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2.  Moderating effects of childhood maltreatment on associations between social information processing and adult aggression 
Psychological medicine  2011;42(6):1293-1304.
Associations between early life maltreatment, social information processing (SIP) and aggression in childhood and adolescence have been widely documented. Few studies have examined the importance of childhood maltreatment independent of SIP in the etiology of adult aggression. Furthermore, moderating effects of childhood maltreatment on the SIP–aggression links have not been explored.
Hierarchical, multi-level models were fitted to data from n=2752 twins aged 20–55 years from the PennTwins Cohort. Adult aggression was assessed with the Life History of Aggression questionnaire. Childhood maltreatment was measured using the Childhood Trauma Questionnaire. Two aspects of SIP were examined : hostile attribution biases (HAB) ; negative emotional responses (NER).
Childhood maltreatment was positively correlated with adult aggression, independently of HAB and NER. In addition, childhood maltreatment moderated the relationships between both aspects of SIP and adult aggression. Specifically, the relationship between NER and aggression was stronger among individuals with higher levels of childhood maltreatment and NER was not associated with aggression for adults who experienced low levels of childhood maltreatment. Moderating effects of childhood maltreatment on the NER–aggression link were supported for total childhood maltreatment, emotional neglect and emotional abuse. In contrast, HAB was more strongly associated with adult aggression at lower levels of emotional abuse and physical neglect.
The current study provides insight into the mechanisms by which early life experiences influence adult aggression. Our findings suggest that childhood maltreatment may not only lead to increased levels of aggression in adulthood but may also modify the associations between SIP and adult aggression.
PMCID: PMC4255557  PMID: 22008562
Adult aggression; childhood maltreatment; hostile attribution biases; moderation; negative emotional responses
3.  Multiplanar 3D ultrasound imaging to assess the anatomy of the upper airway and measure the subglottic and tracheal diameters in adults 
The British Journal of Radiology  2013;86(1030):20130253.
To evaluate the feasibility of using three-dimensional (3D) ultrasound to assess the anatomy of the airway.
11 young volunteers were recruited for 3D ultrasound and MRI of the airway. 3D ultrasound data were obtained from the level of the true vocal cords, cricoid cartilage and upper trachea. Multiplanar 3D ultrasound images were rendered and compared visually with corresponding MRI and cadaver anatomical sections. The anteroposterior (AP) and transverse diameter of the subglottic space and transverse diameter of the upper trachea were also measured in the 3D ultrasound and MR images and compared.
The airway anatomy was clearly delineated in the multiplanar 3D ultrasound images. It was also possible to identify the cricothyroid junction, and a simple method to measure the AP diameter of the subglottic space using this landmark is described. We were also able to accurately measure the transverse diameter of the upper trachea, but the transverse diameter of the subglottic space was overestimated using ultrasound. There was a strong correlation for the AP diameter measurement (r=0.94, p<0.05) and moderate correlation for the transverse diameter measurement (r=0.82, p=0.002) of the subglottic space, and a strong correlation for the transverse diameter measurement (r=0.91, p<0.05) of the upper trachea, in the ultrasound and MR images.
The anatomy of the adult airway can be assessed using 3D ultrasound. It can also be used to accurately measure the AP diameter of the subglottic space and the transverse diameter of the upper trachea.
Advances in knowledge:
This is the first report to describe the use of 3D ultrasound to evaluate the anatomy of the upper airway and accurately measure the AP diameter of the subglottic space and the transverse diameter of the upper trachea.
PMCID: PMC3798330  PMID: 23966375
4.  Antennapedia is involved in the development of thoracic legs and segmentation in the silkworm, Bombyx mori 
Heredity  2013;111(3):182-188.
Homeotic genes, which are associated closely with body patterning of various species, specify segment identity. The Wedge eye-spot (Wes) is a new homeotic mutant located on the sixth linkage group. Homozygous Wes/Wes embryos are lethal and display a pair of antenna-like appendages under the mouthparts as well as fused thoracic segments. These mutants also exhibit a narrower eye-spot at the larval stage compared with the wild type. By positional cloning, we identified the candidate gene of the Wes locus, Bombyx mori Antennapedia (BmAntp). Two BmAntp transcripts were identified in the homozygote of the Wes mutant, including a normal form and an abnormal form with a 1570-bp insertion. Our data showed that the insertion element was a long interspersed nuclear element (LINE)-like transposon that destroyed the original open reading frame of BmAntp. Quantitative RT-PCR analysis showed that the expression levels of normal BmAntp transcripts were increased markedly in the Wes heterozygous larvae compared with the wild type. Furthermore, we performed RNAi of BmAntp and observed fused thoracic segments and defective thoracic legs in the developing embryos. Our results indicated that BmAntp is responsible for the Wes mutant and has an important role in determining the proper development of the thoracic segments. Our identification of a homeotic mutation in the silkworm is an important contribution to our understanding of the regulation of Hox genes at different levels of expression.
PMCID: PMC3746817  PMID: 23652563
Antennapedia; thoracic segment; transposable elements; Bombyx mori
5.  Synergistic interaction of benign prostatic hyperplasia and prostatitis on prostate cancer risk 
British Journal of Cancer  2013;108(9):1778-1783.
The incidence of prostate cancer is much lower in Asian men than in Western men. This study investigated whether prostate cancer is associated with prostatitis, benign prostatic hyperplasia (BPH), and other medical conditions in the low-incidence population.
From the claims data obtained from the universal National Health Insurance of Taiwan, we identified 1184 patients with prostate cancer diagnosed from 1997 to 2008. Controls comprised 4736 men randomly selected from a cancer-free population. Both groups were 50 years of age or above. Medical histories between the two groups were compared.
Multivariate logistic regression analysis showed that prostatitis and BPH had stronger association with prostate cancer than the other medical conditions tested. Compared with men without prostatitis and BPH, a higher odds ratio (OR) for prostate cancer was associated with BPH (26.2, 95% confidence interval (CI) 20.8–33.0) than with prostatitis (10.5, 95% CI=3.36–32.7). Men with both conditions had an OR of 49.2 (95% CI=34.7–69.9).
Men with prostate cancer have strong association with prostatitis and/or BPH. Prostatitis interacts with BPH, resulting in higher estimated relative risk of prostate cancer in men suffering from both conditions.
PMCID: PMC3658521  PMID: 23612451
benign prostatic hyperplasia; prostatitis; diabetes; interaction; prostate cancer
6.  Platonic Scattering Cancellation for Bending Waves in a Thin Plate 
Scientific Reports  2014;4:4644.
We propose an ultra-thin elastic cloak to control the scattering of bending waves in isotropic heterogeneous thin plates. The cloak design makes use of the scattering cancellation technique applied, for the first time, to the biharmonic operator describing the propagation of bending waves in thin plates. We first analyze scattering from hard and soft cylindrical objects in the quasistatic limit, then we prove that the scattering of bending waves from an object in the near and far-field regions can be suppressed significantly by covering it with a suitably designed coating. Beyond camouflaging, these findings may have potential applications in protection of buildings from earthquakes and isolating structures from vibrations in the motor vehicle industry.
PMCID: PMC4027886  PMID: 24844801
7.  Suppression of tumor angiogenesis by targeting the protein neddylation pathway 
Cell Death & Disease  2014;5(2):e1059-.
Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin–RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.
PMCID: PMC3944239  PMID: 24525735
neddylation; MLN4924; tumor angiogenesis; cullin–RING ligase
8.  Self/Co-Assembling Peptide, EAR8-II, as a Potential Carrier for a Hydrophobic Anticancer Drug Pirarubicin (THP)—Characterization and in-Vitro Delivery 
A short ionic-complementary peptide, EAR8-II, was employed to encapsulate the hydrophobic anticancer drug pirarubicin (THP). EAR8-II was designed to inherit advantages from two previously introduced peptides, AAP8 and EAK16-II, in their self/co-assembly. This peptide is short, simple, and inexpensive to synthesize, while possessing a low critical assembly concentration (CAC). The choice of alanine (A) residues in the peptide sequence provides moderate hydrophobic interactions, causing a minimal degree of aggregation, compared with other more hydrophobic residues. EAR8-II is an ionic-complementary peptide, similar to EAK16-II, can self/co-assemble with hydrophobic compounds such as THP, and forms a stable fibular nanostructure in aqueous solution. Physiochemical properties and cellular activities of the EAR8-II and THP complexes were evaluated and show dependency on the peptide-to-drug ratio. The complex at the peptide-to-drug mass ratio of 5:1 provides a stable solution, uniform nanostructure, and highly effective anticancer activity against various cancer cell lines. This work forms the basis for detailed studies on EAR8-II and THP formulations in vitro and in vivo, for future development of peptide-based delivery systems for hydrophobic anticancer drugs.
PMCID: PMC3876047  PMID: 24287908
ionic-complementary; self/co-assembly; encapsulation; stability; anticancer activity
9.  Effectors of alcohol-induced cell killing in Drosophila 
Cell Death and Differentiation  2012;19(10):1655-1663.
Heavy alcohol consumption provokes an array of degenerative pathologies but the signals that couple alcohol exposure to regulated forms of cell death are poorly understood. Using Drosophila as a model, we genetically establish that the severity of ethanol challenge dictates the type of death that occurs. In contrast to responses seen under acute exposure, cytotoxic responses to milder challenges required gene encoding components of the apoptosome, Dronc and Dark. We conducted a genome-wide RNAi screen to capture targets that specifically mediate ethanol-induced cell death. One effector, Drat, encodes a novel protein that contains an ADH domain but lacks essential residues in the catalytic site. In cultured cells and neurons in vivo, depletion of Drat conferred protection from alcohol-induced apoptosis. Adults mutated for Drat showed both improved survival and enhanced propensities toward sedation after alcohol challenge. Together, these findings highlight novel effectors that support regulated cell death incited by alcohol stress in vitro and in vivo.
PMCID: PMC3438496  PMID: 22539005
alcohol; apoptosis; Drosophila
10.  Numerical Modeling of Interstitial Fluid Flow Coupled with Blood Flow through a Remodeled Solid Tumor Microvascular Network 
PLoS ONE  2013;8(6):e67025.
Modeling of interstitial fluid flow involves processes such as fluid diffusion, convective transport in extracellular matrix, and extravasation from blood vessels. To date, majority of microvascular flow modeling has been done at different levels and scales mostly on simple tumor shapes with their capillaries. However, with our proposed numerical model, more complex and realistic tumor shapes and capillary networks can be studied. Both blood flow through a capillary network, which is induced by a solid tumor, and fluid flow in tumor’s surrounding tissue are formulated. First, governing equations of angiogenesis are implemented to specify the different domains for the network and interstitium. Then, governing equations for flow modeling are introduced for different domains. The conservation laws for mass and momentum (including continuity equation, Darcy’s law for tissue, and simplified Navier–Stokes equation for blood flow through capillaries) are used for simulating interstitial and intravascular flows and Starling’s law is used for closing this system of equations and coupling the intravascular and extravascular flows. This is the first study of flow modeling in solid tumors to naturalistically couple intravascular and extravascular flow through a network. This network is generated by sprouting angiogenesis and consisting of one parent vessel connected to the network while taking into account the non-continuous behavior of blood, adaptability of capillary diameter to hemodynamics and metabolic stimuli, non-Newtonian blood flow, and phase separation of blood flow in capillary bifurcation. The incorporation of the outlined components beyond the previous models provides a more realistic prediction of interstitial fluid flow pattern in solid tumors and surrounding tissues. Results predict higher interstitial pressure, almost two times, for realistic model compared to the simplified model.
PMCID: PMC3694139  PMID: 23840579
11.  Response to ‘Alternative diagnoses with ectopia lentis' 
Eye  2011;26(3):481-482.
PMCID: PMC3298994
13.  Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells 
Cell Death & Disease  2013;4(2):e485-.
We investigated the molecular mechanisms underlying the effect of sorafenib and SC-59, a novel sorafenib derivative, on hepatocellular carcinoma (HCC). Sorafenib activated autophagy in a dose- and time-dependent manner in the HCC cell lines PLC5, Sk-Hep1, HepG2 and Hep3B. Sorafenib downregulated phospho-STAT3 (P-STAT3) and subsequently reduced the expression of myeloid cell leukemia-1 (Mcl-1). Inhibition of Mcl-1 by sorafenib resulted in disruption of the Beclin 1-Mcl-1 complex; however, sorafenib did not affect the amount of Beclin 1, suggesting that sorafenib treatment released Beclin 1 from binding with Mcl-1. Silencing of SHP-1 by small interference RNA (siRNA) reduced the effect of sorafenib on P-STAT3 and autophagy. Ectopic expression of Mcl-1 abolished the effect of sorafenib on autophagy. Knockdown of Beclin 1 by siRNA protected the cells from sorafenib-induced autophagy. Moreover, SC-59, a sorafenib derivative, had a more potent effect on cancer cell viability than sorafenib. SC-59 downregulated P-STAT3 and induced autophagy in all tested HCC cell lines. Furthermore, our in vivo data showed that both sorafenib and SC-59 inhibited tumor growth, downregulated P-STAT3, enhanced the activity of SHP-1 and induced autophagy in PLC5 tumors, suggesting that sorafenib and SC-59 activate autophagy in HCC. In conclusion, sorafenib and SC-59 induce autophagy in HCC through a SHP-1-STAT3-Mcl-1-Beclin 1 pathway.
PMCID: PMC3734819  PMID: 23392173
SC-59; sorafenib; STAT3; HCC
14.  Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model 
Rheumatology (Oxford, England)  2005;44(10):1238-1244.
Oxidative stress contributes to atherosclerosis, and evidence of enhanced oxidative stress exists in antiphospholipid syndrome (APS). In a non-lupus murine model, we evaluated whether anticardiolipin (aCL) antibodies could affect the oxidant/antioxidant balance as an early biochemical step of APS.
Hybridomas producing human and murine aCL and anti-β2-glycoprotein I (aβ2-GPI) monoclonal antibodies were injected into three groups of five female BALB/c severe combined immunodeficiency (SCID) mice. Corresponding hybridomas secreting non-antiphospholipid antibodies of the same isotype were employed as controls. Sera and organs were collected after 30 days. Paraoxonase (PON) activity, peroxynitrite, superoxide, nitric oxide (NO) and nitrotyrosine were measured in plasma. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) was assessed by western blot and immunohistochemistry.
PON activity and NO (sum of nitrate and nitrite) levels were reduced in the human aCL IgG group (P<0.002 and P<0.04, respectively), whilst peroxynitrite and superoxide and expression of total antioxidant capacity of plasma were increased (P<0.01). PON and NO were decreased in the murine aβ2-GPI IgG and IgM aCL groups (P<0.03 and P<0.05, respectively). Nitrotyrosine was elevated in the human aCL IgG group (P<0.03). Western blotting showed reduced iNOS expression in the hearts of the IgG aCL group, confirmed by immunostaining. PON inversely correlated with IgG aCL titres (P<0.001), superoxide (P<0.008) and peroxynitrite levels (P<0.0009). Peroxynitrite and total IgG aCL were independent predictors of PON (P<0.0009 and P<0.02, respectively). Superoxide was the only independent predictor of NO (P<0.008) and of nitrotyrosine (P<0.002).
aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.
PMCID: PMC3465365  PMID: 15987712 CAMSID: cams2349
Antiphospholipid antibodies; Oxidative stress; Nitric oxide; Total antioxidant capacity; Paraoxonase
15.  How to predict the outcome in mature T and NK cell lymphoma by currently used prognostic models? 
Blood Cancer Journal  2012;2(10):e93-.
To select an appropriate prognostic model in the treatment of mature T- and natural killer (NK) -cell lymphoma (peripheral T-cell lymphoma (PTCL) and NK-/T-cell lymphoma (NKTCL)) is crucial. This study investigated the usefulness of Ann Arbor staging classification International prognostic index (IPI), prognostic index for T-cell lymphoma (PIT) and International peripheral T-cell lymphoma Project score (IPTCLP). Between 2000 and 2009, 176 patients (122 males) with PTCL and NKTCL were diagnosed and treated from a single institute in Taiwan. The correlation between complete response (CR) rate, 3-year overall survival (OS), early mortality rate and four prognostic models was analyzed. Thirty-one patients received hematopoietic stem cell transplantation (HSCT) and were analyzed separately. Three-year OS rate was 34.7%, and anaplastic large-cell lymphoma harbored better outcome than others. IPI score had the lowest Akaike information criterion value (1081.197) and was the best score in predicting OS and early mortality (P=0.009). Ann Arbor stage classification can predict CR rate more precisely (P=0.006). OS was significantly better in patients who received HSCT, even in patients with unfavorable features compared with chemotherapy alone. All prognostic models were useful to evaluate the outcome of patients with PTCL and NKTCL but IPI score did best in predicting OS in PTCL and PIT score in NKTCL. This study also supported the role of HSCT in patients with high-risk or refractory PTCL or NKTCL.
PMCID: PMC3483618  PMID: 23064741
T-cell lymphoma; prognostic score; hematopoietic stem cell transplantation; Asian population
16.  Angle closure glaucoma associated with ectopia lentis in a patient with Sturge-Weber syndrome 
Eye  2011;25(9):1235-1236.
PMCID: PMC3178240  PMID: 21546921
17.  Pharmacokinetics of Peptide Mediated Delivery of Anticancer Drug Ellipticine 
PLoS ONE  2012;7(8):e43684.
The amino acid pairing peptide EAK16-II (EAK) has shown the ability to stabilize the hydrophobic anticancer agent ellipticine (EPT) in aqueous solution. In this study, we investigate pharmacokinetics of the formulation of EAK-EPT complexes in vivo. The developed formulation can achieve a sufficiently high drug concentration required in vivo animal models. The nanostructure and surface properties of EAK-EPT complexes or nanoparticle were characterized by transmission electron microscopy (TEM) and zeta potential measurements, respectively. 12 healthy male SD rats were divided into EPT group and EAK-EPT group randomly. Rats in EPT group were tail intravenously injected with the EPT (20 mg/kg); rats in EAK-EPT group were injected with EAK-EPT complexes (EPT's concentration is 20 mg/kg). EPT was extracted from rat plasma with dexamethasone sodium phosphate as internal standards (IS). The pharmacokinetic parameters were obtained using high pressure liquid chromatography (HPLC). Significant differences in main pharmacokinetic parameters between EPT and EAK-EPT complexes were observed, demonstrating that the complexation with EAK prolongs the residence time of the drug and enlarges the area under the concentration-time curve (AUC). This means that EAK can serve as a suitable carrier to increase the bioavailability of EPT.
PMCID: PMC3432029  PMID: 22952737
18.  Self-assembling peptide-based nanoparticles enhance anticancer effect of ellipticine in vitro and in vivo 
Background and methods
Applications of the anticancer agent, ellipticine, have been limited by its hydrophobicity and toxicity. An efficient delivery system is required to exploit the enormous potential of this compound. Recently, EAK16-II, an ionic-complementary, self-assembling peptide, has been found to stabilize ellipticine in aqueous solution. Here, the anticancer activity of ellipticine encapsulated in EAK16-II (EAK-EPT) was evaluated in vitro and in vivo.
Our cellular uptake, toxicity, and apoptosis results in an A549 human lung carcinoma cell line indicate that EAK-EPT complexes are significantly more effective than treatment with EAK16-II or ellipticine alone. This is due to the ability of EAK16-II to stabilize ellipticine in a protonated state in well formed nanostructures approximately 200 nm in size. In vivo observations in an A549 nude mouse tumor model show higher antitumor activity and lower cytotoxicity of EAK-EPT complexes than in the control group treated with ellipticine alone. Tumor growth in animals was significantly inhibited after treatment with EAK-EPT complexes, and without any apparent side effects.
The anticancer activity observed in this study coupled with minimal side effects encourages further development of peptide-mediated delivery of anticancer drugs, ellipticine in the present case, for clinical application.
PMCID: PMC3396387  PMID: 22802684
self-assembling peptide; EAK16-II; ellipticine; nanoparticles; drug delivery; antitumor
19.  Focused ion beam induced deflections of freestanding thin films 
Journal of applied physics  2006;100(10):104322-104330.
Prominent deflections are shown to occur in freestanding silicon nitride thin membranes when exposed to a 50 keV gallium focused ion beam for ion doses between 1014 and 1017 ions/cm2. Atomic force microscope topographs were used to quantify elevations on the irradiated side and corresponding depressions of comparable magnitude on the back side, thus indicating that what at first appeared to be protrusions are actually the result of membrane deflections. The shape in high-stress silicon nitride is remarkably flattopped and differs from that in low-stress silicon nitride. Ion beam induced biaxial compressive stress generation, which is a known deformation mechanism for other amorphous materials at higher ion energies, is hypothesized to be the origin of the deflection. A continuum mechanical model based on this assumption convincingly reproduces the profiles for both low-stress and high-stress membranes and provides a family of unusual shapes that can be created by deflection of freestanding thin films under beam irradiation.
PMCID: PMC3319714  PMID: 22485053
20.  Modeling Eye Gaze Patterns in Clinician-Patient Interaction with Lag Sequential Analysis 
Human factors  2011;53(5):502-516.
The aim of this study was to examine whether lag-sequential analysis could be used to describe eye gaze orientation between clinicians and patients in the medical encounter. This topic is particularly important as new technologies are implemented into multi-user health care settings where trust is critical and nonverbal cues are integral to achieving trust. This analysis method could lead to design guidelines for technologies and more effective assessments of interventions.
Nonverbal communication patterns are important aspects of clinician-patient interactions and may impact patient outcomes.
Eye gaze behaviors of clinicians and patients in 110-videotaped medical encounters were analyzed using the lag-sequential method to identify significant behavior sequences. Lag-sequential analysis included both event-based lag and time-based lag.
Results from event-based lag analysis showed that the patients’ gaze followed that of clinicians, while clinicians did not follow patients. Time-based sequential analysis showed that responses from the patient usually occurred within two seconds after the initial behavior of the clinician.
Our data suggest that the clinician’s gaze significantly affects the medical encounter but not the converse.
Findings from this research have implications for the design of clinical work systems and modeling interactions. Similar research methods could be used to identify different behavior patterns in clinical settings (physical layout, technology, etc.) to facilitate and evaluate clinical work system designs.
PMCID: PMC3211102  PMID: 22046723
Nonverbal communication; medical encounter; health care system
21.  A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients 
British Journal of Cancer  2010;103(7):954-960.
Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients.
Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m−2. The primary end point was disease-control rate (DCR).
Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5–43.1) and 7.3 (95% CI: 4.7–9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1–17.9) and 5.8 (95% CI: 1.4–10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1–2 local and/or allergic reactions.
ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.
PMCID: PMC2965867  PMID: 20808309
arginine; arginine deiminase; hepatocellular carcinoma; polyethylene glycol; argininosuccinate synthetase
22.  International medical graduates in the USA: a qualitative study on perceptions of physician migration 
BMJ Open  2011;1(2):e000138.
Physician migration from low-income to high-income nations is a global concern. Despite the centrality of understanding the perspectives of international medical graduates (IMGs) who have experienced migration to understanding the causes and consequences of this phenomenon, empirical literature is limited. The authors sought to characterise the experiences of IMGs from limited resource nations currently practicing primary care in the USA, with a focus on their perspectives on physician migration.
The authors conducted a qualitative study utilising in-depth, in-person interviews and a standardised interview guide. The sample comprised a diverse, purposeful sample of IMGs (n=25) from limited resource nations (defined as having ≤2 physicians per 1000 population).
Analyses revealed four recurrent and unifying themes reflecting the perspectives of IMGs in the USA on physician migration: (1) decisions to migrate were pragmatic decisions made in the context of individual circumstance; (2) the act of migration ultimately affected participants' ability to return home in multiple, unpredictable ways; (3) the ongoing process of acclimation was coupled with inherent conflicts surrounding the decision to remain in the USA; and (4) the effects of policies in both the home country and in the USA occurred at multiple levels.
The perspectives of IMGs who have migrated to the USA are an important addition to the ongoing discussion surrounding the global health workforce. Our findings highlight the effects of workforce policies which are often developed and discussed in abstraction, but have real, measurable impacts on the lives of individuals. Future efforts to address physician migration will need to acknowledge the immediate needs of the health workforce as well as the long-term needs of individuals within health systems.
Article summary
Article focus
International medical graduates (IMGs) play a significant role in the health workforce in many nations.
Prior literature has largely limited the consideration of physician migration to isolated factors such as financial pressures in the home country or expanded training opportunities in the USA.
The experiences and perspectives of IMGs have not been included in current discussions surrounding physician migration.
Key messages
Physician migration is influenced by multi-faceted aspects of experience including individual, environmental and political factors.
IMGs report that both local and global health workforce policies have an impact on their personal and professional lives.
A comprehensive understanding of physician migration is essential to the development of effective and appropriate solutions for global health workforce challenges.
Strengths and limitations of this study
Participants were diverse with regard to age, specialty, geographical regions of origin and years of clinical experience in the USA.
The study utilised recommended strategies to ensure rigour.
The high participation rate suggests this is an issue IMGs are motivated to discuss despite the potentially personal and sensitive nature of the topic.
As a qualitative study, the hypotheses generated should be tested with larger, quantitative studies.
The study was geographically circumscribed to metropolitan regions. Other regions, particularly rural areas, may present a substantially different environment and experience.
PMCID: PMC3191587  PMID: 22021871
23.  Numerical Modeling of Fluid Flow in Solid Tumors 
PLoS ONE  2011;6(6):e20344.
A mathematical model of interstitial fluid flow is developed, based on the application of the governing equations for fluid flow, i.e., the conservation laws for mass and momentum, to physiological systems containing solid tumors. The discretized form of the governing equations, with appropriate boundary conditions, is developed for a predefined tumor geometry. The interstitial fluid pressure and velocity are calculated using a numerical method, element based finite volume. Simulations of interstitial fluid transport in a homogeneous solid tumor demonstrate that, in a uniformly perfused tumor, i.e., one with no necrotic region, because of the interstitial pressure distribution, the distribution of drug particles is non-uniform. Pressure distribution for different values of necrotic radii is examined and two new parameters, the critical tumor radius and critical necrotic radius, are defined. Simulation results show that: 1) tumor radii have a critical size. Below this size, the maximum interstitial fluid pressure is less than what is generally considered to be effective pressure (a parameter determined by vascular pressure, plasma osmotic pressure, and interstitial osmotic pressure). Above this size, the maximum interstitial fluid pressure is equal to effective pressure. As a consequence, drugs transport to the center of smaller tumors is much easier than transport to the center of a tumor whose radius is greater than the critical tumor radius; 2) there is a critical necrotic radius, below which the interstitial fluid pressure at the tumor center is at its maximum value. If the tumor radius is greater than the critical tumor radius, this maximum pressure is equal to effective pressure. Above this critical necrotic radius, the interstitial fluid pressure at the tumor center is below effective pressure. In specific ranges of these critical sizes, drug amount and therefore therapeutic effects are higher because the opposing force, interstitial fluid pressure, is low in these ranges.
PMCID: PMC3108959  PMID: 21673952
24.  Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma 
British Journal of Cancer  2010;102(6):981-986.
Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.
Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg–1 on day 1 and capecitabine 800 mg m–2 twice daily on days 1–14 every 3 weeks as first-line therapy.
A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.
The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.
PMCID: PMC2844032  PMID: 20160718
bevacizumab; capecitabine; hepatocellular carcinoma
25.  Incidence of anomalous origin of coronary artery in 1879 Chinese adults on dual-source CT angiography 
Netherlands Heart Journal  2010;18(10):466-470.
Background and Objective. Dual-source CT (DSCT) has been used to detect coronary artery anomalies. The purpose of this study was to assess the incidence of anomalous origin of the coronary artery in Chinese adults.
Methods. We summarised all patients who underwent DSCT coronary angiography (CTCA) from December 2006 to February 2008, and data of anomalous origin of the coronary artery in Chinese adults were recorded.
Results. 1879 patients underwent CTCA during that period; 24 patients with an anomalous origin of the coronary artery were detected, giving an incidence of 1.3%. Fifteen patients had an anomalous origin of the right coronary artery (12 from left coronary sinus, 3 high takeoff), eight patients had an anomalous origin of the left coronary artery (LCA from posterior sinus of Valsalva in three cases, LCX from the right coronary sinus, LCX from RCA, high takeoff, LCA from right coronary sinus, and single coronary artery in one case, respectively), and one patient had an anomalous origin of both coronary arteries (high takeoff).
Conclusion. The incidence of anomalous origin of the coronary artery in Chinese adults in this study is 1.3%. DSCT can clearly visualise the anomalous origin and course of the coronary artery and is a useful screening modality. (Neth Heart J 2010;18:466–70.)
PMCID: PMC2954298  PMID: 20978590
Coronary Artery Disease; Coronary Artery Anomaly; Tomography; X-ray Computed; Angiography

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