors and 6.6 per 100,000 for malignant brain tumors. The age-adjusted incidence rates of BB brain tumors varied by registry from 9.8 per 100,000 to 19.9 per 100,000, whereas the variations in malignant brain tumors were much smaller from 4.1 per 100,000 to 7.7 per 100,000. BB brain tumor cases were more likely than malignant brain tumors to be diagnosed through radiography without microscopic confirmation or surgery. Overall, the BB brain tumor incidence rate significantly increased by 2.3% per year from 2004 to 2012. In contrast, incidence rates of malignant brain tumors significantly decreased by 0.9% per year in the same period. Higher BB brain tumor incidence rates were significantly associated with higher proportions of cases without microscopic confirmation or surgery. These associations were not observed for malignant brain tumors. CONCLUSIONS: Incidence rates of BB brain tumors varied substantially across 47 US registries and were higher than those of malignant brain tumors in the United States. The variations in incidence rate of BB brain tumors may be largely attributable to difference in identifying clinically diagnosed cases. The increasing incidence rate of BB brain tumors may reflect improved case ascertainment rather than a biological trend. Key words:

A new dicoumarinyl ether from the roots of Stellera chamaejasme L.

A new dicoumarinyl ether, 3-hydroxy-6-methoxy-7,7'-dicoumarinyl ether (1), was isolated from the roots of Stellera chamaejasme L, together with the known compound umbelliferone (2). Their structures were determined on the basis of spectroscopic techniques, including IR, NMR, and HR-ESI-MS.

Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo.

The present study showed that the combination of dasatinib and combretastatin A-4 (CA-4) exhibited synergistic cytotoxicity in multiple types of cancer, including ovarian, hepatocellular, lung and prostate carcinoma. The enhanced apoptosis induced by dasatinib plus CA-4 was accompanied by a greater extent of mitochondrial depolarization, caspase-3 activation and PARP cleavage in HO-8910 cells. Furthermore, elevated expression of Mcl-1 led to a reduced apoptosis induced by dasatinib plus CA-4, highlighting that downregulated Mcl-1 was necessary for the potentiating effect of dasatinib to CA-4-triggered apoptosis. A clear increase in γ-H2AX expression was observed in the dasatinib+CA-4 group compared with the mono-treatment groups, indicating that dasatinib plus CA-4 may induce double-strand breaks (DSBs) in HO-8910 cells. Moreover, the increased anticancer efficacy of dasatinib combined with CA-4 was further validated in a human HO-8910 ovarian cancer xenograft model in nude mice. Our study is the first to show that the combination of dasatinib with CA-4 could be a novel and promising therapeutic approach for the treatment of cancer.

[Components of myrsinane-type diterpenes from Euphorbia prolifera].

OBJECTIVE: To extract and isolate the component from myrsinane-type diterpenes of Euphorbia prolifera. METHODS: Petroleum extraction and chromatography on the silica gel were used to extract and isolate the diterpenes of Euphorbia prolifera. RESULTS: Eight components of myrsinol diterpenes were isolated, namely: Proliferin A(1), Proliferin B (2), Proliferin C(3), Proliferin D(4), Euphorprolitherin B(5), Euphorprolitherin D(6), SPr5(7) and 14-desoxo-3-O-prorionyl-5, 15-di-O-acetyl-7-O-nicotinoyl-myrsinol-14ß-acetate(8). Their structures were identified with mass-spectroscopic methods and NMR techniques. The cytotoxicity of compounds 1, 2, and 4 against cancer cells was evaluated, with compound 1 being active against A2780 cancer cells (IC(50) 7.7 µmol/L). CONCLUSION: Myrsinane-type diterpene Proliferin A from Euphorbia prolifera shows cytotoxic effect against human ovarian cancer cell line A2780.

Relationship between changes in brain MRI and (1)H-MRS, severity of chronic liver damage, and recovery after liver transplantation.

Magnetic resonance imaging (MRI) and (1)H magnetic resonance spectroscopy ((1)H-MRS) have been used in clinics for diagnosis of chronic liver diseases. This study was designed to investigate the relationship between MRI/MRS outcomes and the severity of liver damage. Of 50 patients examined, the MRI signal intensity in the globus pallidus as determined by pallidus index (PI) increased as the disease severity (scored by Child Pugh ranking) worsened (r = 0.353, P < 0.05). The changes in PI values were also linearly associated with Mn concentrations in whole blood (MnB) (r = 0.814, P < 0.01). MRS analysis of four major brain metabolites (i.e., Cho, mI, Glx, and NAA) revealed that the ratios of Cho/Cr and mI/Cr in cirrhosis and CHE patients were significantly decreased in comparison to controls (P < 0.05), whereas the ratio of Glx/Cr was significantly increased (P < 0.05). The Child Pugh scores significantly correlated with mI/Cr (-0.484, P < 0.01) and Glx (0.369, P < 0.05), as well as MnB (0.368, P < 0.05), but not with other brain metabolites. Three patients who received a liver transplant experienced normalization of brain metabolites within 3 months of post-transplantation; the MR imaging of Mn in the globus pallidus completely disappeared 5 months after the surgery. Taken together, this clinical study, which combined MRI/MRS analysis, autopsy exam and liver transplant, clearly demonstrates that liver injury-induced brain Mn accumulation can reversibly alter the homeostasis of brain metabolites Cho, mI and Glx. Our data further suggest that liver transplantation can restore normal brain Mn levels.