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1.  Passive smoking at work as a risk factor for coronary heart disease in Chinese women who have never smoked. 
BMJ : British Medical Journal  1994;308(6925):380-384.
OBJECTIVE--To study whether passive smoking at work is a risk factor for coronary heart disease. DESIGN--Case-control study. SETTING--Xi'an, China. SUBJECTS--59 patients with coronary heart disease and 126 controls, all Chinese women with full time jobs, who had never smoked cigarettes. RESULTS--The crude odds ratio for passive smoking from husband was 2.12 (95% confidence interval 1.06 to 4.25) and at work was 2.45 (1.23 to 4.88). The final logistic regression model, with passive smoking from husband and at work as the base, included age, history of hypertension, type A personality, and total cholesterol and high density lipoprotein cholesterol concentrations; the adjusted odds ratios for passive smoking from husband and at work were 1.24 (0.56 to 2.72) and 1.85 (0.86 to 4.00) respectively. For passive smoking at work, statistically significant linear trends of increasing risks (for both crude and adjusted odds ratios) with increasing exposures (amount exposed daily, number of smokers, number of hours exposed daily, and cumulative exposure) were observed. When these exposure variables were analysed as continuous variables, the crude and adjusted odds ratios were also significant. CONCLUSION--Passive smoking at work is a risk factor for coronary heart disease. Urgent public health measures are needed to reduce smoking and to protect non-smokers from passive smoking in China.
PMCID: PMC2539443  PMID: 8124145
2.  β-Catenin and NF-κB co-activation triggered by TLR3 stimulation facilitates stem cell-like phenotypes in breast cancer 
Jia, D | Yang, W | Li, L | Liu, H | Tan, Y | Ooi, S | Chi, L | Filion, L G | Figeys, D | Wang, L
Cell Death and Differentiation  2014;22(2):298-310.
Cancer stem cells (CSCs) are responsible for tumor initiation and progression. Toll-like receptors (TLRs) are highly expressed in cancer cells and associated with poor prognosis. However, a linkage between CSCs and TLRs is unclear, and potential intervention strategies to prevent TLR stimulation-induced CSC formation and underlying mechanisms are lacking. Here, we demonstrate that stimulation of toll-like receptor 3 (TLR3) promotes breast cancer cells toward a CSC phenotype in vitro and in vivo. Importantly, conventional NF-κB signaling pathway is not exclusively responsible for TLR3 activation-enriched CSCs. Intriguingly, simultaneous activation of both β-catenin and NF-κB signaling pathways, but neither alone, is required for the enhanced CSC phenotypes. We have further identified a small molecule cardamonin that can concurrently inhibit β-catenin and NF-κB signals. Cardamonin is capable of effectively abolishing TLR3 activation-enhanced CSC phenotypes in vitro and successfully controlling TLR3 stimulation-induced tumor growth in human breast cancer xenografts. These findings may provide a foundation for developing new strategies to prevent the induction of CSCs during cancer therapies.
PMCID: PMC4291491  PMID: 25257174
3.  Audit and Feedback of Antibiotic Use 
Applied Clinical Informatics  2013;4(4):583-595.
There is now little doubt that improving antimicrobial use is necessary for the containment of resistance.
To determine whether providing individualised feedback to doctors about their recent compliance with the hospital’s antibiotic policy improves compliance with the policy.
This study was conducted at a teaching hospital in Sydney, Australia. Computerised alerts integrated into the electronic prescribing system (ePS) inform prescribers of the local antibiotic policy. We utilised prescribing data extracted from the ePS for ‘audit and feedback’. Thirty-six prescribers were sent feedback letters via email. We also interviewed doctors who had received letters to explore their views of the feedback and the policy in general.
There was no significant change in compliance with the policy following implementation of the feedback intervention (0% compliant vs 11.9%; p = 0.07). Several problems with the policy and the approval process were identified by researchers during auditing and by prescribers during interviews. Some problems identified made it difficult to accurately assess compliance and for doctors to comply with the policy.
Our intervention did not result in improved compliance with the antibiotic policy but revealed practical problems with the policy and approval process that had not been identified prior to the trial. Greater support for the policy by senior doctors and the assignment of more clearly defined roles and responsibilities associated with antibiotic use and approval may result in improved compliance. Harnessing the full potential of technology would streamline the antimicrobial approval process and allow more efficient and reliable monitoring of antibiotic use and compliance.
Many of the problems we identified are generic issues of importance to all organisations seeking to integrate antimicrobial stewardship into ePS.
PMCID: PMC3885917  PMID: 24454584
Antibiotic; compliance; audit and feedback; electronic prescribing
4.  Postpartum haemorrhage in midwifery care in the Netherlands: validation of quality indicators for midwifery guidelines 
Postpartum haemorrhage (PPH) is still one of the major causes of severe maternal morbidity and mortality worldwide. Currently, no guideline for PPH occurring in primary midwifery care in the Netherlands is available. A set of 25 quality indicators for prevention and management of PPH in primary care has been developed by an expert panel consisting of midwives, obstetricians, ambulance personal and representatives of the Royal Dutch College of Midwives (KNOV) and the Dutch Society of Obstetrics and Gynecology (NVOG). This study aims to assess the performance of these quality indicators as an assessment tool for midwifery care and suitability for incorporation in a professional midwifery guideline.
From April 2008 to April 2010, midwives reported cases of PPH. Cases were assessed using the 25 earlier developed quality indicators. Quality criteria on applicability, feasibility, adherence to the indicator, and the indicator’s potential to monitor improvement were assessed.
98 cases of PPH were reported during the study period, of which 94 were analysed. Eleven indicators were found to be applicable and feasible. Five of these indicators showed improvement potential: routine administration of uterotonics, quantifying blood loss by weighing, timely referral to secondary care in homebirth and treatment of PPH using catherisation, uterine massage and oxytocin and the use of oxygen.
Eleven out of 25 indicators were found to be suitable as an assessment tool for midwifery care of PPH and are therefore suitable for incorporation in a professional midwifery guideline. Larger studies are necessary to confirm these results.
PMCID: PMC4266235  PMID: 25481692
Post-partum hemorrhage; Home birth; Primary care; Midwifery; Quality indicators
5.  Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China 
British Journal of Cancer  2013;109(11):2778-2782.
There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART.
Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART.
Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8% P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm.
Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis.
PMCID: PMC3844910  PMID: 24169350
radical trachelectomy; cervical cancer; fertility; prognosis
6.  Infected hematopoietic stem cells and with integrated HBV DNA generate defective T cells in chronic HBV infection patients 
Shi, Y | Lan, Y | Cao, F | Teng, Y | Li, L | Wang, F | Li, J | Zhou, J | Li, Y
Journal of Viral Hepatitis  2014;21(7):e39-e47.
A weak T-cell response plays a key role in the persistence of hepatitis B virus (HBV) infection. We aimed to confirm that T-cell defects in patients with chronic HBV infection are associated with HBV DNA infection of bone marrow (BM) hematopoietic stem cells (HSCs). Using reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH), we observed the transcription of HBsAg coding genes and confirmed the integration of HBV DNA in CD34+ BM HSCs from chronic HBV infection patients. T cells were generated by coculturing the HSCs with delta-like ligand 1-expressing OP9 (OP9-DL1) cells. The phenotypes of the T cells were then evaluated by flow cytometric (FACS) analysis on days 14 and 25. The results demonstrated that fewer CD3+TCRaβ+ CD3+CD4+ and CD4+CD8+ T cells were generated from the HSCs of the patients than from the healthy controls, (P < 0.01) but the frequency of CD3+D8+ T cells was not significantly different between the two group (P > 0.05). In contrast, CD4+CD25+ T cells were more in the patient group than in healthy controls (P < 0.01) on both days 14 and 25. There were fewer CD3+CD4+/CD3+CD8+ cells in the patient group than in the healthy control group on day 25 (P < 0.05). Less proliferation and lower levels of IL-2 and IFN- γ were also observed in the patient group compared with the control group (P < 0.05).These data suggest that HBV DNA infected and integrated into the BM HSCs from patients with chronic HBV infection and that these BM HSCs generated defective T cells.
PMCID: PMC4237112  PMID: 24620791
HBV DNA; HSCs; integration; replication; T-cell defects
7.  IFN-γ induces aberrant CD49b+ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure 
Cell Death & Disease  2014;5(11):e1512-.
Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-γ-induced abortion mice. By contrast, the percentage of CD3−CD49b+ NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-γ-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-γ was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b+ NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-γ can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b+ NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-γ on pregnancy with the aberrant regulation of CX3CL1 and CD49b+ NK cells.
PMCID: PMC4260728  PMID: 25375377
8.  Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects 
British Journal of Cancer  2013;109(9):2331-2339.
Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy.
Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment.
Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed.
Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.
PMCID: PMC3817329  PMID: 24084768
breast cancer; aromatase inhibitor; breast density; mammogram; polymorphism
9.  Usefulness of ultrasonography in assessment of laryngeal carcinoma 
The British Journal of Radiology  2013;86(1030):20130343.
To evaluate the usefulness of ultrasonography in assessing laryngeal cancer.
72 patients with laryngeal carcinoma proven by surgery and pathology were enrolled. The pre-therapeutic ultrasonography and CT images were retrospectively evaluated, including tumour detection, localisation and invasion of intra- and extralaryngeal structures. A comparative assessment was made between the detection rate, correspondence rate of localisation and sensitivity and specificity of ultrasonography and CT. The mobility of the larynx was observed on real-time ultrasonography and compared with laryngoscopy.
The detection rate of ultrasonography [63 (87.5%)/72] was lower than that of CT [72 (100.0%)/72] (p=0.006). The primary foci were accurately located in 59 (93.7%) of 63 lesions using ultrasonography compared with 70 (97.2%) of 72 lesions using CT (p=0.392). In the evaluation of invasion, the sensitivity and specificity of ultrasonography were similar to that of CT in most of the intra- and extralaryngeal structures (p=0.059–1.000). A higher specificity was obtained during the assessment of the paraglottic space involvement when using ultrasonography than CT (94.9% vs 66.7%, p=0.001). For vocal cord fixation, no statistical difference was found between ultrasonography and laryngoscopy (p=0.223).
Ultrasonography could be used as a valuable supplementary imaging method to CT and laryngoscopy in the assessment of laryngeal carcinoma, even in male adults with some calcifications of the thyroid cartilage.
Advances in knowledge:
Our study demonstrates that ultrasonography, which has been used scarcely in the larynx, could supply useful information on the detection, localisation and intra- and extralaryngeal invasion of laryngeal carcinoma.
PMCID: PMC3798336  PMID: 24004487
10.  Children of Treated Substance-abusing Mothers: A 10-year Prospective Study 
The study examined children of substance-abusing mothers approximately 10 years after mothers’ admission to drug abuse treatment, and identified maternal characteristics that may be risk factors for child behavior problems on the Child Behavior Checklist (CBCL). Data were obtained from 396 mothers who were included in a sample consecutively admitted to 44 treatment programs in 13 California counties during 2000–2002. Addiction Severity Index was administered at both intake and follow-up. Each mother reported on one child 6–17 years of age. All of the children had been exposed to drugs either in utero or postnatally. At follow-up about 22% of the children demonstrated borderline or clinical range problem behaviors. Child behavior problems were related significantly to the mothers’ ethnicity (lower among Hispanics relative to white), and problem severity in family/social relationship and mental health, marginally related to her prior medical/health problem, and not related to severity in alcohol, drug, legal and employment. Assisting mothers to address their family/social relationship and psychological problems may have an added value to prevent or reduce behavioral problems of their children.
PMCID: PMC3879161  PMID: 23677926
Child behavior; maternal drug use; risk-factors
11.  Multiple Shh signaling centers participate in fungiform papilla and taste bud formation and maintenance 
Developmental biology  2013;382(1):82-97.
The adult fungiform taste papilla is a complex of specialized cell types residing in the stratified squamous tongue epithelium. This unique sensory organ includes taste buds, papilla epithelium and lateral walls that extend into underlying connective tissue to surround a core of lamina propria cells. Fungiform papillae must contain long-lived, sustaining or stem cells and short-lived, maintaining or transit amplifying cells that support the papilla and specialized taste buds. Shh signaling has established roles in supporting fungiform induction, development and patterning. However, for a full understanding of how Shh transduced signals act in tongue, papilla and taste bud formation and maintenance, it is necessary to know where and when the Shh ligand and pathway components are positioned. We used immunostaining, in situ hybridization and mouse reporter strains for Shh, Ptch1, Gli1 and Gli2-expression and proliferation markers to identify cells that participate in hedgehog signaling. Whereas there is a progressive restriction in location of Shh ligand-expressing cells, from placode and apical papilla cells to taste bud cells only, a surrounding population of Ptch1 and Gli1 responding cells is maintained in signaling centers throughout papilla and taste bud development and differentiation. The Shh signaling targets are in regions of active cell proliferation. Using genetic-inducible lineage tracing for Gli1-expression, we found that Shh-responding cells contribute not only to maintenance of filiform and fungiform papillae, but also to taste buds. A requirement for normal Shh signaling in fungiform papilla, taste bud and filiform papilla maintenance was shown by Gli2 constitutive activation. We identified proliferation niches where Shh signaling is active and suggest that epithelial and mesenchymal compartments harbor potential stem and/or progenitor cell zones. In all, we report a set of hedgehog signaling centers that regulate development and maintenance of taste organs, the fungiform papilla and taste bud, and surrounding lingual cells. Shh signaling has roles in forming and maintaining fungiform papillae and taste buds, most likely via stage-specific autocrine and/or paracrine mechanisms, and by engaging epithelial/mesenchymal interactions.
PMCID: PMC3968530  PMID: 23916850
fungiform papilla; papilla placode; paracrine signaling; stem cells; taste cell progenitors; Ptch; Gli1; Gli2
12.  The relation of femoral notch stenosis to ACL tears in persons with knee osteoarthritis 
A significant risk factor for anterior cruciate ligament (ACL) tears in young athletes is a reduced femoral Notch Width Index (NWI). The purpose of this study was to test if persons with knee osteoarthritis (OA) and ACL tears have smaller NWI independent of prior joint injury and osteophyte volume.
We included 160 participants from the progression sub-cohort of the Osteoarthritis Initiative (OAI) Study, an ongoing 4-year, multi-center study, focusing on knee OA. The femoral notch width, the condylar notch width at 2/3 of the notch depth, and the intercondylar notch angle (β) were measured on sagittal and coronal MR-images. NWI = notch width/condylar width at 2/3 of the notch depth, was calculated and outcome of ACL tear frequency was compared between two groups; NWI ≤ 0.20 and NWI > 0.20. The NWI and β were analyzed as continuous variables.
Of the 160 subjects [51% female, age 62.1 (±9.9), BMI 30.3 (±4.7) kg/m2] 14.4% showed an ACL tear. Osteophyte bone volume was available for 150 participants, of which 13% had an ACL tear. The continuous measure of NWI on the coronal images was significantly (P = 0.01) smaller in participants with ACL tear [0.246, 95% confidence interval (CI) 0.234–0.258] compared to those without (0.263, 95% CI 0.258–0.268). Adjustment for demographic variables still showed significant results (P = 0.03, mean difference 0.015 95% CI −0.001–0.030) and adjustment for demographic variables and osteophyte bone volume were borderline significant (P = 0.06, mean difference 0.015 95% CI 0.001–0.029).
We identified a smaller NWI in participants with knee OA and ACL tears. Further longitudinal investigation is necessary to determine this as an independent risk factor.
PMCID: PMC4174406  PMID: 19835830
Knee OA; ACL tear; Notch stenosis; NWI
13.  Intermittent hypoxia-induced rat pancreatic β-cell apoptosis and protective effects of antioxidant intervention 
Fang, Y | Zhang, Q | Tan, J | Li, L | An, X | Lei, P
Nutrition & Diabetes  2014;4(9):e131-.
Obstructive sleep apnea hypopnea syndrome (OSAHS), a common sleep and breathing disorder, is independently associated with metabolic dysfunction, including impaired glucose tolerance and insulin resistance. Intermittent hypoxia (IH), a pathological component of OSAHS, increases oxidative stress damage to pancreatic β-cells in animal models resembling patients with OSAHS. However, the precise mechanisms of IH-induced pancreatic β-cell dysfunction are not fully understood. In the present study, we established a mice model to investigate the underlying mechanisms of oxidative stress in IH-induced pancreatic β-cell apoptosis through antioxidant N-acetylcysteine (NAC) pretreatment.
Twenty-four Wistar rats were randomly divided into four experimental groups: normal control group, intermittent normoxia group, IH group and antioxidant intervention group. Pancreatic β-cell apoptosis rates were detected by terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling; Bcl-2 and Bax protein expressions were detected by immunohistochemistry staining and western blotting.
In our study, we demonstrated that IH exposure causes an increased activation of pancreatic β-cell apoptosis compared with that in the normal control group and intermittent normoxia group, accompanied by the downregulation of Bcl-2 and upregulation of Bax (P<0.05). Furthermore, compared with the IH group, antioxidant (NAC) pretreatment significantly decreased IH-mediated β-cell apoptosis and reversed the ratio of Bcl-2/Bax expression (P<0.05).
Taken together, these results demonstrate a critical role of oxidative stress in the regulation of apoptosis through Bcl-2 and Bax signaling. The antioxidant NAC has a protective effect against IH-induced pancreatic β-cell apoptosis.
PMCID: PMC4183969  PMID: 25177911
14.  The Inhibition Of Cocaine-Induced Locomotor Activity By CART 55-102 Is Lost After Repeated Cocaine Administration 
Neuroscience letters  2013;550:179-183.
CART peptide is known for having an inhibitory effect on cocaine- and dopamine-mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine-mediated LMA after chronic administration of cocaine. The loss of CART peptide’s inhibitory effect did not return for up to nine weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction.
PMCID: PMC3901563  PMID: 23819981
CART peptide; CART 55-102; cocaine; acute; chronic
15.  Associations of blood glucose and prevalent diabetes with risk of cardiovascular disease in 500 000 adult Chinese: the China Kadoorie Biobank 
Diabetic Medicine  2014;31(5):540-551.
To examine the relationship of self‐reported diabetes, and of random blood glucose levels among individuals without known diabetes, with the prevalence of cardiovascular disease in Chinese adults.
We examined cross‐sectional data from the China Kadoorie Biobank of 0.5 million people aged 30–79 years recruited from 10 diverse regions of China in the period 2004–2008. Logistic regression was used to estimate the odds ratios of prevalent cardiovascular disease associated with self‐reported diabetes, and with measured random blood glucose levels among participants with no history of diabetes, adjusting simultaneously for age, sex, area, education, smoking, alcohol, blood pressure and physical activity.
A total of 3.2% of participants had self‐reported diabetes (men 2.9%; women 3.3%) and 2.8% had screen‐detected diabetes (men 2.6%; women 2.8%), i.e. they had no self‐reported history of diabetes but a blood glucose level suggestive of a diagnosis of diabetes. Compared with individuals without a history of diabetes, the odds ratios associated with self‐reported diabetes were 2.18 (95% CI 2.06–2.30) and 1.88 (95% CI 1.75–2.01) for prevalent ischaemic heart disease and stroke/transient ischaemic attack, respectively. Among participants without self‐reported diabetes there was a positive association between random blood glucose and ischaemic heart disease and stroke/transient ischaemic attack prevalence (P for trend <0.0001). Below the diabetic threshold (<11.1 mmol/l) each additional 1 mmol/l of random blood glucose was associated with 4% (95% CI 2–5%) and 5% (95% CI 3–7%) higher odds of prevalent ischaemic heart disease and stroke/transient ischaemic attack, respectively.
In this adult Chinese population, self‐reported diabetes was associated with a doubling of the odds of prevalent cardiovascular disease. Below the threshold for diabetes there was still a modest, positive association between random blood glucose and prevalent cardiovascular disease.
PMCID: PMC4114560  PMID: 24344928
16.  Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen: Revised and Updated Results 
We previously reported that the ESR1 XbaI, analyzed by PCR followed by restriction enzyme digestion, was associated with baseline and tamoxifen-induced serum lipid profiles. After re-analysis using more robust Taqman® assays, ~10% of the genotypes for the ESR1 XbaI SNP were revised. Other genotypes (ESR1 PvuII, ESR2, and CYP2D6) were nearly identical. When re-analyzed, previously reported associations between ESR1-Xba1 genotypes and baseline triglyceride levels or LDL cholesterol, or between ESR1 XbaI genotype and tamoxifen-induced changes in total cholesterol, triglycerides or HDL-cholesterol were no longer observed. However, the following observations from the original report have not changed: 1) decreased circulating lipids in women taking tamoxifen 2) an association of changes in triglycerides with ESR2-02 genotype, and 3) no association between either ESR1 PvuII or CYP2D6 and changes in serum lipid concentrations after tamoxifen treatment.
PMCID: PMC4077673  PMID: 20827267
Breast Cancer; tamoxifen; lipids; estrogen receptor; pharmacogenetics
17.  Muscarinic receptors prevent oxidative stress-mediated apoptosis induced by domoic acid in mouse cerebellar granule cells 
Journal of neurochemistry  2009;109(2):525-538.
In mouse cerebellar granule neurons (CGNs) low concentrations of domoic acid (DomA) induce apoptotic cell death, which is mediated by oxidative stress; apoptosis is more pronounced in CGNs from Gclm (−/−) mice, which lack the modifier subunit of glutamate cysteine ligase (GCL) and have very low glutathione (GSH) levels. By activating M3 muscarinic receptors, the cholinergic agonist carbachol inhibits DomA-induced apoptosis, and the anti-apoptotic action of carbachol is more pronounced in CGNs from Gclm (+/+) mice. Carbachol does not prevent DomA-induced increase in reactive oxygen species (ROS), suggesting that its anti-apoptotic effect is downstream of ROS production. Carbachol inhibits DomA-induced activation of JNK and p38 kinases, increased translocation to mitochondria of the pro-apoptotic protein Bax, and activation of caspase-3. Carbachol activates Erk 1/2 mitogen-activated protein kinase (MAPK) and phospahtidylinositol-3 kinase (PI3K) in CGNs from both genotypes. However, while the protective effect of carbachol is mediated by Erk1/2 MAPK in CGNs from both mouse genotypes, inhibitors of PI3K are only effective at antagonizing the action of carbachol in CGNs from Gclm (+/+) mice. In CGNs from both Gclm (+/+) and (−/−) mice, carbachol induces a MAPK-dependent increase in the level of the anti-apoptotic protein Bcl-2. In contrast, carbachol causes a PI3K-dependent increase in GCL activity and of GSH levels only in CGNs from Gclm (+/+) mice. Such increase in GCL is not due to a transcriptionally-mediated increase in GCLC (the catalytic subunit) or GCLM, but rather to an increase in the formation of the GCL holoenzyme. The results indicate that multiple pathways may contribute to the protective action of carbachol toward DomA-induced apoptosis. Compromised GCLM expression, which is also found in a common genetic polymorphism in humans, leads to lower GSH levels, which can exacerbate the neurotoxicity of DomA, and decreases the anti-apoptotic effectiveness of muscarinic agonists.
PMCID: PMC4045406  PMID: 19200344
domoic acid; muscarinic receptors; carbachol; apoptosis; phosphoinositide-3-kinase; glutamate cysteine ligase
18.  Concurrent chemoradiotherapy followed by adjuvant chemotherapy compared with concurrent chemoradiotherapy alone for the treatment of locally advanced nasopharyngeal carcinoma: a retrospective controlled study 
Current Oncology  2014;21(3):e408-e417.
We evaluated the survival benefit of providing concurrent chemoradiotherapy (ccrt) plus adjuvant chemotherapy compared with ccrt alone to patients with locally advanced nasopharyngeal carcinoma.
This retrospective study included 130 patients with nasopharyngeal carcinoma treated with ccrt plus adjuvant chemotherapy from June 2005 to December 2010. Another 130 patients treated with ccrt alone during the same period were matched on age, sex, World Health Organization histology, T stage, N stage, and technology used for radiotherapy. The endpoints included overall survival, locoregional failure-free survival, distant metastasis failure-free survival, and failure-free survival.
At a mean follow-up of 42.1 months (range: 8–85 months), the observed hazard ratios for the group receiving ccrt plus adjuvant chemotherapy compared with the group receiving ccrt alone were: for overall survival, 0.77 [95% confidence interval (ci): 0.37 to 1.57]; for locoregional failure-free survival, 1.00 (95% ci: 0.37 to 2.71); for distant metastasis failure-free survival, 1.15 (95% ci: 0.56 to 2.37); and for failure-free survival, 1.26 (95% ci: 0.69 to 2.28). There were no significant differences in survival between the groups. After stratification by disease stage, ccrt plus adjuvant chemotherapy provided a borderline significant benefit for patients with N2–3 disease (hazard ratio: 0.35; 95% ci: 0.11 to 1.06; p = 0.052). Multivariate analyses indicated that only tumour stage was a prognostic factor for overall survival.
Patients with locally advanced nasopharyngeal carcinoma received no significant survival benefit from the addition of adjuvant chemotherapy to ccrt. However, patients with N2–3 disease might benefit from the addition of adjuvant chemotherapy to ccrt.
PMCID: PMC4059804  PMID: 24940100
Nasopharyngeal carcinoma; concurrent chemoradiotherapy; adjuvant chemotherapy
19.  Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway 
Oncogenesis  2014;3(6):e105-.
Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer.
PMCID: PMC4150214  PMID: 24911876
20.  Evidence of Multi-step Nucleation Leading to Various Crystallization Pathways from an Fe-O-Al Melt 
Scientific Reports  2014;4:5082.
The crystallization process from a solution begins with nucleation, which determines the structure and size of the resulting crystals. Further understanding of multi-pathway crystallizations from solution through two-step nucleation mechanisms is needed. This study uses density functional theory to probe the thermodynamic properties of alumina clusters at high temperature and reveals the thermodynamic relationship between these clusters and the saturation levels of dissolved oxygen and aluminum in an Fe–O–Al melt. Based on the thermodynamics of cluster formation and the experimental evidence for both excess oxygen in the Fe-O-Al melt and for alumina with a polycrystalline structure in solidified iron, we demonstrate that the appearance of various types of clusters that depends on the saturation ratio determines the nucleation steps that lead to the various crystallization pathways. Such mechanisms may also be important in nucleation and crystallization from solution.
PMCID: PMC4035573  PMID: 24866413
21.  Mortality of patients with multiple sclerosis: a cohort study in UK primary care 
Journal of Neurology  2014;261(8):1508-1517.
We aimed to estimate rates, causes and risk factors of all-cause mortality in a large population-based cohort of multiple sclerosis (MS) patients compared with patients without MS. Using data from the UK General Practice Research Database, we identified MS cases diagnosed during 2001–2006 and validated using patients’ original records where possible. We also included MS cases during 1993–2000 identified and validated in an earlier study. Cases were matched to up to ten referents without MS by age, sex, index date (date of first MS diagnosis for cases and equivalent reference date for controls), general practice and length of medical history before first MS diagnosis. Patients were followed up to identify deaths; hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using Cox-proportional regression. MS patients (N = 1,822) had a significantly increased risk of all-cause mortality compared with referents (N = 18,211); adjusted HR 1.7 (95 % CI 1.4–2.1). Compared with referents, female MS patients had a higher but not significantly different HR for death than males; adjusted HR 1.86 (95 % CI 1.46–2.38) vs. HR 1.31 (95 % CI 0.93–1.84), respectively. The most commonly recorded cause of death in MS patients was ‘MS’ (41 %), with a higher proportion recorded among younger patients. A significantly higher proportion of referents than MS patients had cancer recorded as cause of death (40 vs. 19 %). Patients with MS have a significant 1.7-fold increased risk of all-cause mortality compared with the general population. MS is the most commonly recorded cause of death among MS patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-014-7370-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4119255  PMID: 24838537
Multiple sclerosis; Epidemiology; Cause of death; Cohort analysis; Mortality
22.  Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance 
The organic cation transporter 2 (OCT2) regulates uptake of cisplatin in proximal tubules and inhibition of OCT2 protects against severe cisplatin-induced nephrotoxicity. However, it remains uncertain whether potent OCT2 inhibitors such as cimetidine can influence the antitumor properties and/or disposition of cisplatin. Using an array of preclinical assays, we found that cimetidine had no effect on the uptake and cytotoxicity of cisplatin in ovarian cancer cells with high OCT2 mRNA levels (IGROV-1). Moreover, the antitumor efficacy of cisplatin in mice bearing luciferase-tagged IGROV-1 xenografts was unaffected by cimetidine (P = 0.39). Data obtained in 18 patients receiving cisplatin (100 mg/m2) in a randomized crossover fashion with or without cimetidine (800 mg×2) revealed that cimetidine did not alter exposure to unbound cisplatin, a marker of antitumor efficacy (4.37 vs 4.38 μg×h/mL; P = 0.86). These results support the future clinical exploration of OCT2 inhibitors as specific modifiers of cisplatin-induced nephrotoxicity.
PMCID: PMC3832209  PMID: 23863876
SLC22A2 (OCT2); Cisplatin; Nephrotoxicity; cimetidine
23.  Rasfonin, a novel 2-pyrone derivative, induces ras-mutated Panc-1 pancreatic tumor cell death in nude mice 
Xiao, Z | Li, L | Li, Y | Zhou, W | Cheng, J | Liu, F | Zheng, P | Zhang, Y | Che, Y
Cell Death & Disease  2014;5(5):e1241-.
Rasfonin is a novel 2-pyrone derivative reported to induce apoptosis in ras-dependent cells. In this study, its effects on ras-mutated pancreatic cancer cells were investigated in vitro and in vivo. Two human pancreatic cancer cell lines Panc-1 (mutated K-ras) and BxPC-3 (wild-type K-ras) were selected to test the effects of rasfonin on cell proliferation, clone formation, migration and invasion in vitro. Immunoblotting was used to detect the expressions of EGFR–Ras–Raf–MEK–ERK signaling pathway proteins. Ras activity was measured using a pull-down ELISA kit and guanine exchange factor (GEF)/GTPase-activating proteins (GAP) activity was measured by [3H]-GDP radiometric ligand binding. For an in vivo study, CD1 nude mice bearing Panc-1 cells were treated with rasfonin or Salirasib (FTS). We found that rasfonin suppressed proliferation more strongly in Panc-1 cells (IC50=5.5 μM) than BxPC-3 cells (IC50=10 μM) in vitro. Clone formation, migration and invasion by Panc-1 cells were also reduced by rasfonin. Rasfonin had little effect on the farnesylation of Ras, but it strongly downregulated Ras activity and consequently phosphorylation of c-Raf/MEK/ERK. Further experiments indicated that rasfonin reduced Son of sevenless (Sos1) expression but did not alter GEF and GAP activities. The in vivo experiments also revealed that rasfonin (30 mg/kg) delayed the growth of xenograft tumors originating from Panc-1 cells. Tumor weight was ultimately decreased after 20 days of treatment of rasfonin. Rasfonin is a robust inhibitor of pancreatic cancers with the K-ras mutation. The reduction of Sos1 expression and the consequently depressed Ras–MAPK activity could be important in its anticancer activity.
PMCID: PMC4047882  PMID: 24853419
rasfonin; ras; pancreatic cancer; sos1; Panc-1 cell
24.  Strategies for Profiling Single Mouse Intestinal Epithelial Cells by Targeted Gene Expression 
Targeted gene expression profiling of single cells permits the study of heterogeneity in cell populations. Here, a pool of mouse intestinal crypt-base CD44+/GRP78- cells was collected by fluorescence activated cell sorting. Aliquots were either loaded onto Fluidigm's C1 System for microfluidic cell capture and cDNA synthesis in nanoliter volumes, or flow-sorted directly into individual PCR plate wells for cDNA synthesis in microliter volumes. The pre-amplified cDNAs were transferred to the BioMark System for EvaGreen real-time PCR. The two sample preparation methods were compared by expression analysis of 86 genes, using Fluidigm's SINGuLAR R-scripts. After outlier identification, gene expression values from 42% of the “C1” and 92% of the “flow” wells were retained. For 55 of the genes, expression was measured in both the “C1” and “flow” cells. Genes with a high variance in expression likely stemming from the sample preparation method and/or unspecific amplification were removed. Hierarchical clustering on the remaining data revealed gene clusters that contributed to the expected Lgr5hi and Lgr5lo intestinal stem cell (ISC) populations as well as a small population of differentiated cells. The subpopulations could be defined by either method. However, as ISCs quickly undergo apoptosis at room temperature, the use of the C1 System provided no clear advantage over the direct sorting of the fragile cells into lysis/RT reaction buffer. Specifically, the C1 quality control step to verify the number of captured cells and cell viability was omitted to accelerate processing.
PMCID: PMC4162251
25.  Mesenteric lymph reperfusion exacerbates spleen injury caused by superior mesenteric artery occlusion shock 
The intestinal lymph pathway plays an important role in the pathogenesis of organ injury following superior mesenteric artery occlusion (SMAO) shock. We hypothesized that mesenteric lymph reperfusion (MLR) is a major cause of spleen injury after SMAO shock. To test this hypothesis, SMAO shock was induced in Wistar rats by clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h. Similarly, MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h, followed by reperfusion for 2 h. In the MLR+SMAO group rats, both the SMA and MLD were clamped and then released for reperfusion for 2 h. SMAO shock alone elicited: 1) splenic structure injury, 2) increased levels of malondialdehyde, nitric oxide (NO), intercellular adhesion molecule-1, endotoxin, lipopolysaccharide receptor (CD14), lipopolysaccharide-binding protein, and tumor necrosis factor-α, 3) enhanced activities of NO synthase and myeloperoxidase, and 4) decreased activities of superoxide dismutase and ATPase. MLR following SMAO shock further aggravated these deleterious effects. We conclude that MLR exacerbates spleen injury caused by SMAO shock, which itself is associated with oxidative stress, excessive release of NO, recruitment of polymorphonuclear neutrophils, endotoxin translocation, and enhanced inflammatory responses.
PMCID: PMC4075305  PMID: 24760116
Mesenteric lymph reperfusion; Superior mesenteric artery; Shock; Spleen injury; Endotoxin; Inflammation

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