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1.  An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma 
British Journal of Cancer  2013;110(2):510-519.
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumour originating in the thoracic mesothelium. Prognosis remains poor with 9- to 12-month median survival, and new targets for treatments are desperately needed.
Methods:
Utilising an RNA interference (RNAi)-based screen of 40 genes overexpressed in tumours, including genes involved in the control of cell cycle, DNA replication and repair, we investigated potential therapeutic targets for MPM. Following in vitro characterisation of the effects of target silencing on MPM cells, candidates were assessed in tumour samples from 154 patients.
Results:
Gene knockdown in MPM cell lines identified growth inhibition following knockdown of NDC80, CDK1 and PLK1. Target knockdown induced cell-cycle arrest and increased apoptosis. Using small-molecule inhibitors specific for these three proteins also led to growth inhibition of MPM cell lines, and Roscovitine (inhibitor of CDK1) sensitised cells to cisplatin. Protein expression was also measured in tumour samples, with markedly variable levels of CDK1 and PLK1 noted. PLK1 expression in over 10% of cells correlated significantly with a poor prognosis.
Conclusion:
These results suggest that RNAi-based screening has utility in identifying new targets for MPM, and that inhibition of NDC80, CDK1 and PLK1 may hold promise for treatment of this disease.
doi:10.1038/bjc.2013.731
PMCID: PMC3899767  PMID: 24327015
RNAi; malignant mesothelioma; NDC80; CDK1; PLK1
2.  Value of ultrasonography for detecting chronic injury of the lateral ligaments of the ankle joint compared with ultrasonography findings 
The British Journal of Radiology  2013;87(1033):20130406.
Objective:
The aim of this study was to assess the accuracy of ultrasonography in the diagnosis of chronic lateral ankle ligament injury.
Methods:
A total of 120 ankles in 120 patients with a clinical suspicion of chronic ankle ligament injury were examined by ultrasonography by using a 5- to 17-MHz linear array transducer before surgery. The results of ultrasonography were compared with the operative findings.
Results:
There were 18 sprains and 24 partial and 52 complete tears of the anterior talofibular ligament (ATFL); 26 sprains, 27 partial and 12 complete tears of the calcaneofibular ligament (CFL); and 1 complete tear of the posterior talofibular ligament (PTFL) at arthroscopy and operation. Compared with operative findings, the sensitivity, specificity and accuracy of ultrasonography were 98.9%, 96.2% and 84.2%, respectively, for injury of the ATFL and 93.8%, 90.9% and 83.3%, respectively, for injury of the CFL. The PTFL tear was identified by ultrasonography. The accuracy of identification between acute-on-chronic and subacute–chronic patients did not differ. The accuracies of diagnosing three grades of ATFL injuries were almost the same as those of diagnosing CFL injuries.
Conclusion:
Ultrasonography provides useful information for the evaluation of patients presenting with chronic pain after ankle sprain.
Advances in knowledge:
Intraoperative findings are the reference standard. We demonstrated that ultrasonography was highly sensitive and specific in detecting chronic lateral ligments injury of the ankle joint.
doi:10.1259/bjr.20130406
PMCID: PMC3898969  PMID: 24352708
3.  ING4 regulates JWA in angiogenesis and their prognostic value in melanoma patients 
British Journal of Cancer  2013;109(11):2842-2852.
Background:
We previously showed that inhibitor of growth family member 4 (ING4) inhibits melanoma angiogenesis, and JWA suppresses the metastasis of melanoma cells. As angiogenesis is essential for tumour metastasis, further investigation of the function of ING4 and JWA in melanoma angiogenesis is needed, and their prognostic value are of great interest.
Methods:
Western blot, tube-formation assays and luciferase assays were used to investigate the correlation between ING4 and JWA in melanoma angiogenesis. JWA and integrin-linked kinase (ILK) expression was determined on a tissue microarray constructed from 175 biopsies.
Results:
ING4 promoted JWA expression by activating JWA promoter. Furthermore, the regulation of growth and tube formation of endothelial cells by ING4 was partially JWA dependent. Also, ING4 inhibited the ILK-induced angiogenesis signalling pathway via JWA. Moreover, reduced JWA, or increased ILK, expression was closely associated with 5-year disease-specific survival of melanoma patients (P=0.001 and 0.007, respectively). There was also a positive correlation between ING4 and JWA yet a negative correlation between ING4 and ILK. Importantly, their concomitant expressions were significantly related to 5-year survival of melanoma patients (P=0.002 and 0.003, respectively).
Conclusion:
JWA has an important role in ING4-regulated melanoma angiogenesis, and ING4/JWA/ILK are promising prognostic markers and may be used as anti-angiogenic therapeutic targets for melanoma.
doi:10.1038/bjc.2013.670
PMCID: PMC3844917  PMID: 24157826
ING4; JWA; melanoma; angiogenesis; prognosis; ILK
4.  Comparative Outcomes among the Problem Areas of Interpersonal Psychotherapy for Depression 
Depression and anxiety  2010;27(5):434-440.
Background
Although interpersonal psychotherapy (IPT) is an efficacious treatment for acute depression, the relative efficacy of treatment in each of the four IPT problem areas (grief, role transitions, role disputes, interpersonal deficits) has received little attention. We evaluated the specificity of IPT by comparing treatment success among patients whose psychotherapy focused on each problem area. Moreover, we sought to understand how the patient characteristics and interpersonal problems most closely linked to the onset of a patient’s current depression contributed to IPT success.
Methods
Patients meeting DSM-IV criteria for an episode of major depressive disorder (n=182) were treated with weekly IPT. Remission was defined as an average Hamilton Rating Scale for Depression 17-item score of 7 or below over 3 weeks. Personality disorders were diagnosed using the Structured Clinical Interview for DSM-IV Personality Disorders.
Results
Contrary to our prediction that patients whose treatment was focused on interpersonal deficits would take longer to remit, survival analyses indicated that patients receiving treatment focused on each of the four problem areas did not differ in their times to remission. Nor were patients in the interpersonal deficits group more likely to have an Axis II diagnosis. Patients whose treatment focused on role transitions remitted faster than those whose treatment focused on role disputes, after controlling for covariates.
Conclusion
With skillful use of IPT strategies and tactics and with careful medication management where appropriate, patients in this study whose treatment focused on each problem area were treated with equal success by trained IPT clinicians.
doi:10.1002/da.20661
PMCID: PMC4228685  PMID: 20099274
mood disorders; treatment outcome; personality disorders; specificity; pharmacotherapy
5.  Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model 
British Journal of Cancer  2013;109(7):1775-1781.
Background:
Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised.
Methods:
The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared.
Results:
Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug.
Conclusion:
Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer.
doi:10.1038/bjc.2013.575
PMCID: PMC3790193  PMID: 24045660
gene methylation; 5-azacytidine; aerosol delivery; lung cancer; epigenome
6.  Dietary Supplementation of Magnesium Sulfate during Late Gestation and Lactation Affects the Milk Composition and Immunoglobulin Levels in Sows 
This experiment was conducted to investigate the effects of dietary supplementation of magnesium sulfate (MgSO4) during late gestation and lactation on sow and litter performance, fecal moisture, blood biochemistry parameters, immunoglobulin levels and milk composition in sows. Forty-eight sows (Yorkshire×Landrace, 4th to 5th parity) were randomly allocated to 1 of 4 dietary treatments supplemented with 0, 200, 400, or 600 mg/kg MgSO4 (n = 12). The experiment started on day 90 of gestation and continued through day 21 of lactation. Blood samples were collected on day 107 of gestation, day 0 (farrowing) and 21 (weaning) of lactation for the analyses of the blood biochemistry parameters and immunoglobulin levels. The colostrum and milk samples were obtained on day 0 and 14 of lactation, respectively. Fecal samples were collected from the sows on day 107 of gestation as well as day 7 and 20 of lactation to determine fecal moisture content. The results showed that the survival percentage of piglets and the litter weight at weaning were decreased linearly (p<0.05) and other parameters of the sow or litter performance were not influenced (p>0.05) by MgSO4 supplementation. The fecal moisture content of the sows were increased (p<0.05) linearly as dietary MgSO4 increased on day 7 and 20 of lactation. Supplementation with MgSO4 increased the plasma magnesium (Mg) level linearly (p<0.05) and had a trend to increase total protein level (p>0.05 and p<0.10). However, an increase in the dietary MgSO4 level resulted in a linear decrease in the colostrum fat content (p<0.05). Dietary MgSO4 supplementation enhanced the immunoglobulin G (IgG) level (linear, p<0.05) in plasma on day of farrowing and immunoglobulin A (IgA) level in colostrum (quadratic, p<0.05) and milk (linear, p<0.05) of the sows. These results indicated that supplementation with MgSO4 during late gestation and lactation may have the potential to prevent sow constipation, but may also result in some negative effects.
doi:10.5713/ajas.2014.14190
PMCID: PMC4150180  PMID: 25178299
Magnesium Sulfate; Sow; Performance; Fecal Moisture; Immunoglobulin; Milk Composition
7.  Haemophilus ducreyi Associated with Skin Ulcers among Children, Solomon Islands 
Emerging Infectious Diseases  2014;20(10):1705-1707.
During a survey of yaws prevalence in the Solomon Islands, we collected samples from skin ulcers of 41 children. Using PCR, we identified Haemophilus ducreyi infection in 13 (32%) children. PCR-positive and PCR-negative ulcers were phenotypically indistinguishable. Emergence of H. ducreyi as a cause of nongenital ulcers may affect the World Health Organization’s yaws eradication program.
doi:10.3201/eid2010.140573
PMCID: PMC4193279  PMID: 25271477
Haemophilus ducreyi; chancre; chancroid; yaws; ulcer; Buruli ulcer; skin; lesion; cutaneous; nongenital; bacterial; ulcerative; pediatric; children; Solomon Islands
8.  Differences between unipolar depression and bipolar II depression in women 
Journal of affective disorders  2013;150(3):1120-1124.
Background
Bipolar disorder II (BPII) and unipolar depression (UD) are both characterized by episodes of major depression (MDE), however DSM-IV criteria for MDE are identical, regardless of diagnosis. As a result, misdiagnosis of BP II and UD is common, leading to inappropriate treatment. Because women are twice as likely as men to experience MDE, differentiating UD from BP II in the context of depression is especially important for women. We examined symptoms and clinical features of MDE in women with UD and BPII to compare presentations of the two disorders in women.
Methods
We compared characteristics of depressed women meeting DSM-IV criteria for BPII (n=48) or UD (n=48), matched on age.
Results
Feelings of worthlessness occurred in 98% of participants with UD versus 85% with BPII (p=0.03). Participants with UD experienced either insomnia or hypersomnia, but participants with BPII were more likely to experience both simultaneously (p=0.04). Those with UD were significantly less likely to have >5 prior mood episodes compared to those with BP II (12% versus 61%; p<0.0001) and had a later age of onset (p= 0.003).
Limitations
Small sample size and exclusion criteria (i.e., comorbid substance abuse) may limit generalizability of findings.
Conclusions
Among a sample of women, number of prior episodes, feelings of worthlessness, age of onset, and sleep patterns distinguished between UD and BP II depressive episodes. A better understanding of differential presentation of BP II versus UD depression in women may help guide clinicians to more accurate diagnoses and, ultimately, better treatment.
doi:10.1016/j.jad.2013.05.003
PMCID: PMC3759529  PMID: 23721924
depression; bipolar disorder type II; women
9.  Flat Focusing Mirror 
Scientific Reports  2014;4:6326.
The control of spatial propagation properties of narrow light beams such as divergence, focusing or imaging are main objectives in optics and photonics. In this letter, we propose and demonstrate experimentally a flat focusing mirror, based on an especially designed dielectric structure without any optical axis. More generally, it also enables imaging any light pattern in reflection. The flat focusing mirror with a transversal invariance can largely increase the applicability of structured photonic materials for light beam propagation control in small-dimension photonic circuits.
doi:10.1038/srep06326
PMCID: PMC4165978  PMID: 25228358
10.  ATP during Early Bladder Stretch Is Important for Urgency in Detrusor Overactivity Patients 
BioMed Research International  2014;2014:204604.
ATP is an important mediator of urgency in women with detrusor overactivity (DO). In order to understand how different degrees of bladder stretch elicited ATP release in DO patients compared with controls, sequential aliquots were collected during cystometry and ATP release was measured at each degree of bladder filling, in female patients with DO and controls. In both DO and control groups, ATP release was induced during bladder filling, suggesting that stretch stimulated further ATP release. However, the luminal ATP concentrations were already high at early filling stage (200 mL), which was even greater than those at the later filling stages (400 mL and maximum cystometric capacity, MCC), indicating that a substantial ATP release has been induced during early filling (200 mL) in both DO and controls. In DO, ATP release at 200 mL was significantly higher in those with low first desire to void (FDV) (≤200 mL) than in those with higher FDV (>200 mL); this may suggest that ATP release at early stretch may play an important role in urgency (early sensation) in DO. ATP concentrations remained unchanged after voiding, suggesting that voiding did not further induce ATP release into intraluminal fluid.
doi:10.1155/2014/204604
PMCID: PMC4058262  PMID: 24971316
11.  Improving Susceptibility Mapping Using a Threshold-Based K-space/Image Domain Iterative Reconstruction Approach 
To improve susceptibility quantification, a threshold-based k-space/image domain iterative approach that uses geometric information from the susceptibility map itself as a constraint to overcome the ill-posed nature of the inverse filter is introduced. Simulations were used to study the accuracy of the method and its robustness in the presence of noise. In vivo data was processed and analyzed using this method. Both simulations and in vivo results show that most streaking artifacts inside the susceptibility map caused by the ill-defined inverse filter were suppressed by the iterative approach. In simulated data, the bias toward lower mean susceptibility values inside vessels has been shown to decrease from around 10% to 2% when choosing an appropriate threshold value for the proposed iterative method. Typically, three iterations are sufficient for this approach to converge and this process takes less than 30 seconds to process a 512 × 512 × 256 dataset. This iterative method improves quantification of susceptibility inside vessels and reduces streaking artifacts throughout the brain for data collected from a single-orientation acquisition. This approach has been applied to vessels alone as well as to vessels and other structures with lower susceptibility to generate whole brain susceptibility maps with significantly reduced streaking artifacts.
doi:10.1002/mrm.24384
PMCID: PMC3482302  PMID: 22736331
oxygen saturation; susceptibility mapping; susceptibility weighted imaging
12.  Large duplication in MTM1 associated with myotubular myopathy 
Neuromuscular disorders : NMD  2012;23(3):214-218.
Myotubular myopathy is a subtype of centronuclear myopathy with X-linked inheritance and distinctive clinical and pathologic features. Most boys with myotubular myopathy have MTM1 mutations. In remaining individuals, it is not clear if disease is due to an undetected alteration in MTM1 or mutation of another gene. We describe a boy with myotubular myopathy but without mutation in MTM1 by conventional sequencing. Array-CGH analysis of MTM1 uncovered a large MTM1 duplication. This finding suggests that at least some unresolved cases of myotubular myopathy are due to duplications in MTM1, and that array-CGH should be considered when MTM1 sequencing is unrevealing.
doi:10.1016/j.nmd.2012.11.010
PMCID: PMC3594803  PMID: 23273872
Myotubular myopathy; Congenital myopathy; MTM1; Gene duplication; Diagnostic testing
13.  Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer 
Cell Death & Disease  2014;5(2):e1047-.
Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, may target mitochondrial proteins for lysine deacetylation and also regulate cellular functions. And, SIRT3 is an emerging instrumental regulator of the mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. Accumulating evidence has recently demonstrated that SIRT3 may function as either oncogene or tumor suppressor on influencing cell death by targeting a series of key modulators and their relevant pathways in cancer. Thus, in this review, we present the structure, transcriptional regulation, and posttranslational modifications of SIRT3. Subsequently, we focus on highlighting the Janus role of SIRT3 with oncogenic or tumor-suppressive function in cancer, which may provide more new clues for exploring SIRT3 as a therapeutic target for drug discovery.
doi:10.1038/cddis.2014.14
PMCID: PMC3944233  PMID: 24503539
sirtuin-3 (SIRT3); mitochondria; oncogene; tumor suppressor; therapeutic target
14.  Some insight on censored cost estimators 
Statistics in medicine  2011;30(19):10.1002/sim.4295.
Censored survival data analysis has been studied for many years. Yet, the analysis of censored mark variables, such as medical cost, quality-adjusted lifetime, and repeated events, faces a unique challenge that makes standard survival analysis techniques invalid. Because of the ‘informative’ censorship imbedded in censored mark variables, the use of the Kaplan–Meier (Journal of the American Statistical Association 1958; 53:457–481) estimator, as an example, will produce biased estimates. Innovative estimators have been developed in the past decade in order to handle this issue. Even though consistent estimators have been proposed, the formulations and interpretations of some estimators are less intuitive to practitioners. On the other hand, more intuitive estimators have been proposed, but their mathematical properties have not been established. In this paper, we prove the analytic identity between some estimators (a statistically motivated estimator and an intuitive estimator) for censored cost data. Efron (1967) made similar investigation for censored survival data (between the Kaplan–Meier estimator and the redistribute-to-the-right algorithm). Therefore, we view our study as an extension of Efron’s work to informatively censored data so that our findings could be applied to other marked variables.
doi:10.1002/sim.4295
PMCID: PMC3880208  PMID: 21748774
inverse-probability weighting; marked process; medical cost; redistribute-to-the-right; replace-from-the-right; survival analysis
15.  Optimizing Melphalan Pharmacokinetics in Regional Melanoma Therapy: Does Correcting for Ideal Body Weight Alter Regional Response or Toxicity? 
Annals of surgical oncology  2009;16(4):10.1245/s10434-008-0288-1.
Background
This study aims to determine what effect correcting melphalan dosing for ideal body weight (IBW) has on toxicity and response in isolated limb infusion (ILI) in patients with advanced extremity melanoma.
Methods
This was an open observational study examining whether correcting the melphalan dose for IBW will influence response and toxicity in patients undergoing ILI for advanced extremity melanoma in 41 patients undergoing 42 procedures (13 without correction for IBW; and 29 with correction for IBW). Melphalan pharmacokinetics, limb toxicity, serologic toxicity, and response at 3 months were compared.
Results
The corrected group had a lower estimated limb volume (Vesti) to melphalan volume at steady state (Vss) (P < .0001) ratio as well as lower incidence of grade ≥3 regional toxicity, serologic toxicity, and compartment syndrome (P = .0249, P = .027, P = .02). There was a positive correlation of Vesti/Vss to toxicity (P = .0127, r = .382). No significant difference in response (P = .3609) between the groups was found, although there was a trend of association between Vesti/Vss and response (P = .051, r = .3383).
Conclusions
Correcting for IBW in ILI lowers toxicity without significantly altering response rates.
doi:10.1245/s10434-008-0288-1
PMCID: PMC3872993  PMID: 19184236
16.  Susceptibility-Weighted Imaging: Technical Aspects and Clinical Applications, Part 1 
SUMMARY
Susceptibility-weighted imaging (SWI) is a new neuroimaging technique, which uses tissue magnetic susceptibility differences to generate a unique contrast, different from that of spin density, T1, T2, and T2*. In this review (the first of 2 parts), we present the technical background for SWI. We discuss the concept of gradient-echo images and how we can measure local changes in susceptibility. Armed with this material, we introduce the steps required to transform the original magnitude and phase images into SWI data. The use of SWI filtered phase as a means to visualize and potentially quantify iron in the brain is presented. Advice for the correct interpretation of SWI data is discussed, and a set of recommended sequence parameters for different field strengths is given.
doi:10.3174/ajnr.A1400
PMCID: PMC3805391  PMID: 19039041
17.  (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD 
Cell Death and Differentiation  2012;19(10):1623-1633.
(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser257, and protein expression of active phospho-MKK4Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNKThr183/Tyr185 and phospho-c-JunSer63, downstream targets of phospho-MKK4Ser257, was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-JunSer63, and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.
doi:10.1038/cdd.2012.42
PMCID: PMC3438494  PMID: 22539006
Parkinson's disease; (G2019S) LRRK2; dopaminergic neurons; MKK4; JNK
18.  Activity and Mechanism of Action of HDVD, a Novel Pyrimidine Nucleoside Derivative with High Levels of Selectivity and Potency against Gammaherpesviruses 
Journal of Virology  2013;87(7):3839-3851.
A novel nucleoside analogue, 1-[(2S,4S-2-(hydroxymethyl)-1,3-dioxolan-4-yl]5-vinylpyrimidine-2,4(1H,3H)-dione, or HDVD, was evaluated against a wide variety of herpesviruses and was found to be a highly selective inhibitor of replication of the gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). HDVD had also a pronounced inhibitory activity against murine herpesvirus 68 (MHV-68) and herpes simplex virus 1 (HSV-1). In contrast, replication of herpesvirus saimiri (HVS), HSV-2, and varicella-zoster virus (VZV) was weakly inhibited by the compound, and no antiviral activity was determined against human cytomegalovirus (HCMV) and rhesus rhadinovirus (RRV). The HDVD-resistant virus phenotype contained point mutations in the viral thymidine kinase (TK) of HSV-1, MHV-68, and HVS isolates. These mutations conferred cross-resistance to other TK-dependent drugs, with the exception of an MHV-68 mutant (E358D) that exhibited resistance only to HDVD. HSV-1 and HVS TK-mutants isolated under selective pressure with bromovinyldeoxyuridine (BVDU) also showed reduced sensitivity to HDVD. Oral treatment with HDVD and BVDU was assessed in an intranasal model of MHV-68 infection in BALB/c mice. In contrast to BVDU treatment, HDVD-treated animals showed a reduction in viral DNA loads and diminished viral gene expression during acute viral replication in the lungs in comparison to levels in untreated controls. The valyl ester prodrug of HDVD (USS-02-71-44) suppressed the latent infection in the spleen to a greater extent than HDVD. In the present study, HDVD emerged as a highly potent antiviral with a unique spectrum of activity against herpesviruses, in particular, gammaherpesviruses, and may be of interest in the treatment of virus-associated diseases.
doi:10.1128/JVI.03338-12
PMCID: PMC3624198  PMID: 23345517
19.  Survival or death: disequilibrating the oncogenic and tumor suppressive autophagy in cancer 
Cell Death & Disease  2013;4(10):e892-.
Autophagy (macroautophagy) is an evolutionarily conserved lysosomal degradation process, in which a cell degrades long-lived proteins and damaged organelles. Recently, accumulating evidence has revealed the core molecular machinery of autophagy in carcinogenesis; however, the intricate relationship between autophagy and cancer continue to remain an enigma. Why does autophagy have either pro-survival (oncogenic) or pro-death (tumor suppressive) role at different cancer stages, including cancer stem cell, initiation and progression, invasion and metastasis, as well as dormancy? How does autophagy modulate a series of oncogenic and/or tumor suppressive pathways, implicated in microRNA (miRNA) involvement? Whether would targeting the oncogenic and tumor suppressive autophagic network be a novel strategy for drug discovery? To address these problems, we focus on summarizing the dynamic oncogenic and tumor suppressive roles of autophagy and their relevant small-molecule drugs, which would provide a new clue to elucidate the oncosuppressive (survival or death) autophagic network as a potential therapeutic target.
doi:10.1038/cddis.2013.422
PMCID: PMC3920945  PMID: 24176850
autophagy; cancer; oncogene; tumor suppressor; microRNA
20.  EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway 
Oncogene  2011;31(36):4054-4066.
Sustaining a high growth rate requires tumors to exploit resources in their microenvironment. One example of this is the extensive angiogenesis that is a typical feature of high-grade gliomas. Here, we show that expression of the constitutively active mutant epidermal growth factor receptor, ΔEGFR (EGFRvIII, EGFR*, de2-7EGFR) is associated with significantly higher expression levels of the pro-angiogenic factor interleukin (IL)-8 in human glioma specimens and glioma stem cells. Furthermore, the ectopic expression of ΔEGFR in different glioma cell lines caused up to 60-fold increases in the secretion of IL-8. Xenografts of these cells exhibit increased neovascularization, which is not elicited by cells overexpressing wildtype (wt)EGFR or ΔEGFR with an additional kinase domain mutation. Analysis of the regulation of IL-8 by site-directed mutagenesis of its promoter showed that ΔEGFR regulates its expression through the transcription factors nuclear factor (NF)-κB, activator protein 1 (AP-1) and CCAAT/enhancer binding protein (C/EBP). Glioma cells overexpressing ΔEGFR showed constitutive activation and DNA binding of NF-κB, overexpression of c-Jun and activation of its upstream kinase c-Jun N-terminal kinase (JNK) and overexpression of C/EBPβ. Selective pharmacological or genetic targeting of the NF-κB or AP-1 pathways efficiently blocked promoter activity and secretion of IL-8. Moreover, RNA interference-mediated knock-down of either IL-8 or the NF-κB subunit p65, in ΔEGFR-expressing cells attenuated their ability to form tumors and to induce angiogenesis when injected subcutaneously into nude mice. On the contrary, the overexpression of IL-8 in glioma cells lacking ΔEGFR potently enhanced their tumorigenicity and produced highly vascularized tumors, suggesting the importance of this cytokine and its transcription regulators in promoting glioma angiogenesis and tumor growth.
doi:10.1038/onc.2011.563
PMCID: PMC3537826  PMID: 22139077
glioblastoma; EGFR; ΔEGFR; angiogenesis; NF-κB; IL-8
21.  Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke 
Cell Death & Disease  2013;4(9):e790-.
Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen–glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1β and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1β and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.
doi:10.1038/cddis.2013.326
PMCID: PMC3789184  PMID: 24008734
IVIg; ischemic stroke; inflammasome; cell death; caspase
22.  Optical pacing of the adult rabbit heart 
Biomedical Optics Express  2013;4(9):1626-1635.
Optical pacing has been demonstrated to be a viable alternative to electrical pacing in embryonic hearts. In this study, the feasibility of optically pacing an adult rabbit heart was explored. Hearts from adult New Zealand White rabbits (n = 9) were excised, cannulated and perfused on a modified Langendorff apparatus. Pulsed laser light (λ = 1851 nm) was directed to either the left or right atrium through a multimode optical fiber. An ECG signal from the left ventricle and a trigger pulse from the laser were recorded simultaneously to determine when capture was achieved. Successful optical pacing was demonstrated by obtaining pacing capture, stopping, then recapturing as well as by varying the pacing frequency. Stimulation thresholds measured at various pulse durations suggested that longer pulses (8 ms) had a lower energy capture threshold. To determine whether optical pacing caused damage, two hearts were perfused with 30 µM of propidium iodide and analyzed histologically. A small number of cells near the stimulation site had compromised cell membranes, which probably limited the time duration over which pacing was maintained. Here, short-term optical pacing (few minutes duration) is demonstrated in the adult rabbit heart for the first time. Future studies will be directed to optimize optical pacing parameters to decrease stimulation thresholds and may enable longer-term pacing.
doi:10.1364/BOE.4.001626
PMCID: PMC3771833  PMID: 24049683
(140.3460) Lasers; (170.3890) Medical optics instrumentation
23.  Preoperative Lifestyle Intervention in Bariatric Surgery: Initial Results from a Randomized, Controlled Trial 
Obesity (Silver Spring, Md.)  2013;21(2):254-260.
In this initial report, we document preoperative outcomes of a behavioral lifestyle intervention delivered to patients prior to bariatric surgery. Participants (N = 240) were 86.7% female, 82.9% white, 52.3% married, and 85.8% had ≥ high school education. Mean BMI was 47.9 ± 6.7 kg/m2 and age was 45.2 ± 11 years. After completing a baseline assessment, patients were randomized to a 6-month, evidence-informed, manualized lifestyle intervention (LIFESTYLE, n = 121) or to preoperative care as usual (USUAL CARE, n = 119). At 6 months, 187 participants remained candidates for bariatric surgery and were included in the analyses. Results indicated that LIFESTYLE participants lost significantly more weight than those receiving USUAL CARE [8.3 ± 7.8 kg vs. 3.3 ± 5.5 kg, F(1,182) = 23.6, p < 0.0001], with an effect size of 0.72. LIFESTYLE patients were more likely to lose at least 5% of initial body weight than those in USUAL CARE (OR = 4.98, p < 0.0001), as were participants who were older (OR = 1.04, p = 0.01 for every year increase in age) or heavier (OR = 1.06, p = 0.02 for each unit increase in BMI). A behavioral lifestyle intervention for severely overweight individuals leads to clinically significant weight loss prior to bariatric surgery. Post-surgery follow-up will allow us to examine the impact of the preoperative intervention on postoperative outcomes.
doi:10.1002/oby.20069
PMCID: PMC3610845  PMID: 23404832
24.  Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma 
Oncogene  2011;31(16):2007-2016.
Thyroid cancers are the most common malignancy of the endocrine system in humans. To understand the molecular genetic events underlying thyroid carcinogenesis, we have generated a mouse model that spontaneously develops follicular thyroid carcinoma similar to human thyroid cancer (ThrbPV/PV mouse). This mutant mouse harbors a dominantnegative mutated thyroid hormone receptor β (denoted PV). The PV mutation was identified in a patient with resistance to thyroid hormone (TH). ThrbPV/PV mice exhibit highly elevated serum thyroid-stimulating hormone levels and increased TH. We have previously shown that thyroidstimulating hormone is required, but not sufficient to induce metastatic follicular thyroid cancer in ThrbPV/PV mice. However, whether the elevated TH also contributes to the thyroid carcinogenesis of ThrbPV/PV mice was not elucidated. To understand the role of TH in thyroid carcinogenesis, we blocked the production of TH by treating ThrbPV/PV mice with propylthiouracil (ThrbPV/PV-PTU mice) and compared the development of thyroid cancer in ThrbPV/PV-PTU and untreated ThrbPV/PV mice. We found that thyroid tumor growth was reduced by ~42% in ThrbPV/PV-PTU mice as compared with ThrbPV/PV mice. Analysis by bromodeoxyuridine- nuclear labeling showed decreased incorporation of bromodeoxyuridine in thyroid tumor cells of ThrbPV/PV-PTU mice, indicative of decreased tumor cell proliferation. However, cleaved-caspase 3 staining showed no apparent changes in apoptosis of tumor cells in ThrbPV/PV-PTU mice. Molecular studies identified a marked attenuation of the PI3K–AKT–β-catenin signaling pathway that led to decreased protein levels of cyclin D2, thereby decreasing tumor cell proliferation in ThrbPV/PV-PTU mice. Furthermore, matrix metalloproteinase-2, a downstream target of β-catenin and a key regulator during tumor invasion and metastasis, was also decreased. Thus, the present study uncovers a critical role of TH in promoting the thyroid carcinogenesis of ThrbPV/PV mice via membrane signaling events. Importantly, these findings suggest that anti-thyroid drugs could be considered as possible therapeutic agents of thyroid cancer.
doi:10.1038/onc.2011.390
PMCID: PMC3728834  PMID: 21909131
thyroid hormone; follicular thyroid carcinoma; animal model; protein kinase B/AKT; PTEN
25.  Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress 
Cell Death & Disease  2013;4(7):e731-.
Sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, targets various mitochondrial proteins for lysine deacetylation and regulates important cellular functions such as energy metabolism, aging, and stress response. In this study, we identified the human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine (8-oxoG) from damaged genome, as a new target protein for Sirt3. We found that Sirt3 physically associated with OGG1 and deacetylated this DNA glycosylase and that deacetylation by Sirt3 prevented the degradation of the OGG1 protein and controlled its incision activity. We further showed that regulation of the acetylation and turnover of OGG1 by Sirt3 played a critical role in repairing mitochondrial DNA (mtDNA) damage, protecting mitochondrial integrity, and preventing apoptotic cell death under oxidative stress. We observed that following ionizing radiation, human tumor cells with silencing of Sirt3 expression exhibited deteriorated oxidative damage of mtDNA, as measured by the accumulation of 8-oxoG and 4977 common deletion, and showed more severe mitochondrial dysfunction and underwent greater apoptosis in comparison with the cells without silencing of Sirt3 expression. The results reported here not only reveal a new function and mechanism for Sirt3 in defending the mitochondrial genome against oxidative damage and protecting from the genotoxic stress-induced apoptotic cell death but also provide evidence supporting a new mtDNA repair pathway.
doi:10.1038/cddis.2013.254
PMCID: PMC3730425  PMID: 23868064
Sirt3; OGG1; mitochondria; DNA repair; apoptosis

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