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1.  Anti-Cancer Activities of Tea Epigallocatechin-3-Gallate in Breast Cancer Patients under Radiotherapy 
Current Molecular Medicine  2012;12(2):163-176.
The purpose of this study was to test the hypothesis that administration of epigallocatechin-3-gallate (EGCG), a polyphenol present in abundance in widely consumed tea, inhibits cell proliferation, invasion, and angiogenesis in breast cancer patients. EGCG in 400 mg capsules was orally administered three times daily to breast cancer patients undergoing treatment with radiotherapy. Parameters related to cell proliferation, invasion, and angiogenesis were analyzed while blood samples were collected at different time points to determine efficacy of the EGCG treatment. Compared to patients who received radiotherapy alone, those given radiotherapy plus EGCG for an extended time period (two to eight weeks) showed significantly lower serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and reduced activation of metalloproteinase-9 and metalloproteinase-2 (MMP9/MMP2). Addition of sera obtained from patients treated with combination of radiotherapy and EGCG feeding for 2–8 weeks to in vitro cultures of highly-metastatic human MDA-MB-231 breast cancer cells resulted in the following significant changes: (1) suppression of cell proliferation and invasion; (2) arrest of cell cycles at the G0/G1 phase; (3) reduction of activation of MMP9/MMP2, expressions of Bcl-2/Bax, c-Met receptor, NF-κB, and the phosphorylation of Akt. MDA-MB-231 cells exposed to 5–10 µM EGCG also showed significant augmentation of the apoptosis inducing effects of γ-radiation, concomitant with reduced NF-κB protein level and AKT phosphorylation. These results provide hitherto unreported evidence that EGCG potentiated efficacy of radiotherapy in breast cancer patients, and raise the possibility that this tea polyphenol has potential to be a therapeutic adjuvant against human metastatic breast cancer.
PMCID: PMC3305796  PMID: 22280355
Adjuvant therapy; breast cancer patients; EGCG; γ-radiation; HGF; MMP9/MMP2; VEGF
3.  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
4.  The features of breast lymphoma on MRI 
The British Journal of Radiology  2013;86(1031):20130220.
To investigate the morphological features of breast lymphoma (BL) on MRI.
MRI features of 20 patients with BL (12 primary and 8 secondary) were reviewed according to Breast Imaging-Reporting and Data System categories.
19 cases were unilateral and 1 was bilateral. According to the enhanced images, of the 20 cases, BL presented as a mass in 11 (55%), as an enhancement with no mass effect in 7 (35%) and as a mass and mixed enhancement with no mass effect in 2 (10%). There were 38 masses and 44 lesions with no mass effect in our study. All lesions showed mild heterogeneous internal enhancement. For lesions with mass effect, the margins were smooth in 32% (12/38) and irregular in 68% (26/38); and the shape was oval in 87% (32/38). Kinetic curve assessment (13 cases, 38 lesions) revealed that the average initial rise rate was 104%. The type II enhancement curve appeared in 55% (21/38) of lesions. No significant differences between the primary and secondary BL were observed for any of the MRI features.
BL mostly appeared oval with irregular margins showing mild heterogeneous internal enhancement and/or as enhanced lesions with no mass effect with mild heterogeneous internal enhancement.
Advances in knowledge:
Some special features on MRI are useful for the diagnosis of BL.
PMCID: PMC3830428  PMID: 24029630
5.  Role of leptin receptor gene polymorphisms in susceptibility to the development of essential hypertension: a case–control association study in a Northern Han Chinese population 
Journal of human hypertension  2014;28(9):551-556.
In order to explore the potential association between the leptin receptor (LEPR) gene polymorphisms and essential hypertension (EH) risk in the Northern Han Chinese population, we recruited 823 hypertensive subjects and 491 healthy control subjects from the Northern Han Chinese. Genotyping was performed to identify the Lys109Arg, Gln223Arg and Lys656Asn polymorphisms of the LEPR gene. Significant associations were found in a dominant genetic model ([GG+AG] vs AA), P=0.007, odds ratio (OR)=3.697, 95% confidence interval (CI) 1.442–9.482), and in homozygote comparison (GG vs AA, P=0.005, OR=3.890, 95% CI 1.501–10.077) for the Gln223Arg polymorphism. No significant association could be found between Lys109Arg or Lys656Asn polymorphism and EH risk. Linkage disequilibrium was detected between the Lys109Arg and Gln223Arg polymorphisms, and haplotype analyses identified that the G-A haplotype was a protective haplotype for EH. Our studies demonstrated that the LEPR Gln223Arg polymorphism had an important role in a patient's susceptibility to EH in the Northern Han Chinese population.
PMCID: PMC4133281  PMID: 24522342
leptin receptor; polymorphism; essential hypertension; Chinese; linkage disequilibrium; haplotypes
6.  Ethnicity, plasma phospholipid fatty acid composition and inflammatory/endothelial activation biomarkers in the Multi-Ethnic Study of Atherosclerosis (MESA) 
It has been recognized that certain long-chain polyunsaturated fatty acids (LC-PUFAs) are involved in inflammation and its resolution. It has also been shown that ethnicity may be a factor in affecting systemic inflammation, and limited evidence suggests it may influence plasma LC-PUFA composition. Given the links among these three factors, we aim to determine ethnicity-based differences in plasma LC-PUFA composition among White, Black, Hispanic and Chinese participants, and whether such differences contribute to variations in markers of inflammation and endothelial activation in a sub-cohort of the Multi-Ethnic Study of Atherosclerosis (MESA).
Plasma phospholipid LC-PUFAs levels (%) were determined in 2848 MESA participants using gas chromatography-flame ionization detection. Enzyme immunoassays determined inflammatory markers levels for high-sensitivity C-reactive protein (n =2848), interleukin-6 (n =2796), soluble tumor necrosis factor-α receptor type 1 (n =998), and endothelial activation markers soluble intercellular adhesion molecule-1 (n =1192) and soluble E-selectin (n =998).
The modifying influence of ethnicity was tested by linear regression analysis.
Chinese adults were found to have the highest mean levels of plasma eicosapentaenoic acid (EPA, 1.24%) and docosahexaenoic acid (DHA, 4.95%), and the lowest mean levels of γ-linolenic (0.10%), dihomo-γ-linolenic (DGLA, 2.96%) and arachidonic (10.72%) acids compared with the other ethnicities (all P≤0.01). In contrast, Hispanics had the lowest mean levels of plasma EPA (0.70%) and DHA (3.49%), and the highest levels of DGLA (3.59%; all P≤0.01). Significant differences in EPA and DHA among ethnicities were attenuated following adjustment for dietary non-fried fish and fish oil supplementation. Ethnicity did not modify the associations of LC-PUFAs with markers of inflammation or endothelial activation (all Pinteraction>0.05).
The absence of a modifying effect of ethnicity indicates that the putative benefits of LC-PUFAs with respect to inflammation are pan-ethnic. Future longitudinal studies may elucidate the origin(s) of ethnicity-based differences in LC-PUFA composition and whether certain patterns, that is, high plasma levels of DGLA and low levels of EPA/DHA, contribute to inflammation-associated health outcomes.
PMCID: PMC4096912  PMID: 22215136
race; endothelial activation; inflammation; fatty acid; omega-3; omega-6
7.  Periodontitis-specific molecular signatures in gingival crevicular fluid 
Journal of periodontal research  2010;45(3):345-352.
Background and Objective
Periodontitis is currently diagnosed almost entirely on gross clinical manifestations that have been in situ for more than 50 years without significant improvement. The general objective of this study was, therefore, to evaluate whether mid-infrared spectroscopy can be used to identify disease-specific molecular alterations to the overall biochemical profile of tissues and body fluids.
Material and Methods
A total of 190 gingival crevicular fluid samples were obtained from periodontitis (n = 64), gingivitis (n = 61) and normal sites (n = 65). Corresponding infrared absorption spectra of gingival crevicular fluid samples were acquired and processed, and the relative contributions of key functional groups in the infrared spectra were analysed. The qualitative assessment of clinical relevance of these gingival crevicular fluid spectra was interpreted with the multivariate statistical analysis-linear discriminant analysis.
Using infrared spectroscopy, we have been able to identify four molecular signatures (representing vibrations in amide I, amide II/tyrosine rings and symmetric and asymmetric stretching vibrations of phosphodiester groups in DNA) in the gingival crevicular fluid of subjects with periodontitis or gingivitis and healthy control subjects that clearly demarcate healthy and diseased periodontal tissues. Furthermore, the diagnostic accuracy for distinction between periodontally healthy and periodontitis sites revealed by multivariate classification of gingival crevicular fluid spectra was 98.4% for a training set of samples and 93.1% for a validation set.
We have established that mid-infrared spectroscopy can be used to identify periodontitis-specific molecular signatures in gingival crevicular fluid and to confirm clinical diagnoses. Future longitudinal studies will assess whether mid-infrared spectroscopy represents a potential prognostic tool, recognized as key to advancement of periodontics.
PMCID: PMC4078927  PMID: 20337898
gingival crevicular fluid; inflammation; infrared spectroscopy; periodontitis
8.  Using Electronic Dental Record Data for Research 
Journal of Dental Research  2013;92(7 Suppl):S90-S96.
Anecdotal evidence suggests that, during the clinical care process, many dental practices record some data that are also collected in dental practice based research network (PBRN) studies. Since the use of existing, electronically stored data for research has multiple benefits, we investigated the overlap between research data fields used in dental PBRN studies and clinical data fields typically found in general dental records. We mapped 734 unique data elements from the Dental Information Model (DIM) to 2,487 Common Data Elements (CDE) curated by the NIDCR’s PBRNs in the Cancer Data Standards Registry and Repository (caDSR). Thirty-three percent of the DIM data elements matched at least one CDE completely and 9% partially, translating to about 9% and 2%, respectively, of all data elements used in PBRN studies. The most frequently used CDEs found in the DIM included data about dental anatomy, medications, and items such as oral biopsy and caries. Our study shows that a non-trivial number of data elements in general dental records can be mapped either completely or partially to data fields in research studies. Further studies should investigate the feasibility of electronic clinical data for research purposes.
PMCID: PMC3706179  PMID: 23690362
dental records; dental informatics; electronic health records; computerized Patient Records; clinical research; dental research
9.  CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing Beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2 
Liu, K | Shi, Y | Guo, X | Wang, S | Ouyang, Y | Hao, M | Liu, D | Qiao, L | Li, N | Zheng, J | Chen, D
Cell Death & Disease  2014;5(7):e1323-.
Apoptosis-stimulating protein of p53-2 (ASPP2) induces apoptosis by promoting the expression of pro-apoptotic genes via binding to p53 or p73; however, the exact mechanisms by which ASPP2 induces apoptotic death in hepatoma cells are still unclear. Here, we show that the transient overexpression of ASPP2 induces autophagic apoptosis in hepatoma cells by promoting p53- or p73-independent C/EBP homologous protein (CHOP) expression. CHOP expression decreases the expression of Bcl-2; this change releases Beclin-1 from cytoplasmic Bcl-2-Beclin-1 complexes and allows it to initiate autophagy. However, transient overexpression of Beclin-1 can induce autophagy but not apoptosis. Our results show that ASPP2 induces the expression of damage-regulated autophagy modulator (DRAM), another critical factor that cooperates with free Beclin-1 to induce autophagic apoptosis. The effect of CHOP on the translocation and sequestration of Bcl-2 in the nucleus, which requires the binding of Bcl-2 to ASPP2, is also critical for ASPP2-induced autophagic apoptosis. Although the role of nuclear ASPP2–Bcl-2 complexes is still unclear, our results suggest that nuclear ASPP2 can prevent the translocation of the remaining Bcl-2 to the cytoplasm by binding to Bcl-2 in a CHOP-dependent manner, and this effect also contributes to Beclin-1-initiated autophagy. Thus, CHOP is critical for mediating ASPP2-induced autophagic apoptosis by decreasing Bcl-2 expression and maintaining nuclear ASPP2–Bcl-2 complexes. Our results, which define a mechanism whereby ASPP2 overexpression induces autophagic apoptosis, open a new avenue for promoting autophagy in treatments to cure hepatocellular carcinoma.
PMCID: PMC4123070  PMID: 25032846
10.  Safety culture in a pharmacy setting using a pharmacy survey on patient safety culture: a cross-sectional study in China 
BMJ Open  2014;4(6):e004904.
To explore the attitudes and perceptions of patient safety culture for pharmacy workers in China by using a Pharmacy Survey on Patient Safety Culture (PSOPSC), and to assess the psychometric properties of the translated Chinese language version of the PSOPSC.
Cross-sectional study.
Data were obtained from 20 hospital pharmacies in the southwest part of China.
We performed χ2 test to explore the differences on pharmacy staff in different hospital and qualification levels and countries towards patient safety culture. We also computed descriptive statistics, internal consistency coefficients and intersubscale correlation analysis, and then conducted an exploratory factor analysis. A test–retest was performed to assess reproducibility of the items.
A total of 630 questionnaires were distributed of which 527 were responded to validly (response rate 84%). The positive response rate for each item ranged from 37% to 90%. The positive response rate on three dimensions (‘Teamwork’, ‘Staff Training and Skills’ and ‘Staffing, Work Pressure and Pace’) was higher than that of Agency for Healthcare Research and Quality (AHRQ) data (p<0.05). There was a statistical difference in the perception of patient safety culture at different hospital and qualification levels. The internal consistency of the total survey was comparatively satisfied (Cronbach's α=0.89).
The results demonstrated that among the pharmacy staffs surveyed in China, there was a positive attitude towards patient safety culture in their organisations. Identifying perspectives of patient safety culture from pharmacists in different hospital and qualification levels are important, since this can help support decisions about action to improve safety culture in pharmacy settings. The Chinese translation of the PSOPSC questionnaire (V.2012) applied in our study is acceptable.
PMCID: PMC4078772  PMID: 24980042
Health Services Administration & Management
11.  Utility of Intraoperative Angiography during Subaxial Foramen Transversarium Decompression for Bow Hunter's Syndrome 
Interventional Neuroradiology  2013;19(2):240-244.
Bow hunter's syndrome is an uncommon cause of vertebrobasilar insufficiency resulting from rotational compression of the extracranial vertebral artery. While positional compression of any portion of the extracranial vertebral artery has been reported to result in bow hunter's syndrome, the most common site of compression is the V2 segment as it passes through the foramen transversarium of the subaxial cervical spine. A 43-year-old woman presented with increasingly frequent pre-syncopal and syncopal episodes upon leftward head rotation. Pre-operative angiographic studies with the neck rotated to the left demonstrated occlusion of the left vertebral artery by a C4-5 osteophyte arising from the C4 uncinate process. The patient underwent microsurgical decompression of the vertebral artery at C4-5 through a standard anterior transcervical retropharyngeal approach. Selective vertebral artery intraoperative angiography performed with the head passively rotated to the left before and after left vertebral artery decompression showed marked improvement in the luminal diameter and blood flow. The patient's symptoms resolved post-operatively. This case illustrates the second instance of intraoperative angiography used to confirm adequate vertebral artery decompression for bow hunter's syndrome. Intraoperative angiography can be safely used to decrease the extent of vertebral artery decompression in order to minimize the risk of operative complications.
PMCID: PMC3670065  PMID: 23693050
vertebrobasilar insufficiency, stroke, endovascular procedures, vertebral artery, spondylosis
12.  The 4G/4G Genotype of the PAI-1 (Serpine-1) 4G/5G Polymorphism Is Associated With Decreased Lung Allograft Utilization 
Widespread thrombi are found among donor lungs rejected for transplantation. The 4G/5G polymorphism in the plasminogen activator inhibitor (PAI-1) gene impacts transcription and the 4G allele is associated with increased PAI-1 levels. We hypothesized that the 4G/4G genotype would be associated with decreased lung graft utilization, potentially because of worse oxygenation in the donor. We genotyped donors managed by the California Transplant Donor Network from 2001 to 2008 for the 4G/5G polymorphism in the PAI-1 gene. Non-Hispanic donors from 2001 to 2005 defined the discovery cohort (n = 519), whereas donors from 2006 to 2008 defined the validation cohort (n = 369). We found, that the odds of successful lung utilization among Non-Hispanic white donors were lower among donors with the 4G/4G genotype compared to those without this genotype in both the discovery (OR = 0.55, 95% CI 0.3–0.9, p = 0.02) and validation (OR = 0.5, 95% CI = 0.3–0.9, p = 0.03) cohorts. This relationship was independent of age, gender, cause ocause of death, drug use and history of smoking. Donors with the 4G/4G genotype also had a lower PaO2/FiO2 ratio (p = 0.03) and fewer donors with the 4G/4G geno-type achieved the threshold PaO2/FiO2 ratio ≥ 300 (p = 0.05). These findings suggest a role for impaired 1848 fibrinolysis resulting in worse gas exchange and decreased donor utilization.
PMCID: PMC4018219  PMID: 22390401
PAI-1; polymorphisms; transplantation
13.  Understanding the roadmaps to induced pluripotency 
Liu, K | Song, Y | Yu, H | Zhao, T
Cell Death & Disease  2014;5(5):e1232-.
Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by ectopic expression of transcription factors Oct4, Sox2, Klf4 and cMyc. Recent advancements have shown that small-molecule compounds can induce pluripotency, indicating that cell fate can be regulated by direct manipulation of intrinsic cell signaling pathways, thereby innovating our current understanding of reprogramming. The fact that lineage specifiers can induce pluripotency suggests that the pluripotent state is a fine balance between competing differentiation forces. Dissection of pluripotent roadmaps indicates that reprogramming is a process of reverse development, involving a series of complicated and distinct reprogramming stages. Evidence from mouse iPSC transplantation studies demonstrated that some certain but not all cells derived from iPSCs are immunogenic. These studies provide new ways to minimize reprogramming-induced abnormalities and maximize reprogramming efficiency to facilitate clinical development and use of iPSCs.
PMCID: PMC4047905  PMID: 24832604
induced pluripotent stem cells (iPSC); see-saw model; mesenchymal-to-epithelial transition (MET); epithelial-to-mesenchymal transition (EMT); small molecules; immunogenicity
14.  Potassium intake and risk of incident type 2 diabetes mellitus: the Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Diabetologia  2012;55(5):1295-1303.
Serum potassium has been found to be a significant predictor of diabetes risk, but the effect of dietary potassium on diabetes risk is not clear. We sought to determine if dietary potassium is associated with risk of incident type 2 diabetes in young adults.
We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Potassium intake was measured by (1) an average of three 24 h urinary potassium collections at the 5-year study visit, and (2) the CARDIA dietary assessment instrument at baseline. Incident type 2 diabetes cases were ascertained on the basis of use of diabetes medication and laboratory measurements. Analyses were adjusted for relevant confounders including intake of fruit and vegetables and other dietary factors.
Of 1,066 participants with urinary potassium measurements, 99 (9.3%) developed diabetes over 15 years of follow-up. In multivariate models, adults in the lowest urinary potassium quintile were more than twice as likely to develop diabetes as their counterparts in the highest quintile (HR 2.45; 95% CI 1.08, 5.59). Of 4,754 participants with dietary history measurements, 373 (7.8%) developed diabetes over 20 years of follow-up. In multivariate models, African-Americans had a significantly increased risk of diabetes with lower potassium intake, which was not found in whites.
Low dietary potassium is associated with increased risk of incident diabetes in African-Americans. Randomised clinical trials are needed to determine if potassium supplementation, from either dietary or pharmacological sources, could reduce the risk of diabetes, particularly in higher-risk populations.
PMCID: PMC3934349  PMID: 22322920
Diabetes risk; Dietary potassium
15.  Phosphorylated AKT inhibits the apoptosis induced by DRAM-mediated mitophagy in hepatocellular carcinoma by preventing the translocation of DRAM to mitochondria 
Cell Death & Disease  2014;5(2):e1078-.
Increasing autophagy is beneficial for curing hepatocellular carcinoma (HCC). Damage-regulated autophagy modulator (DRAM) was recently reported to induce apoptosis by mediating autophagy. However, the effects of DRAM-mediated autophagy on apoptosis in HCC cells remain unclear. In this study, normal hepatocytes (7702) and HCC cell lines (HepG2, Hep3B and Huh7) were starved for 48 h. Starvation induced apoptosis and autophagy in all cell lines. We determined that starvation also induced DRAM expression and DRAM-mediated autophagy in both normal hepatocytes and HCC cells. However, DRAM-mediated autophagy was involved in apoptosis in normal hepatocytes but not in HCC cells, suggesting that DRAM-mediated autophagy fails to induce apoptosis in hepatoma in response to starvation. Immunoblot and immunofluorescence assays demonstrated that DRAM translocated to mitochondria and induced mitophagy, which led to apoptosis in 7702 cells. In HCC cells, starvation also activated the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which blocks the translocation of DRAM to mitochondria through the binding of p-AKT to DRAM in the cytoplasm. Inactivation of the PI3K/AKT pathway rescued DRAM translocation to mitochondria; subsequently, mitochondrial DRAM induced apoptosis in HCC cells by mediating mitophagy. Our findings open new avenues for the investigation of the mechanisms of DRAM-mediated autophagy and suggest that promoting DRAM-mediated autophagy together with PI3K/AKT inhibition might be more effective for autophagy-based therapy in hepatoma.
PMCID: PMC3944266  PMID: 24556693
hepatocellular carcinoma; DRAM; AKT; apoptosis; autophagy
16.  Regulation of lipid stores and metabolism by lipophagy 
Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial β-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases.
PMCID: PMC3524634  PMID: 22595754
apoptosis; autophagy; cholesterol; hypothalamus; triglycerides
17.  Association of AXIN2 with Non-syndromic Oral Clefts in Multiple Populations 
Journal of Dental Research  2012;91(5):473-478.
We have previously shown the association of AXIN2 with oral clefts in a US population. Here, we expanded our study to explore the association of 11 AXIN2 markers in 682 cleft families from multiple populations. Alleles for each AXIN2 marker were tested for transmission distortion with clefts by means of the Family-based Association Test. We observed an association with SNP rs7224837 and all clefts in the combined populations (p = 0.001), and with SNP rs3923086 and cleft lip and palate in Asian populations (p = 0.004). We confirmed our association findings in an additional 528 cleft families from the United States (p < 0.009). We tested for gene-gene interaction between AXIN2 and additional cleft susceptibility loci. We assessed and detected Axin2 mRNA and protein expression during murine palatogenesis. In addition, we also observed co-localization of Axin2 with Irf6 proteins, particularly in the epithelium. Our results continue to support a role for AXIN2 in the etiology of human clefting. Additional studies should be performed to improve our understanding of the biological mechanisms linking AXIN2 to oral clefts.
PMCID: PMC3327729  PMID: 22370446
cleft lip and palate; genetics; gene expression; gene-gene interactions; wnt pathway; craniofacial anomalies
18.  3D Pathology Volumetric Technique: A Method for Calculating Breast Tumour Volume from Whole-Mount Serial Section Images 
Tumour size, most commonly measured by maximum linear extent, remains a strong predictor of survival in breast cancer. Tumour volume, proportional to the number of tumour cells, may be a more accurate surrogate for size. We describe a novel “3D pathology volumetric technique” for lumpectomies and compare it with 2D measurements. Volume renderings and total tumour volume are computed from digitized whole-mount serial sections using custom software tools. Results are presented for two lumpectomy specimens selected for tumour features which may challenge accurate measurement of tumour burden with conventional, sampling-based pathology: (1) an infiltrative pattern admixed with normal breast elements; (2) a localized invasive mass separated from the in situ component by benign tissue. Spatial relationships between key features (tumour foci, close or involved margins) are clearly visualized in volume renderings. Invasive tumour burden can be underestimated using conventional pathology, compared to the volumetric technique (infiltrative pattern: 30% underestimation; localized mass: 3% underestimation for invasive tumour, 44% for in situ component). Tumour volume approximated from 2D measurements (i.e., maximum linear extent), assuming elliptical geometry, was seen to overestimate volume compared to the 3D volumetric calculation (by a factor of 7x for the infiltrative pattern; 1.5x for the localized invasive mass).
PMCID: PMC3540737  PMID: 23320179
20.  Drug Eluting Stents for Symptomatic Intracranial and Vertebral Artery Stenosis 
Interventional Neuroradiology  2011;17(2):241-247.
The use of bare metal stents (BMS) to prevent recurrent stroke due to stenosis of the cerebral vasculature is associated with high rates of restenosis. Drug-eluting stents (DES) may decrease this risk. We evaluated the performance of DES in a cohort of patients treated at our institution.
Consecutive patients treated with DES were identified by a case log and billing records; data regarding procedural details, clinical outcome and angiographic follow-up was obtained by retrospective chart review.
Twenty-six patients (27 vessels; 14 vertebral origin (VO); 13 intracranial) were treated. Stenosis was reduced from mean 81% to 8% at the VO and 80% to 2% intracranially. No strokes occurred in the first 24 hours after stenting or at any time point in the VO group during a mean follow-up period of nine months. Among patients with intracranial stents, stroke with permanent disability occurred within 30 days in 1/12 (8%) and after 30 days in 1/11 (9%) with clinical follow-up (mean follow-up, 14 months). Follow-up catheter angiography was obtained in 14/14 (100%) in the VO group at mean eight months and in 8/11 surviving patients (73%) at a mean of ten months after stenting in the intracranial group. The restenosis rate was 21% at the VO (3/14) and 38% (3/8) for intracranial stents.
Restenosis at the VO was less frequent than might have been expected from reports utilizing BMS, however, overall restenosis rates appeared higher than previously reported for patients with intracranial DES and comparable with restenosis rates for intracranial BMS.
PMCID: PMC3287278  PMID: 21696666
stroke, intracranial stenosis, endovascular, intracranial stent, drug-eluting stent
21.  Community and gene composition of a human dental plaque microbiota obtained by metagenomic sequencing 
Molecular oral microbiology  2010;25(6):391-405.
Human dental plaque is a complex microbial community containing an estimated 700 to 19,000 species/phylotypes. Despite numerous studies analysing species richness in healthy and diseased human subjects, the true genomic composition of the human dental plaque microbiota remains unknown. Here we report a metagenomic analysis of a healthy human plaque sample using a combination of second-generation sequencing platforms. A total of 860 million base pairs of non-human sequences were generated. Various analysis tools revealed the presence of 12 well-characterized phyla, members of the TM-7 and BRC1 clade, and sequences that could not be classified. Both pathogens and opportunistic pathogens were identified, supporting the ecological plaque hypothesis for oral diseases. Mapping the metagenomic reads to sequenced reference genomes demonstrated that 4% of the reads could be assigned to the sequenced species. Preliminary annotation identified genes belonging to all known functional categories. Interestingly, although 73% of the total assembled contig sequences were predicted to code for proteins, only 51% of them could be assigned a functional role. Furthermore, ~ 2.8% of the total predicted genes coded for proteins involved in resistance to antibiotics and toxic compounds, suggesting that the oral cavity is an important reservoir for antimicrobial resistance.
PMCID: PMC2975940  PMID: 21040513
22.  Effectiveness of Lexico-Syntactic Pattern Matching for Ontology Enrichment with Clinical Documents 
To evaluate the effectiveness of a Lexico-Syntactic Pattern (LSP) matching method for ontology enrichment using clinical documents.
Two domains were separately studied using the same methodology. We used radiology documents to enrich RadLex and pathology documents to enrich National Cancer Institute Thesaurus (NCIT). Several known LSPs were used for semantic knowledge extraction. We first retrieved all sentences that contained LSPs across two large clinical repositories, and examined the frequency of the LSPs. From this set, we randomly sampled LSP instances which were examined by human judges. We used a two-step method to determine the utility of these patterns for enrichment. In the first step, domain experts annotated Medically Meaningful Terms (MMTs) from each sentence within the LSP. In the second step, RadLex and NCIT curators evaluated how many of these MMTs could be added to the resource. To quantify the utility of this LSP method, we defined two evaluation metrics: Suggestion Rate (SR) and Acceptance Rate (AR). We used these measures to estimate the yield of concepts and relationships, for each of the two domains.
For NCIT, the concept SR was 24%, and the relationship SR was 65%. The concept AR was 21%, and the relationship AR was 14%. For RadLex, the concept SR was 37%, and the relationship SR was 55%. The concept AR was 11%, and the relationship AR was 44%.
The LSP matching method is an effective method for concept and concept relationship discovery in biomedical domains.
PMCID: PMC3125434  PMID: 21057720
Ontology Learning from Text; Knowledge Acquisition; Ontology Enrichment; Natural Language Processing; Lexico-Syntactic Pattern
23.  PARP-1 initiated neuronal cell death pathway–do androgens matter? 
Neuroscience  2009;166(2):476-481.
Activation of poly (ADP-ribose) polymerases contributes to ischemic damage by causing neuronal NAD+ depletion, release of apoptosis-inducing factor and consequent caspase-independent cell death. PARP-mediated cell death is sexually dimorphic, participating in ischemic damage in the male brain, but not the female brain. We tested the hypothesis that androgen signaling is required for this male-specific neuronal cell death pathway. We observed smaller damage following focal cerebral ischemia (MCAO) in male PARP-1 knockout mice compared to WT as well as decreased damage in male mice treated with the PARP inhibitor PJ34. Protection from ischemic damage provided by PJ-34 in WT mice is lost after removal of testicular androgens (CAST) and rescued by androgen replacement. CAST PARP-1 KO mice exhibit increased damage compared to intact male KO mice, an effect reversed by androgen replacement in an androgen receptor-dependent manner. Lastly, we observed that ischemia causes an increase in PARP-1 expression that is diminished in the absence of testicular androgens. Our data indicates that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.
PMCID: PMC3098136  PMID: 20035840
cerebral ischemia; stroke; poly-adp ribose polymerase; androgen
24.  Prevalence and Correlates of Diabetes in South Asian Indians in the United States: Findings From the Metabolic Syndrome and Atherosclerosis in South Asians Living in America Study and the Multi-Ethnic Study of Atherosclerosis 
Individuals from South Asia have high diabetes prevalence despite low body weight. We compared the prevalence of diabetes among South Asian Indians with other U.S. ethnic groups and explored correlates of diabetes.
This was a cross-sectional study of 150 South Asian Indians (ages 45–79) in California, using similar methods to the Multi-Ethnic Study of Atherosclerosis (MESA). Type 2 diabetes was classified by fasting plasma glucose (FPG) ≥126 mg/dL, 2-h postchallenge glucose ≥200 mg/dL, or use of hypoglycemic medication.
A total of 29% of Asian Indians had diabetes, 37% had prediabetes, and 34% had normal glucose tolerance. After full adjustment for covariates, Indians still had significantly higher odds of diabetes compared to whites and Latinos, but not significantly different from African Americans and Chinese Americans in MESA: Indians [odds ratio (OR), 1.0], whites [OR, 0.29; 95% confidence interval (CI), 0.17–0.49], Latinos (OR, 0.59; CI, 0.34–1.00) African Americans (OR, 0.77; CI 0.45–1.32), Chinese Americans (OR, 0.78, CI, 0.45–1.32). Variables associated with prediabetes or diabetes among Indians included hypertension, fatty liver, visceral adiposity, microalbuminuria, carotid intima media thickness, and stronger traditional Indian beliefs.
Indian immigrants may be more likely to have diabetes than other U.S. ethnic groups, and cultural factors may play a role, suggesting that this is a promising area of research.
PMCID: PMC3139526  PMID: 19943798
25.  Counting single molecules in sub-nanolitre droplets 
Lab on a chip  2009;10(2):161-164.
We demonstrate single biomolecule detection and quantification within sub-nanolitre droplets through application of Cylindrical Illumination Confocal Spectrosocpy (CICS) and droplet confinement within a retractable microfluidic constriction.
PMCID: PMC3000353  PMID: 20066242

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