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1.  Reflecting optics in the diverticular eye of a deep-sea barreleye fish (Rhynchohyalus natalensis) 
We describe the bi-directed eyes of a mesopelagic teleost fish, Rhynchohyalus natalensis, that possesses an extensive lateral diverticulum to each tubular eye. Each diverticulum contains a mirror that focuses light from the ventro-lateral visual field. This species can thereby visualize both downwelling sunlight and bioluminescence over a wide field of view. Modelling shows that the mirror is very likely to be capable of producing a bright, well focused image. After Dolichopteryx longipes, this is only the second description of an eye in a vertebrate having both reflective and refractive optics. Although superficially similar, the optics of the diverticular eyes of these two species of fish differ in some important respects. Firstly, the reflective crystals in the D. longipes mirror are derived from a tapetum within the retinal pigment epithelium, whereas in R. natalensis they develop from the choroidal argentea. Secondly, in D. longipes the angle of the reflective crystals varies depending on their position within the mirror, forming a Fresnel-type reflector, but in R. natalensis the crystals are orientated almost parallel to the mirror's surface and image formation is dependent on the gross morphology of the diverticular mirror. Two remarkably different developmental solutions have thus evolved in these two closely related species of opisthoproctid teleosts to extend the restricted visual field of a tubular eye and provide a well-focused image with reflective optics.
PMCID: PMC3973263  PMID: 24648222
Rhynchohyalus natalensis; vision; mirror optics; deep-sea
2.  Osteoblast CFTR Inactivation Reduces Differentiation and Osteoprotegerin Expression in a Mouse Model of Cystic Fibrosis-Related Bone Disease 
PLoS ONE  2013;8(11):e80098.
Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF). CF-related bone disease (CFBD) is characterized by uncoupled bone turnover—impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR), the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr−/−) mouse model. In the murine calvarial organ culture assay, Cftr−/− calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+) littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr−/− compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl) mRNA was detected, significantly less osteoprotegerin (Opg) was expressed in Cftr−/− compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr−/− murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt signaling was defective in Cftr−/− murine calvarial osteoblasts. These results support that genetic inactivation of CFTR in osteoblasts contributes to low bone mass and that targeting osteoblasts may represent an effective strategy to treat CFBD.
PMCID: PMC3827431  PMID: 24236172
3.  Role of retinoid signaling in the regulation of spermatogenesis 
Cytogenetic and genome research  2004;105(0):189-202.
While the need for vitamin A for the normal progression of male germ cell differentiation has been known for many years, the molecular mechanisms underlying this requirement are poorly understood. This review will explore the aspects of the effects on spermatogenesis of dietary deprivation of vitamin A, in particular as to how they compare to the male sterility that results from the genetic ablation of function of the retinoid receptor RAR·. The effects of other genes involved with retinoid synthesis, transport, and degradation are also considered. The possible cellular mechanisms that may be affected by the lack of retinoid signaling are discussed, in particular, cell cycle regulation and cell-cell interaction, both of which are critical for normal spermatogenesis.
PMCID: PMC3803148  PMID: 15237207
4.  MRI to differentiate benign from malignant soft-tissue tumours of the extremities: a simplified systematic imaging approach using depth, size and heterogeneity of signal intensity 
The British Journal of Radiology  2012;85(1018):e831-e836.
Differentiating between malignant and benign lesions on the basis of MR images depends on the experience of the radiologist. For non-experts, we aimed to develop a simplified systematic MRI approach that uses depth, size and heterogeneity on T2 weighted MR images (T2WI) to differentiate between malignant and benign lesions, and evaluated its diagnostic accuracy.
MR images of 266 patients with histologically proven soft-tissue tumours of the extremities (102 malignant, 164 benign) were analysed according to depth (superficial or deep), size (<50, ≥50 mm) and signal intensity (homogeneous or heterogeneous) on T2WI, to determine the ability of each to predict benign and malignant tumours. These three parameters were categorised into systematic combinations of different orders of application, and each combination was assessed for its ability to differentiate between benign and malignant lesions.
Univariate analysis showed that depth, size and heterogeneity on T2WI differed significantly between benign and malignant masses (p<0.0001 each). Multiple logistic regression analysis, however, showed that depth was not helpful in distinguishing benign from malignant lesions. The systematic combination of signal intensity, size and depth, in that order, was superior to other combinations, resulting in higher diagnostic values for malignancy, with a sensitivity of 64%, a specificity of 85%, a positive predictive value of 32%, a negative predictive value of 59% and an accuracy of 77%.
A simplified systematic imaging approach, in the order signal intensity, size and depth, would be a reference to distinguish between benign and malignant soft-tissue tumours for non-experts.
PMCID: PMC3474004  PMID: 22553293
5.  Unusual Presentation of Propionic Acidemia as Isolated Cardiomyopathy 
Propionic acidemia (PA) is an autosomal recessive disease that results from deficiency of propionyl-CoA carboxylase (PCC). In virtually all reported cases of PA, the phenotype includes metabolic acidosis and/or neurological deficits. We report on a 14-year-old Asian male with PA who presented with isolated cardiomyopathy without any episodes of metabolic acidosis or evidence of any neurocognitive deficits. On routine metabolic screening, the patient was found to have urine organic acids suggestive of PA. Biochemical and genetic characterization confirmed a PCC deficiency with two novel mutations in PCCB: IVS7+2 T>G (c.763+2 T>G) and p.R410Q (c.1229 G>A). Residual enzyme activity likely explains our patient’s mild phenotype. Splicing mutations tend to result in a milder phenotype as these mutations may still produce small amounts of normal enzyme. In addition, the similar p.R410W mutation has been shown to have partial residual activity.
Moreover, this case illustrates the important but under-recognized manifestation of isolated cardiomyopathy as the sole clinical presentation in PA. A thorough metabolic evaluation should be performed in all pediatric patients with cardiomyopathy. Such an evaluation has important implications for clinical management and genetic counseling.
PMCID: PMC3777722  PMID: 19238581
6.  Validation of AJCC TNM staging for breast tumors diagnosed before 2004 in cancer registries 
Cancer causes & control : CCC  2012;23(9):1587-1591.
American Joint Committee on Cancer (AJCC) Tumor (T), Nodal (N) and Metastatic (M) staging is commonly used in clinical practice for treatment decisions, yet before 2004, Surveillance Epidemiology and End Results (SEER)-affiliated cancer registries did not routinely include TNM staging defined by AJCC criteria, reporting instead SEER Summary Staging.
We developed and validated an algorithm to determine AJCC TNM staging from Extent of Disease information for 17,133 female breast cancer cases diagnosed from 1988–2003 in the cancer registries of Kaiser Permanente Northern and Southern California. Test characteristics (percent agreement, Cohen’s kappa, sensitivity, specificity) were calculated to compare derived TNM with gold-standard TNM available in the registry.
Agreement for TNM variables was excellent (range 0.91–1.00 for percent agreement and Cohen’s kappa). The sensitivity and specificity, respectively, of the algorithm for AJCC TNM Version 6 staging was: Stage 0 (0.99, 1.00), Stage I (0.97, 0.98), Stage II (0.91, 0.96), Stage III (0.69, 0.99), Stage IV (0.92, 1.00). Stage III had lower sensitivity due to reclassification of supraclavicular lymph node positivity from M1 (Stage IV) to N3 (Stage IIIC) in AJCC Version 6.
Derived AJCC staging for breast tumors diagnosed before 2004 is feasible and accurate using cancer registry data.
PMCID: PMC3418812  PMID: 22798182
breast cancer; American Joint Committee on Cancer; tumor; nodal; metastatic cancer staging; cancer registry; validation study
7.  Adverse childhood experiences and risk of physical violence in adolescent dating relationships 
This study evaluates associations of commonly co-occurring childhood adversities with physical violence in dating relationships to identify potential strategies for refining and targeting dating violence prevention programmes.
Data on 5130 adult respondents to a nationally representative survey with at least one dating relationship before the age of 21 years were analysed. Logistic regression models assessed associations between 12 childhood adversities and physical dating violence (PDV).
Adjusting for the number of co-occurring adversities, 10 of the 12 childhood adversities were significantly associated with PDV perpetration or victimisation (OR 1.5–2.8). The population attributable risk proportion of PDV due to all 12 childhood adversities was 53.4%. Childhood adversities with the highest attributable risk proportions were sexual abuse (13.8%), interparental violence (11.6%) and parent mental illness (10.7%). Multivariate prediction equations ranked respondents by their childhood adversity risk profiles; 46.4% of PDV cases occurred in the top two risk deciles.
Assessment of a broad range of childhood exposures to familial adversities may help to identify adolescents at particularly high risk of PDV and to guide prevention efforts.
PMCID: PMC3686487  PMID: 21321063
8.  Protease Inhibitor Levels in Periodontal Health and Disease 
Journal of Periodontal Research  2011;47(2):228-235.
Background and Objectives
Our previous study showed protease inhibitors were attenuated by periopathogen Porphyromonas gingivalis in cultured gingival epithelial cells. We hypothesize fewer protease inhibitors would be present in more advanced periodontal sites where the level of P. gingivalis may be high. The goal of this study was to investigate the relationship between the protease inhibitor (SLPI, ELAFIN, SCCA) levels in gingival crevicular fluid (GCF) and the number of P. gingivalis in subgingival plaque.
Materials and Methods
Plaque samples from subjects without (n=18) and with moderate to advanced periodontitis (n=41) were used to quantify P. gingivalis using real-time PCR. Protease inhibitor levels in the GCF of all the subjects were determined by ELISA.
P. gingivalis was detected in 68.3% of subjects with periodontitis, while 16.7% of patients without periodontitis had detectable level of P. gingivalis. Subjects with periodontitis and P. gingivalis in their plaque exhibited lower SLPI and ELAFIN levels (p<0.001) compare to control subjects without periodontitis. SLPI was also reduced (p<0.05) in GCF of periodontal patients without detectable level of P. gingivalis. Periodontal patients with high vs. low levels of P. gingivalis exhibited reciprocal mean levels of SLPI and ELAFIN concentrations.
The reduced concentrations of SLPI and ELAFIN may contribute to the loss of host protective capacity and increase susceptibility to breakdown from chronic infection. The work of this investigation may aid in finding diagnostic and prognostic markers in periodontal health and disease and may further help in finding pharmacological targets directed against periodontal inflammation.
PMCID: PMC3270203  PMID: 22029638
protease inhibitors; periodontitis; Porphyromonas gingivalis; gingival crevicular fluid
9.  Acinar cell carcinoma with fatty change arising from the pancreas 
The British Journal of Radiology  2011;84(1008):e226-e228.
Acinar cell carcinoma of the pancreas is a rare malignant tumour developing from acinar cells, accounting for approximately 1% of pancreatic exocrine tumours. We experienced a case of an acinar cell carcinoma with fatty change. To the best of our knowledge, this is the first case report of an acinar cell carcinoma with fatty change in the clinical literature.
PMCID: PMC3473822  PMID: 22101587
10.  Childhood and adolescent onset psychiatric disorders, substance use, and failure to graduate high school on time 
Journal of psychiatric research  2010;45(3):295-301.
We examined the joint predictive effects of childhood and adolescent onset psychiatric and substance use disorders on failure to graduate high school (HS) on time. Structured diagnostic interviews were conducted with a US national sample of adults (18 and over). The analysis sample included respondents with at least 8 years of education who were born in the US or arrived in the US prior to age 13 (N=29,662). Psychiatric disorders, substance use and substance use disorders were examined as predictors of termination or interruption of educational progress prior to HS graduation, with statistical adjustment for demographic characteristics and childhood adversities. Failure to graduate HS on time was more common among respondents with any of the psychiatric and substance use disorders examined, ranging from 18.1% (specific phobia) to 33.2% (ADHD-combined type), compared with respondents with no disorder (15.2%). After adjustment for co-occurring disorders, significant associations with failure to graduate on time remained only for conduct disorder (OR=1.89, 95%CI 1.57–2.26) and the three ADHD subtypes (Inattentive OR=1.78, 95%CI 1.44–2.20, Hyperactive-Impulsive OR=1.38, 95%CI 1.14–1.67, and Combined OR=2.06, 95%CI 1.66–2.56). Adjusting for prior disorders, tobacco use was associated with failure to graduate on time (OR=1.97, 95%CI 1.80–2.16). Among substance users, substance use disorders were not associated with on time graduation. The findings suggest that the adverse impact of childhood and adolescent onset psychiatric disorders on HS graduation is largely accounted for by problems of conduct and inattention. Adjusting for these disorders, smoking remains strongly associated with failure to graduate HS on time.
PMCID: PMC2962709  PMID: 20638079
Psychiatric Disorders; Educational Attainment; Epidemiology; Substance Use; Smoking
11.  Emerging Roles of the Host Defense Peptide LL-37 in Human Cancer and its Potential Therapeutic Applications 
Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does it eliminate pathogenic microbes directly, LL-37 also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. While overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide.
PMCID: PMC2930073  PMID: 20521250
12.  Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma 
British Journal of Cancer  2010;103(1):52-60.
The current standard of care for pancreatic cancer is weekly gemcitabine administered for 3 of 4 weeks with a 1-week break between treatment cycles. Maximum tolerated dose (MTD)-driven regimens as such are often associated with toxicities. Recent studies demonstrated that frequent dosing of chemotherapeutic drugs at relatively lower doses in metronomic regimens also confers anti-tumour activity but with fewer side effects.
Herein, we evaluated the anti-tumour efficacy of metronomic vs MTD gemcitabine, and investigated their effects on the tumour microenvironment in two human pancreatic cancer xenografts established from two different patients.
Metronomic and MTD gemcitabine significantly reduced tumour volume in both xenografts. However, Ktrans values were higher in metronomic gemcitabine-treated tumours than in their MTD-treated counterparts, suggesting better tissue perfusion in the former. These data were further supported by tumour-mapping studies showing prominent decreases in hypoxia after metronomic gemcitabine treatment. Metronomic gemcitabine also significantly increased apoptosis in cancer-associated fibroblasts and induced greater reductions in the tumour levels of multiple pro-angiogenic factors, including EGF, IL-1α, IL-8, ICAM-1, and VCAM-1.
Metronomic dosing of gemcitabine is active in pancreatic cancer and is accompanied by pronounced changes in the tumour microenvironment.
PMCID: PMC2905290  PMID: 20531411
tumour microenvironment; pancreatic cancer; metronomic chemotherapy; gemcitabine; anti-angiogenesis
13.  Compound Deficiencies in Multiple Fibroblast Growth Factor Signalling Components Differentially Impact the Murine Gonadotrophin-Releasing Hormone System 
Journal of neuroendocrinology  2010;22(8):944-950.
Gonadotrophin-releasing hormone (GnRH) neurones control the onset and maintenance of fertility. Aberrant development of the GnRH system underlies infertility in Kallmann syndrome [KS; idiopathic hypogonadotropic hypogonadism (IHH) and anosmia]. Some KS patients harbour mutations in the fibroblast growth factor receptor 1 (Fgfr1) and Fgf8 genes. The biological significance of these two genes in GnRH neuronal development was corroborated by the observation that GnRH neurones were severely reduced in newborn transgenic mice deficient in either gene. In the present study, we hypothesised that the compound deficiency of Fgf8 and its cognate receptors, Fgfr1 and Fgfr3, may lead to more deleterious effects on the GnRH system, thereby resulting in a more severe reproductive phenotype in patients harbouring these mutations. This hypothesis was tested by counting the number of GnRH neurones in adult transgenic mice with digenic heterozygous mutations in Fgfr1/Fgf8, Fgfr3/Fgf8 or Fgfr1/Fgfr3. Monogenic heterozygous mutations in Fgfr1, Fgf8 or Fgfr3 caused a 30–50% decrease in the total number of GnRH neurones. Interestingly, mice with digenic mutations in Fgfr1/Fgf8 showed a greater decrease in GnRH neurones compared to mice with a heterozygous defect in the Fgfr1 or Fgf8 alone. This compounding effect was not detected in mice with digenic heterozygous mutations in Fgfr3/Fgf8 or Fgfr1/Fgfr3. These results support the hypothesis that IHH/KS patients with digenic mutations in Fgfr1/Fgf8 may have a further reduction in the GnRH neuronal population compared to patients harbouring monogenic haploid mutations in Fgfr1 or Fgf8. Because only Fgfr1/Fgf8 compound deficiency leads to greater GnRH system defect, this also suggests that these fibroblast growth factor signalling components interact in a highly specific fashion to support GnRH neuronal development.
PMCID: PMC3102046  PMID: 20553372
fibroblast growth factor receptor; fibroblast growth factor 8; gonadotrophin-releasing hormone neurones; hypogonadotropic hypogonadism; Kallmann syndrome
14.  Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy 
Neurology  2010;74(10):833-838.
In spinal muscular atrophy (SMA), weakness, decreased endurance, and fatigue limit mobility. Scales have been developed to measure function across the wide spectrum of disease severity. However, these scales typically are observer dependent, and scores are based on sums across Likert-scaled items. The Six-Minute Walk Test (6MWT) is an objective, easily administered, and standardized evaluation of functional exercise capacity that has been proven reliable in other neurologic disorders and in children.
To study the performance of the 6MWT in SMA, 18 ambulatory participants were evaluated in a cross-sectional study. Clinical measures were 6MWT, 10-m walk/run, Hammersmith Functional Motor Scale–Expanded (HFMSE), forced vital capacity, and handheld dynamometry. Associations between the 6MWT total distance and other outcomes were analyzed using Spearman correlation coefficients. A paired t test was used to compare the mean distance walked in the first and sixth minutes.
The 6MWT was associated with the HFMSE score (r = 0.83, p < 0.0001), 10-m walk/run (r = −0.87, p < 0.0001), and knee flexor strength (r = 0.62, p = 0.01). Gait velocity decreased during successive minutes in nearly all participants. The average first minute distance (57.5 m) was significantly more than the sixth minute distance (48 m) (p = 0.0003).
The Six-Minute Walk Test (6MWT) can be safely performed in ambulatory patients with spinal muscular atrophy (SMA), correlates with established outcome measures, and is sensitive to fatigue-related changes. The 6MWT is a promising candidate outcome measure for clinical trials in ambulatory subjects with SMA.
= forced vital capacity;
= Hammersmith Functional Motor Scale–Expanded;
= handheld dynamometry;
= Six-Minute Walk Test;
= spinal muscular atrophy.
PMCID: PMC2839195  PMID: 20211907
15.  Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-κB 
Journal of neurochemistry  2009;110(1):182-193.
Nuclear factor-κB (NF-κB) is a pleiotropic transcription factor that generally enhances cellular resistance to apoptotic cell death. It has been shown to be constitutively active in some cancers and is being pursued as potential anticancer target. Sulfasalazine which is used clinically to treat Crohn's disease has emerged as a potential inhibitor of NF-κB and has shown promising results in two pre-clinical studies to target primary brain tumors, gliomas. Once digested, sulfasalazine is cleaved into sulfapyridine and 5-aminosalicylic acid (5-ASA; mesalamine) by colonic bacteria, and the latter, too, is reported to suppress NF-κB activity. We now show that glioma cells obtained from patient biopsies or glioma cell lines do not show significant constitutive NF-κB activation, unless exposed to inflammatory cytokines. This does not change when gliomas are implanted into the cerebrum of severe combined immundeficient mice. Nevertheless, sulfasalazine but not its cleaved form 5-ASA caused a dose-dependent inhibition of glioma growth. This effect was entirely attributable to the inhibition of cystine uptake via the system xc− cystine–glutamate transporter. It could be mimicked by S-4-carboxy-phenylglycine (S-4-CPG) a more specific system xc− inhibitor, and lentiviral expression of a constitutively active form of IκB kinase b was unable to overcome the growth retarding effects of sulfasalazine or S-4-CPG. Both drugs inhibited cystine uptake causing a chronic depletion of intracellular GSH and consequently compromised cellular redox defense which stymied tumor growth. This data suggests that system xc− is a promising therapeutic target in gliomas and possibly other cancers and that it can be pharmacologically inhibited by Sulfasalazine, an FDA-approved drug.
PMCID: PMC3031868  PMID: 19457125
glioma; glutamate; glutathione; reactive oxygen species; S-4-carboxy-phenylglycine; system xc−
16.  Differential utilization of nuclear factor-κB signaling pathways for gingival epithelial cell responses to oral commensal and pathogenic bacteria 
Oral microbiology and immunology  2008;23(2):119-126.
Human β-defensin-2 (hBD-2) is an antimicrobial peptide, induced by bacterial stimuli and inflammation, that plays a role in mucosal and skin innate immune defense. The nuclear factor-κB (NF-κB) transcription factor family is important in innate and adaptive immune responses to bacteria and proinflammatory cytokines. NF-κB operates via the traditional IKKβ signaling, as well as an alternative pathway utilizing IKKα signaling, which is important in keratinocyte differentiation. Our previous studies showed that pathogenic, but not commensal, bacteria used NF-κB signaling in hBD-2 induction. The objective of this study was to understand which arm of the NF-κB pathway is involved in gingival epithelial cell responses to pathogenic bacteria, including hBD-2 induction.
Cultured oral epithelial cells were transfected with synthetic small interfering RNAs (siRNAs) specific for various steps in each pathway, namely IKKβ, TRAF6 and MyD88 in the canonical, and IKKα and TRAF3 in the alternative pathway, and subsequently stimulated with various oral bacteria.
The hBD-2 induction level was reduced to 21–61% in cells in which the alternative NF-κB pathway was blocked and subsequently stimulated with pathogenic bacteria, while cells in which the canonical pathway was blocked showed reduction to 78–99%. Cells stimulated with commensals showed little change in hBD-2 induction level regardless of the siRNA used. Microarray analysis showed that oral epithelia differentially regulated numerous innate immune markers in response to pathogens and commensals.
Our data suggest a role for the IKKα/TRAF3 pathway in NF-κB activation by pathogenic bacteria, while commensal bacteria do not utilize either NF-κB pathway, for hBD-2 induction.
PMCID: PMC2826319  PMID: 18279179
commensals; gingival epithelium; innate immunity; nuclear factor-κB; pathogens
Neurology  2008;71(24):2010-2012.
PMCID: PMC2676977  PMID: 19064884
18.  Growth arrest-specific gene 6 expression in human breast cancer 
British Journal of Cancer  2008;98(6):1141-1146.
Growth arrest-specific gene 6 (Gas6), identified in 1995, acts as the ligand to the Axl/Tyro3 family of tyrosine kinase receptors and exerts mitogenic activity when bound to these receptors. Overexpression of the Axl/Tyro3 receptor family has been found in breast, ovarian and lung tumours. Gas6 is upregulated 23-fold by progesterone acting through the progesterone receptor B (PRB). Recently, Gas6 has been shown to be a target for overexpression and amplification in breast cancer. Quantitative real-time PCR analysis was used to determine the levels of Gas6 mRNA expression in 49 primary breast carcinomas. Expression of PRB protein was evaluated immunohistochemically with a commercially available PRB antibody. The results showed a positive association between PRB protein and Gas6 mRNA levels (P=0.04). Gas6 correlated positively with a number of favourable prognostic variables including lymph node negativity (P=0.0002), younger age at diagnosis (P=0.04), smaller size of tumours (P=0.02), low Nottingham prognostic index scores (P=0.03) and low nuclear morphology (P=0.03). This study verifies for the first time the association between PRB and Gas6 in breast cancer tissue.
PMCID: PMC2275480  PMID: 18283315
growth arrest-specific gene 6; Axl tyrosine kinase receptor; progesterone receptor B; breast cancer
19.  Autocrine Glutamate Signaling Promotes Glioma Cell Invasion 
Cancer research  2007;67(19):9463-9471.
Malignant gliomas have been shown to release glutamate, which kills surrounding brain cells, creating room for tumor expansion. This glutamate release occurs primarily via system xC−, a Na+-independent cystine-glutamate exchanger. We show here, in addition, that the released glutamate acts as an essential autocrine/paracrine signal that promotes cell invasion. Specifically, chemotactic invasion and scrape motility assays each show dose-dependent inhibition of cell migration when glutamate release was inhibited using either S-(4)-CPG or sulfasalazine, both potent blockers of system xC−. This inhibition could be overcome by the addition of exogenous glutamate (100 μmol/L) in the continued presence of the inhibitors. Migration/invasion was also inhibited when Ca2+-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPA-R) were blocked using GYKI or Joro spider toxin, whereas CNQX was ineffective. Ca2+ imaging experiments show that the released glutamate activates Ca2+-permeable AMPA-R and induces intracellular Ca2+ oscillations that are essential for cell migration. Importantly, glioma cells release glutamate in sufficient quantities to activate AMPA-Rs on themselves or neighboring cells, thus acting in an autocrine and/or paracrine fashion. System xC− and the appropriate AMPA-R subunits are expressed in all glioma cell lines, patient-derived glioma cells, and acute patient biopsies investigated. Furthermore, animal studies in which human gliomas were xenographed into scid mice show that chronic inhibition of system xC−–mediated glutamate release leads to smaller and less invasive tumors compared with saline-treated controls. These data suggest that glioma invasion is effectively disrupted by inhibiting an autocrine glutamate signaling loop with a clinically approved candidate drug, sulfasalazine, already in hand.
PMCID: PMC2045073  PMID: 17909056
20.  Are marketing campaigns in Taiwan by foreign tobacco companies targeting young smokers? 
Tobacco Control  2005;14(Suppl 1):i38-i44.
Objective: To assess the impact of promotions on cigarette sales in Taiwan after the cigarette market opened to foreign companies, and to assess whether young smokers were targeted by these companies.
Methods: Trends in cigarette sales, advertising expenditure, brand preference, and cigarette consumption were examined for the period following the 1987 opening of the cigarette market. Tobacco industry internal documents from Legacy Tobacco Documents Library of the University of California, San Francisco, were searched for corporate strategies on promoting youth consumption in Taiwan.
Results: Between 1995 and 2000, the inflation adjusted advertising expenditures by all foreign firms increased fourfold. Much of the expenditure was spent on brand stretching the Mild Seven (Japan) and Davidoff (Germany) brands in television advertising. By 2000, the market share of foreign cigarettes exceeded domestics by three to one among young smokers and the leading brand preferred by this segment shifted from the most popular domestic brand (Long Life) to a foreign brand (Mild Seven). Furthermore, there was a sudden increase of 16.4% in smoking rates among young adults (from 36.1% to 42.0%) during the first five years after the market opened. This was also accompanied by increased per capita cigarette consumption and decreased age of smoking initiation. Industry documents confirmed the use of strategies targeted at the young. In particular, establishing new point of sale (POS) retail stores or promotional activities at POS were found to be more effective than advertising in magazines.
Conclusions: This study provides evidence that advertising increased with increased competition following the market opening, which, in turn, spurred cigarette sales and consumption. Foreign tobacco companies have deliberately targeted youth in Taiwan and succeeded in gaining three quarters of their cigarette purchases within a decade. Expanding youth consumption will incur excessive future health care costs borne by society. Foreign tobacco companies should be obligated to reimburse these expenses through higher tariffs on cigarettes.
PMCID: PMC1766177  PMID: 15923447
21.  Excess injury mortality among smokers: a neglected tobacco hazard 
Tobacco Control  2005;14(Suppl 1):i28-i32.
Objective: To assess the mortality risks from injuries for smokers and ex-smokers and to quantify the mortality burden of smoking from injury in Taiwan.
Methods: Smokers' (and ex-smokers') mortality risks from injuries were compared with that of non-smokers in a merged cohort from Taiwan. A total of 64 319 male subjects were followed up for 12–18 years. Relative risks (RR) (adjusted for age and alcohol use) and 95% confidence intervals (CI) for cause specific injury deaths were calculated using the Cox proportional hazard model. Relative risks of injury mortality were also calculated to assess the presence of dose–response relations with daily smoking quantity.
Results: Alcohol use adjusted relative mortality risks for all injuries (RR 1.69, 95% CI 1.39 to 2.05) including those from motor vehicle accidents (RR 1.88, 95% CI 1.44 to 2.45) and non-motor vehicle accidents (RR 1.48, 95% CI 1.11 to 1.99) were significantly higher for smokers than non-smokers. Mortality was also increased for most subtypes of non-motor vehicle injuries including falls, fires, and job related injuries. Furthermore, these increases were dose dependent, with the heaviest smokers having the highest risk and the lightest smokers the lowest risk, and ex-smokers, no increase. In 2001, over one fifth (23%) of all male injury deaths in Taiwan was associated with smoking.
Conclusion: This study demonstrated the significant association between fatal injuries and smoking. This relation adds further weight to smoking cessation campaigns.
PMCID: PMC1766175  PMID: 15923444
22.  Reducing health disparity in Taiwan: quantifying the role of smoking 
Tobacco Control  2005;14(Suppl 1):i23-i27.
Objective: To assess the impact of smoking disparities on health disparities, in terms of gap in life expectancy, in Taiwan cities and counties.
Methods: Using the decomposition method of life expectancy, the contribution of each disease category to the life expectancy gap was quantitatively expressed as the number of years of life. The smoking attributable fraction (SAF) was calculated for each city and county based on their respective smoking prevalence and relative risk for each smoking related disease. The smoking attributable gap (SAG) in life expectancy between two sites is the sum of the difference in SAF between two sites for each smoking related disease multiplied by the number of years this disease contributed to the life expectancy gap.
Results: Significant health and smoking disparities were present among the 23 cities and counties in Taiwan. These health disparities and smoking disparities were highly correlated (R2 = 0.3676). Generally, the health gap increased with increasing smoking disparity. The disparity in smoking prevalence and intensity among cities and counties in Taiwan was responsible for up to 19% of the health disparity. The health disparity is also highly correlated (R2 = 0.3745) with SAG in life expectancy.
Conclusions: Reducing smoking is important to health, and reducing the smoking disparity is also important for reducing the health disparity observed in Taiwan. The larger the health disparity is, the more important the smoking attributable disparity could be. The reduction of smoking disparities could be a realistic and cost effective way toward reducing health disparities.
PMCID: PMC1766179  PMID: 15923443
23.  Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease and rheumatic diseases with vasculitis 
Kim, J | Chang, H | Lee, S | Kim, J | Kim, K | Lee, S | Chung, W
Annals of the Rheumatic Diseases  2003;62(11):1083-1087.
Objective: To assess potential associations between Korean Behçet's disease (BD) or other rheumatic diseases with vasculitis and two polymorphisms of the endothelial nitric oxide synthase (eNOS) gene, which include the Glu298Asp polymorphism in exon 7 and a variable number of tandem repeats (VNTR) polymorphism in intron 4.
Methods: 65 patients with BD, 27 with rheumatic diseases with vasculitis, and 80 controls were studied. Analyses of the Glu298Asp polymorphism in exon 7 and VNTR polymorphism in intron 4 of the eNOS gene were made by the polymerase chain reaction (PCR)-restriction fragment length polymorphism technique and PCR genotyping, respectively. Additionally, HLA-B51 typing was performed in the BD group and controls by a two step PCR sequence-specific primers method.
Results: Significant differences in Glu298Asp genotype frequencies were found between the BD or vasculitis groups and the controls (BD group v controls: pcorr=0.006; vasculitis group v controls: p<0.001). The Asp298 frequency was much higher in the BD and vasculitis groups than in the controls. Even after stratification of the BD group based on the results of HLA-B51 testing, a significant association of the Glu298Asp polymorphism was still found (p=0.002, Mantel-Haenszel weighted odds ratio 4.3, 95% confidence interval 1.7 to 10.9). Distribution of the genotype frequencies in two eNOS gene polymorphisms was similar in connective tissue diseases-associated vasculitis and primary vasculitic syndromes. In contrast, distribution of alleles and genotypes of VNTR polymorphism did not differ between BD or vasculitis groups and the controls.
Conclusion: The Glu298Asp polymorphism in exon 7 of the eNOS gene seems to be a susceptibility gene for Korean BD and other rheumatic diseases.
PMCID: PMC1754357  PMID: 14583572
24.  Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity 
Diabetologia  2006;50(2):395-403.
Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake.
Materials and methods
Insulin sensitivity in Pten heterozygous (Pten+/−) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten+/− mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3β (GSK3β), a substrate of PKB/Akt, was determined by western immunoblotting.
Following i.p. insulin challenge, blood glucose levels in Pten+/− mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten+/− mice. Enhanced glucose uptake was observed both in Pten+/− myocytes and in skeletal muscle of Pten+/− mice by PET. PKB and GSK3β phosphorylation was enhanced and prolonged in Pten+/− myocytes.
Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten+/− mice.
PMCID: PMC1781097  PMID: 17195063
Glucose uptake; Insulin hypersensitivity; Insulin sensitivity; Pten haploinsufficiency

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