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1.  Nutrition deficiency increases the risk of stomach cancer mortality 
BMC Cancer  2012;12:315.
The purpose of the study is to determine whether exposure to malnutrition during early life is associated with increased risk of stomach cancer in later life.
The design protocol included analyzing the trend of gastric cancer mortality and nutrition and evaluating the association between nutrient deficiency in early life and the risk of gastric cancer by hierarchical age–period–birth cohort (APC) analysis using general log-linear Poisson models and to compare the difference between birth cohorts who were exposed to the 1959–1961 Chinese famine and those who were not exposed to the famine. Data on stomach cancer mortality from 1970 to 2009 and the dietary patterns from 1955 to 1985 which included the 1959–1961 Chinese famine period in the Zhaoyuan County population were obtained. The nutrition information was collected 15 years prior to the mortality data as based on the latest reference of disease incubation.
APC analysis revealed that severe nutrition deficiency during early life may increase the risk of stomach cancer. Compared with the 1960–1964 birth cohort, the risk for stomach cancer in all birth cohorts from 1900 to 1959 significantly increased; compared with the 1970–1974 cohort, the risk for stomach cancer in the 1975–1979 cohort significantly increased, whereas the others had a steadily decreased risk; compared with 85–89 age group in the 2005–2009 death survey, the ORs decreased with younger age and reached significant levels for the 50–54 age group after adjusting the confounding factors. The 1930 to 1964 group (exposed to famine) had a higher mortality rate than the 1965 to 1999 group (not exposed to famine). For males, the relative risk (RR) was 2.39 and the 95% confidence interval (CI) was 1.51 to 3.77. For females, RR was 1.64 and 95% CI was 1.02 to 2.62.
The results of the present study suggested that prolonged malnutrition during early life may increase the risk of stomach cancer mortality in later life.
PMCID: PMC3443031  PMID: 22838407
Nutritive deficiency; Stomach Cancer; Mortality; Famine exposure
2.  The effect of oxidized low-density lipoprotein combined with adriamycin on the proliferation of Eca-109 cell line 
The purpose of this study was to identify the affect on the proliferation Eca-109 cells treated with oxidized low-density lipoprotein (ox-LDL) combined with adriamycin (ADM).
Eca-109 cell were cultured in the presence of oxLDL/ADM, and cell proliferation tested by MTT and cell apoptosis was monitored by the proportion of apoptosis and cell cycle by flow cytomester. We simultaneously evaluated the level of associated- apoptosis Bcl-2, Bax, and Caspase-3 gene mRNA and protein.
OxLDL were cytotoxic and activate apoptosis. OxLDL combined with ADM significant enhanced the proportion rate of apoptosis on a time and dose dependency. The expressions of the inhibiting apoptosis Bcl-2 gene mRNA and protein were down regulated, whereas, the expressions of the promoting apoptosis Bax, and Caspase-3 genes mRNA and protein were up regulation.
These results suggested that oxLDL have cytotoxicity and activate apoptosis on the Eca-109 cells. OxLDL combined with ADM have a synergistic effect on the apoptosis induced Eca-109 cells. Furthermore, oxLDL may contribute to the improvement of clinical chemotherapy of cancer need to make further investigation.
PMCID: PMC3150309  PMID: 21711568
Esophagueal squamous cell line; low-density lipoprotein; adriamycin; apoptosis; gene; protein; expression
3.  Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County 
BMC Gastroenterology  2011;11:74.
The purpose of this study was to evaluate the association of multi-genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC) and the possibility of predicting those at higher risk.
A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH), 262 patients with esophageal squamous cell dysplasia (ESCD), 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants.
The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the ALDH 1*1 genotype, the ALDH 2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of MTHFR C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (ORG) of the two combined genotypes was 1.83 (95%CI: 1.55-2.16), indicating a strong genetic association with the risk of carcinogenic progression in the esophagus.
The study demonstrated that the genotypes ALDH2*2 and MTHFR 677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk.
PMCID: PMC3141752  PMID: 21672255
4.  Multiple degradation pathways of phenanthrene by Stenotrophomonas maltophilia C6 
Stenotrophomonas maltophilia strain C6, capable of utilizing phenanthrene as a sole source of carbon and energy, was isolated from creosote-contaminated sites at Hilo, Hawaii. Twenty-two metabolites of phenanthrene, covering from dihydrodiol to protocatechuic acid, were isolated and characterized. Phenanthrene was degraded via an initial dioxygenation on 1,2-, 3,4-, and 9,10-C, where the 3,4-dioxygenation and subsequent metabolisms were most dominant. The metabolic pathways were further branched by ortho- and meta-cleavage of phenanthrenediols to produce 1-hydroxy-2-naphthoic acid, 2-hydroxy-1-naphthoic acid, and naphthalene-1,2-dicarboxylic acid. These intermediates were then transformed to naphthalene-1,2-diol. 1-Hydroxy-2-naphthoic acid was also degraded via a direct ring cleavage. Naphthalene-1,2-diol underwent primarily ortho-cleavage to produce trans-2-carboxycinnamic acid and then to form phthalic acid, 4,5-dihydroxyphthalic acid and protocatechuic acid. Accumulation of salicylic acid in prolonged incubation indicated that a limited extent of meta-cleavage of naphthalene-1, 2-diol also occurred. This is the first study of detailed phenanthrene metabolic pathways by Stenotrophomonas maltophilia.
PMCID: PMC3607548  PMID: 23539472
phenanthrene; Stenotrophomonas maltophilia; dioxygenaton; ortho-cleavage; meta-cleavage
5.  Efficient simulation of epistatic interactions in case-parent trios 
Human heredity  2013;75(1):12-22.
Statistical approaches to evaluate interactions between single nucleotide polymorphisms (SNPs) and SNP-environment interactions are of great importance in genetic association studies, as susceptibility to complex disease might be related to the interaction of multiple SNPs and/or environmental factors. With these methods under active development, algorithms to simulate genomic data sets are needed, to ensure proper type I error control of newly proposed methods, and to compare power with existing methods. In this manuscript we propose an efficient method for a haplotype-based simulation of case-parent trios, when the disease risk is thought to depend on possibly higher order epistatic interactions, or gene-environment interactions with binary exposures.
PMCID: PMC3800020  PMID: 23548797
Case-parent trios; interactions; single nucleotide polymorphisms; haplotypes
6.  A Dual-Role of Gu-4 in Suppressing HMGB1 Secretion and Blocking HMGB1 Pro-Inflammatory Activity during Inflammation 
PLoS ONE  2014;9(3):e89634.
High mobility group box 1(HMGB1) was first recognized as a nuclear protein that increased the chromatin remodeling and regulates transcription of many genes. In recent years, HMGB1 has been identified as a critical “late” pro-inflammatory mediator due to its unique secretion pattern and lethal effects in sepsis. Therefore, preventing the active release and inhibiting the pro-inflammatory activity of HMGB1 become promising strategies for the treatment of sepsis. Here, we reported the therapeutic effects of Gu-4, a lactosyl derivative, on sepsis and the underlying molecular mechanisms.
Methodology/Principal Findings
In an experimental rat model of sepsis caused by cecal ligation and puncture (CLP), Gu-4 administration prominently attenuated lung injury and improved the survival of the septic animals, which was positively correlated with the decrease of the serum HMGB1 level. Using RAW264.7 macrophage cell line, we further showed that Gu-4 significantly suppressed the lipopolysaccharide (LPS)-induced release and cytoplasmic translocation of HMGB1. Moreover, Gu-4 not only dose-dependently attenuated recombinant human (rhHMGB1)-induced production of TNF-α, IL-6, and IL-1β in THP-1 cells, but also greatly inhibited the adhesion of rhHMGB1-challenged THP-1 cells to HUVECs. Analyses of flow cytometry demonstrated that Gu-4 could effectively reduce the activation of CD11b elicited by rhHMGB1. Western blot analyses revealed that Gu-4 treatment could partially block the rhHMGB1-induced activation of ERK and NF-κB signalings. Meanwhile, CD11b knockdown also obviously attenuated the rhHMGB1-induced phosphorylations of ERK and IKKα/β.
Taken together, our results suggest that Gu-4 possesses a therapeutic potential in the treatment of sepsis probably via inhibiting the LPS-induced release of HMGB1 from macrophages and via suppressing the pro-inflammatory activity of HMGB1.
PMCID: PMC3945943  PMID: 24603876
7.  Chemical Composition and Sensory Evaluation of Fermented Tea with Medicinal Mushrooms 
Indian Journal of Microbiology  2013;53(1):70-76.
In commercial tea production, plenty of tea leaf waste is generated, which may not only exert pollution risk to environment, but also a huge waste of bioactive ingredients in tea. In this study, the 4th to 7th leaves of tea bush were collected and used as substrate for mycelial culture of two renown medicinal mushrooms Grifola frondosa and Tianzhi (new variants of Ganoderma lucidum) to obtain a new type of solid-state fermented tea. Result showed that the polysaccharides of Grifola frondosa and Tianzhi fermented tea were 1.52 and 4.14 %, tea polyphenols were 1.51 and 1.85 %, the free amino acids were 1.52 and 0.94 %, caffeine were 1.16 and 1.70 %, polyphenols/amid acids ratio were 1.0 and 1.98, water extractions were 35.53 and 32.86 %, protein contents were 17.63 and 6.13 mg/g, respectively. The volatile components were mainly composed of alcohols, esters, aldehydes and ketones. The contents of major flavor compositions of fermented tea had changed and their relation tended to be harmonious, and the variety of amino acids significantly increased. Therefore, the sensory flavor and therapeutic qualities of fermented tea were significantly improved.
PMCID: PMC3587500  PMID: 24426081
Fermentation tea; Medicinal mushroom; Sensory evaluation; Polyphenols/amino acids ratio
8.  Functional and Structural Analysis of Influenza Virus Neuraminidase N3 Offers Further Insight into the Mechanisms of Oseltamivir Resistance 
Journal of Virology  2013;87(18):10016-10024.
The influenza virus neuraminidase H274Y substitution is a highly prevalent amino acid substitution associated with resistance to the most heavily used influenza drug, oseltamivir. Previous structural studies suggest that the group specific 252 residue (Y252 in group 1 and T252 in group 2) might be a key factor underlying H274Y resistance. However, H274Y has only been reported in N1 subtypes, which indicates that there must be additional key residues that determine H274Y resistance. Furthermore, we found that members of NA serotype N3 also possess Y252, raising the key question as to whether or not H274Y resistance may also be possible for some group 2 NAs. Here, we demonstrate that the H274Y substitution results in mild oseltamivir resistance for N3. Comparative structural analysis of N3, N1, and their 274Y variants indicates that the interaction of residue 296 (H in N1 and nonaromatic for other serotypes) with conserved W295 is another important determinant of oseltamivir resistance.
PMCID: PMC3753999  PMID: 23824808
9.  All roads lead to chromatin: multiple pathways for histone deposition 
Biochimica et biophysica acta  2011;1819(0):238-246.
PMCID: PMC3932183  PMID: 21763476
10.  Lemur tyrosine kinase-3 is a significant prognostic marker for patients with colorectal cancer 
Lemur tyrosine kinase-3 (LMTK3) belongs to the family of serine-threonine-tyrosine kinases and the aberrant expression of LMTK3 was observed in several human malignancies. However, the association of LMTK3 with clinical outcomes in colorectal cancer patients is unclear. Thus, this present study was to evaluate the association of LMTK3 expression level with clinicopathologic factors and prognosis of patients with colorectal cancer (CRC). The expression level of LMTK3 in 69 archival paraffin-embedded colorectal tumor tissue specimens was examined by immunohistochemistry (IHC). As a result, we found that the LMTK3 expression level was significantly elevated in CRC tissues as compared with Crohn’s disease or colorectal polyp tissues (P<0.0001, P<0.0001, respectively). Positive LMTK3 signals in the colorectal cancer cells were observed in about 89.9% (62 of 69) CRC tissue specimens. Additionally, LMTK3 expression was significantly correlated with lymph node metastasis and tumor-node-metastasis (TNM) classification (P=0.003, and P=0.008, respectively), but not with sex, age, tumor location, histological differentiation, tumor size, or depth of tumor invasion (all P>0.05). Kaplan-Meier survival curves showed that the overall survival rate was significantly higher in the patients with low expression of LMTK3 when compared with those patients with high LMTK3 (P=0.010). Moreover, multivariate analysis revealed that LMTK3 expression was an independent prognostic factor for CRC patients (P=0.047). These results suggest that LMTK3 protein could serve as a prognostic marker for CRC patients.
PMCID: PMC3971314
Colorectal cancer; lemur tyrosine kinase-3 (lmtk3); immunohistochemistry (ihc); prognosis
11.  Influence of Forest Therapy on Cardiovascular Relaxation in Young Adults 
Background. Despite increasing attention toward forest therapy as an alternative medicine, very little evidence continues to be available on its therapeutic effects. Therefore, this study was focused on elucidating the health benefits of forest walking on cardiovascular reactivity. Methods. Within-group comparisons were used to examine the cardiovascular responses to walking in forest and urban environments. Forty-eight young adult males participated in the two-day field research. Changes in heart rate variability, heart rate, and blood pressure were measured to understand cardiovascular reactivity. Four different questionnaires were used to investigate the changes in psychological states after walking activities. Results. Forest walking significantly increased the values of ln(HF) and significantly decreased the values of ln(LF/HF) compared with the urban walking. Heart rate during forest walking was significantly lower than that in the control. Questionnaire results showed that negative mood states and anxiety levels decreased significantly by forest walking compared with urban walking. Conclusion. Walking in the forest environment may promote cardiovascular relaxation by facilitating the parasympathetic nervous system and by suppressing the sympathetic nervous system. In addition, forest therapy may be effective for reducing negative psychological symptoms.
PMCID: PMC3934621  PMID: 24660018
12.  A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients 
Tumor-associated macrophages (TAMs) are classified into two major phenotypes, M1 and M2. M1 TAMs suppress cancer progression, while M2 TAMs promote it. However, little is known regarding the role of TAMs in the development of ovarian cancer. Here, we investigated the relationship between TAM distribution patterns (density, microlocalization, and differentiation) and ovarian cancer histotypes, and we explored whether altered TAM distribution patterns influence long-term outcomes in ovarian cancer patients.
A total of 112 ovarian cancer patients were enrolled in this study, and the subjects were divided into two groups according to their survival (< 5 years vs. ≥ 5 years). Immunohistochemistry and immunofluorescence were used to determine the density, microlocalization, and differentiation status of TAMs in ovarian cancer tissues for each histotype. Kaplan-Meier survival and multivariate Cox regression analyses were used to evaluate the prognostic significance of TAM-related parameters in ovarian cancer.
TAMs most frequently infiltrated into the cancer tissue of the serous histotype, followed by mucinous, undifferentiated, endometrioid, and clear cell histotypes (p = 0.049). The islet/stroma ratio of total TAMs varied among the cancer histotypes, with mucinous and undifferentiated cancers displaying the lowest and highest ratios, respectively (p = 0.005). The intratumoral TAM density significantly increased with increasing cancer stage and grade (p = 0.023 and 0.006, respectively). However, the overall M1/M2 TAM ratio decreased as the cancer stage increased (p = 0.012). In addition, the intra-islet M1/M2 ratio inversely correlated with the residual site size (p = 0.004). Among the TAM-related parameters, only the increased overall and intra-islet M1/M2 TAM ratios displayed prognostic significance in both the Kaplan-Meier survival and multivariate Cox regression analyses; however, the values of these two parameters did not differ significantly among the cancer histotypes.
The patients with increased overall or intra-islet M1/M2 TAM ratios presented with an improved 5-year prognosis. Nevertheless, the TAM distribution patterns did not influence the overall outcomes of different ovarian cancer histotypes.
PMCID: PMC3939626  PMID: 24507759
Ovarian cancer; Tumor-associated macrophage; M1; M2; Prognosis
13.  A Novel Cellular Senescence Gene, SENEX, Is Involved in Peripheral Regulatory T Cells Accumulation in Aged Urinary Bladder Cancer 
PLoS ONE  2014;9(2):e87774.
Regulatory T cells (Tregs) play an essential role in sustaining self-tolerance and immune homeostasis. Despite many studies on the correlation between Tregs accumulation and age, or malignancies, the related mechanism hasn’t been well explored. To find out the mechanism of Tregs accumulation in aged urinary bladder cancer, we examined the novel cellular senesence gene SENEX and relevant apoptosis gene mRNA expression in sorted CD4+CD25hi Tregs from aged UBC donors, evaluated serum cytokine profiles related to tumor immunopathology, and further explored the relationship between SENEX expression, apoptosis gene expression and cytokine secretion. After having silenced down SENEX gene expression with RNA interference, we also evaluated the cellular apoptosis of Tregs sorted from aged UBC patients in response to H2O2-mediated stress. Our data indicated that upregulated SENEX mRNA expression in Tregs of aged UBC patients was correlated with pro-apoptotic gene expression and cytokine concentration. Silencing SENEX gene expression increased cellular apoptosis and pro-apoptotic gene expression of Tregs, in response to H2O2-mediated stress. Upregulated SENEX mRNA expression together with decreased pro-apoptotic gene expression and disturbances in cytokines synthesis may contribute to the Tregs proliferation and promote tumorigenesis and metastasis. Overall, upregulation of cellular senescence gene SENEX, was associated to regulatory T cells accumulation in aged urinary bladder cancer. Our study provides a new insight into understanding of peripheral Tregs accumulation in aged malignancies.
PMCID: PMC3914842  PMID: 24505313
14.  Ectopic pancreas in the anterior mediastinum: A report of two cases and review of the literature 
Oncology Letters  2014;7(4):1053-1056.
Ectopia of the pancreatic tissue is a developmental anomaly found in ~2% of all autopsies, and 70~90% of these anomalies are located in the gastrointestinal tract. Mediastinal localization of an ectopic pancreas is extremely rare. Herein, we report two cases with mediastinal ectopic pancreas clarified by pathology and shown by thoracic contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). In addition, a brief review of the relevant literatures is presented. Although CT and MRI manifestations of this lesion are nonspecific, certain notable findings need to be focused on. When there is a mass in the anterior mediastinum with marked and heterogeneous enhancement, along with necrotic and liquefied non-enhanced areas in the center, ectopic pancreas should be considered and differentiated from other neoplasms in this region.
PMCID: PMC3961199  PMID: 24660035
ectopic pancreas; computed tomography; magnetic resonance imaging; anterior mediastinum
15.  Functional Polymorphisms of Interferon-gamma Affect Pneumonia-Induced Sepsis 
PLoS ONE  2014;9(1):e87049.
Sepsis is an inflammatory syndrome caused by infection, and both its incidence and mortality are high. Because interferon-gamma (IFN-γ) plays an important role in inflammation, this work assessed IFN-γ single nucleotide polymorphism (SNPs) that may be associated with sepsis.
A total of 196 patients with pneumonia-induced sepsis and 213 age- and sex-matched healthy volunteers participated in our study from July 2012 to July 2013 in Guangzhou, China. Patient clinical information was collected. Clinical pathology was assessed in subgroups defined based on clinical criteria, APACHE II (acute physiology and chronic health evaluation) and SOFA (sepsis-related organ failure assessment) scores and discharge rate. Four functional SNPs, −1616T/C (rs2069705), −764G/C (rs2069707), +874A/T (rs2430561) and +3234C/T (rs2069718), were genotyped by Snapshot in both sepsis patients and healthy controls. Pearson’s chi-square test or Fisher’s exact test were used to analyze the distribution of the SNPs, and the probability values (P values), odds ratios (OR) and 95% confidence intervals (CIs) were calculated.
No mutations in the IFN-γ −764G/C SNP were detected among the participants in our study. The +874A/T and +3234C/T SNPs were in strong linkage disequilibrium (LD) (r2 = 0.894). The −1616 TC+TT, +874 AT+AA genotype and the TAC haplotype were significantly associated with sepsis susceptibility, while the CTT haplotype was associated with protection against sepsis incidence. Genotype of −1616 TT wasn’t only protective against severity of sepsis, but also against higher APACHE II and SOFA scores as +874 AA and +3234 CC. The TAC haplotype was was protective against progression to severe sepsis either.
Our results suggest that functional IFN-γ SNPs and their haplotypes are associated with pneumonia-induced sepsis.
PMCID: PMC3901723  PMID: 24475220
16.  Concentrations, Source and Risk Assessment of Polycyclic Aromatic Hydrocarbons in Soils from Midway Atoll, North Pacific Ocean 
PLoS ONE  2014;9(1):e86441.
This study was designed to determine concentrations of polycyclic aromatic hydrocarbons (PAHs) in soil samples collected from Midway Atoll and evaluate their potential risks to human health. The total concentrations of 16 PAHs ranged from 3.55 to 3200 µg kg−1 with a mean concentration of 198 µg kg−1. Higher molecular weight PAHs (4–6 ring PAHs) dominated the PAH profiles, accounting for 83.3% of total PAH mass. PAH diagnostic ratio analysis indicated that primary sources of PAHs in Midway Atoll could be combustion. The benzo[a]pyrene equivalent concentration (BaPeq) in most of the study area (86.5%) was less than 40 µg kg−1 BaPeq and total incremental lifetime cancer risks of PAHs ranged from 1.00×10−10 to 9.20×10−6 with a median value of 1.24×10−7, indicating a minor carcinogenic risk of PAHs in Midway Atoll.
PMCID: PMC3900525  PMID: 24466100
17.  EGFR protein expression and gene amplification in squamous intraepithelial lesions and squamous cell carcinomas of the cervix 
The purpose of this study was to evaluate the protein expression and gene amplification of epithelial growth factor receptor (EGFR) in intraepithelial neoplasias and squamous cell carcinoma of the cervix and to determine the value of EGFR in carcinogenesis, progression, and prognosis of cervical cancer. EGFR protein expression and gene amplification involved gene copy number in 75 cases of cervical various lesions were evaluated using immunohistochemistry and by fluorescence in situ hybridization (FISH) techniques. Expression of EGFR was observed in 76.00% of the high-grade CIN and 79.17% of the invasive carcinomas. In contrast, there were low levels of EGFR expression in chronic cervicitis (1/10) and low-grade CIN (7/16). There were statistically significant differences among them (P<0.05). Gene amplification was detected in 20.51% high-grade CIN and invasive carcinoma, but there only 4.35% EGFR gene amplification was observed in chronic cervicitis and low grade CIN. Among the 42 patients with negative or low levels of EGFR expression, 26 patients (61.90%) were found to have diploidy and 11 patients (26.20%) to have balanced triploidy. However, among the 20 patients with an intermediate and high levels of EGFR protein expression, 13 (65.00%) were found to have balanced polyploidy or gene amplification. All cases of EGFR gene amplification involved intermediate and high levels of protein expression. EGFR may be involved in the carcinogenesis of the cervix and may be an early event during the carcinogenesis. Overexpression of EGFR protein may result from gene amplification and increases in gene copy number.
PMCID: PMC3925921  PMID: 24551297
Cervix neoplasms; EGFR; protein expression; gene amplification; gene copy number; FISH
18.  Hand-Schüller-Christian Disease and Erdheim-Chester Disease: Coexistence and Discrepancy 
The Oncologist  2013;18(1):19-24.
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease share similar clinical features and mechanisms; very rarely, the two diseases coexist in the same patient. This case report presents such a patient, who was first diagnosed with Hand-Schüller-Christian disease (HSC), a type of LCH.
CME Learning Objectives
Distinguish Erdheim-Chester disease from Langerhans cell histiocytosis.Cite the keys to diagnosis of Hand-Schüller-Christian disease in a patient with only central diabetes insipidus.List the signs linking a Hand-Schüller-Christian disease patient to coexisting ECD.
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) share similar clinical features and mechanisms. In very rare circumstances, the two diseases coexist in the same patient. Here we report such a patient, who was first diagnosed with Hand-Schüller-Christian disease (HSC), a type of LCH. Several years later, the patient presented with severe exophthalmos and osteosclerosis on radiograph. New biopsy revealed ECD. We also analyze 54 cases of LCH and 6 cases of ECD diagnosed in our hospital, as well as their progression during a follow-up period of 8 years. In five cases of HSC (9.3% of LCH), a triad of central diabetes insipidus, hyperprolactinemia, and pituitary stalk thickening on magnetic resonance imaging (MRI) preceded the typical bone lesions by 4–9 years. In addition, LCH was featured as elevated plasma alkaline phosphatase (ALP), which was normal in ECD. Combined with a literature review, several features are summarized to differentiate ECD from HSC. In patients with diabetes insipidus, concomitant hyperprolactinemia and pituitary stalk thickening on MRI indicate a possible HSC. Additionally, if osteosclerosis is observed in a patient with LCH, the coexistence of ECD should be considered.
PMCID: PMC3556249  PMID: 23299772
Langerhans cell histiocytosis; Erdheim-Chester disease; Hand-Schüller-Christian disease; Central diabetes insipidus
19.  Prevalence and risk factors for insomnia among breast cancer patients on aromatase inhibitors 
Insomnia is increasingly recognized as a major symptom outcome in breast cancer; however, little is known about its prevalence and risk factors among women receiving aromatase inhibitors (AIs), a standard treatment to increase disease free survival among breast cancer patients.
A cross-sectional survey study was conducted among postmenopausal women with stage 0-III breast cancer receiving adjuvant AI therapy at an outpatient breast oncology clinic of a large university hospital. The Insomnia Severity Index (ISI) was used as the primary outcome. Multivariate logistic regression analyses were performed to evaluate risk factors.
Among 413 participants, 130 (31.5%) had sub-threshold insomnia on the ISI and 77 (18.64%) exceeded the threshold for clinically significant insomnia. In a multivariate logistic regression model, clinically significant insomnia was independently associated with severe joint pain (adjusted odds ratio, 4.84, 95% confidence interval, 1.71–13.69, P=0.003), mild/moderate hot flashes (AOR, 2.28, 95% CI, 1.13–4.60, P=0.02), severe hot flashes (AOR, 2.29, 95% CI, 1.23–6.81, P=0.015), anxiety (AOR, 1.99, 95% CI, 1.08–3.65, P=0.027), and depression (AOR, 3.57, 95% CI, 1.48–8.52, P=0.004). Age (>65 vs. <55 years, AOR, 2.31, 95% CI, 1.11–4.81, p=0.026), and time since breast cancer diagnosis (<2 years vs. 2–5 years, AOR, 1.94, 95% CI, 1.02–3.69, p=0.045) were also found to be significant risk factors. Clinical insomnia was more common among those who used medication for treating insomnia and pain.
Insomnia complaints exceed 50% among AI users. Clinically significant insomnia is highly associated with joint pain, hot flashes, anxiety and depression, age, and time since diagnosis.
PMCID: PMC3600410  PMID: 22584732
Breast cancer; Insomnia; Aromatase Inhibitors
20.  Brd4-Mediated Nuclear Retention of the Papillomavirus E2 Protein Contributes to Its Stabilization in Host Cells 
Viruses  2014;6(1):319-335.
Papillomavirus E2 is a multifunctional viral protein that regulates many aspects of the viral life cycle including viral episome maintenance, transcriptional activation, and repression. E2 is degraded by the ubiquitin-proteasome pathway. Cellular bromodomain protein Brd4 has been implicated in the stabilization of the E2 protein. E2 normally shuttles between the cytoplasm and the nucleus. In this study, we demonstrate that E2 ubiquitylation mostly occurs in the cytoplasm. We also find that the interaction with Brd4 promotes nuclear retention of papillomavirus E2 proteins and contributes to their stabilization in the nucleus. Compared to wild type E2 proteins, nuclear-localization-defective mutants are rapidly degraded by the ubiquitin-proteasome pathway; however, co-expression of Brd4 redirects these mutants into the nucleus and significantly increases their stability. We further demonstrate that tethering E2 proteins to chromatin as either double-bromodomain fusion proteins or histone 2B (H2B) fusion proteins significantly stabilizes the E2 proteins. Our studies suggest that chromatin recruitment of the E2 protein via interaction with Brd4 prevents E2 ubiquitylation and proteasomal degradation in the cytoplasm, leading to its stabilization in the nucleus. These studies bring new insights for understanding Brd4-mediated E2 stabilization, and provide an additional mechanism by which the chromatin-associated Brd4 regulates E2 functions.
PMCID: PMC3917445  PMID: 24448221
papillomavirus; E2; Brd4; stability
21.  An Uncommon Plant Growth Regulator, Diethyl Aminoethyl Hexanoate, Is Highly Effective in Tissue Cultures of the Important Medicinal Plant Purple Coneflower (Echinacea purpurea L.) 
BioMed Research International  2013;2013:540316.
We investigated the effects of various concentrations of diethyl aminoethyl hexanoate (DA-6) on the regeneration and growth of adventitious buds in in vitro purple coneflower cultures. Among the 3 types of explants tested, leaf explants required higher concentrations of DA-6 than petiole and root explants in order to obtain high regeneration rates, while root explants required the lowest concentration of DA-6. Additionally, explants with higher ploidy levels were more sensitive to the addition of DA-6, while explants with lower ploidy levels required higher concentrations of DA-6 to achieve its maximal regeneration rate. Interestingly, the application of a concentration that was conducive to the regeneration of explants with lower ploidy levels was inhibitory to the regeneration of explants with higher ploidy levels. Moreover, during the growth of regenerated buds, DA-6 application significantly improved plant height and weight, root weight, root thickness, root number, primary root length, total root length, and root/top ratio. Differences in the responses of explants to supplementation with DA-6 were also observed among explants with different ploidy levels, with buds having lower ploidy levels responding to lower concentrations of DA-6. Taken together, the results of the present experiments showed that proper application of DA-6 could increase in vitro culture efficiency in purple coneflower.
PMCID: PMC3884859  PMID: 24455702
22.  Fast-track rehabilitation vs conventional care in laparoscopic colorectal resection for colorectal malignancy: A meta-analysis 
AIM: To evaluate the fast-track rehabilitation protocol and laparoscopic surgery (LFT) vs conventional care strategies and laparoscopic surgery (LCC).
METHODS: Studies and relevant literature comparing the effects of LFT and LCC for colorectal malignancy were identified in MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE. The complications and re-admission after approximately 1 mo were assessed.
RESULTS: Six recent randomized controlled trials (RCTs) were included in this meta-analysis, which related to 655 enrolled patients. These studies demonstrated that compared with LCC, LFT has fewer complications and a similar incidence of re-admission after approximately 1 mo. LFT had a pooled RR of 0.60 (95%CI: 0.46-0.79, P < 0.001) compared with a pooled RR of 0.69 (95%CI: 0.34-1.40, P > 0.5) for LCC.
CONCLUSION: LFT for colorectal malignancy is safe and efficacious. Larger prospective RCTs should be conducted to further compare the efficacy and safety of this approach.
PMCID: PMC3870567  PMID: 24379639
Laparoscopic surgery; Fast-track rehabilitation; Enhanced recovery; Colorectal surgery; Complications; Readmission
23.  Detection of Neovascularization Based on Fractal and Texture Analysis with Interaction Effects in Diabetic Retinopathy 
PLoS ONE  2013;8(12):e75699.
Diabetic retinopathy is a major cause of blindness. Proliferative diabetic retinopathy is a result of severe vascular complication and is visible as neovascularization of the retina. Automatic detection of such new vessels would be useful for the severity grading of diabetic retinopathy, and it is an important part of screening process to identify those who may require immediate treatment for their diabetic retinopathy. We proposed a novel new vessels detection method including statistical texture analysis (STA), high order spectrum analysis (HOS), fractal analysis (FA), and most importantly we have shown that by incorporating their associated interactions the accuracy of new vessels detection can be greatly improved. To assess its performance, the sensitivity, specificity and accuracy (AUC) are obtained. They are 96.3%, 99.1% and 98.5% (99.3%), respectively. It is found that the proposed method can improve the accuracy of new vessels detection significantly over previous methods. The algorithm can be automated and is valuable to detect relatively severe cases of diabetic retinopathy among diabetes patients.
PMCID: PMC3864789  PMID: 24358105
24.  Biomass digestibility is predominantly affected by three factors of wall polymer features distinctive in wheat accessions and rice mutants 
Wheat and rice are important food crops with enormous biomass residues for biofuels. However, lignocellulosic recalcitrance becomes a crucial factor on biomass process. Plant cell walls greatly determine biomass recalcitrance, thus it is essential to identify their key factors on lignocellulose saccharification. Despite it has been reported about cell wall factors on biomass digestions, little is known in wheat and rice. In this study, we analyzed nine typical pairs of wheat and rice samples that exhibited distinct cell wall compositions, and identified three major factors of wall polymer features that affected biomass digestibility.
Based on cell wall compositions, ten wheat accessions and three rice mutants were classified into three distinct groups each with three typical pairs. In terms of group I that displayed single wall polymer alternations in wheat, we found that three wall polymer levels (cellulose, hemicelluloses and lignin) each had a negative effect on biomass digestibility at similar rates under pretreatments of NaOH and H2SO4 with three concentrations. However, analysis of six pairs of wheat and rice samples in groups II and III that each exhibited a similar cell wall composition, indicated that three wall polymer levels were not the major factors on biomass saccharification. Furthermore, in-depth detection of the wall polymer features distinctive in rice mutants, demonstrated that biomass digestibility was remarkably affected either negatively by cellulose crystallinity (CrI) of raw biomass materials, or positively by both Ara substitution degree of non-KOH-extractable hemicelluloses (reverse Xyl/Ara) and p-coumaryl alcohol relative proportion of KOH-extractable lignin (H/G). Correlation analysis indicated that Ara substitution degree and H/G ratio negatively affected cellulose crystallinity for high biomass enzymatic digestion. It was also suggested to determine whether Ara and H monomer have an interlinking with cellulose chains in the future.
Using nine typical pairs of wheat and rice samples having distinct cell wall compositions and wide biomass saccharification, Ara substitution degree and monolignin H proportion have been revealed to be the dominant factors positively determining biomass digestibility upon various chemical pretreatments. The results demonstrated the potential of genetic modification of plant cell walls for high biomass saccharification in bioenergy crops.
PMCID: PMC3878626  PMID: 24341349
Cell wall; Cellulose crystallinity; Arabinose substitution degree; p-coumaryl alcohol proportion; Biomass digestibility; Chemical pretreatment; Wheat; Rice
25.  Biosynthesis of the active compounds of Isatis indigotica based on transcriptome sequencing and metabolites profiling 
BMC Genomics  2013;14:857.
Isatis indigotica is a widely used herb for the clinical treatment of colds, fever, and influenza in Traditional Chinese Medicine (TCM). Various structural classes of compounds have been identified as effective ingredients. However, little is known at genetics level about these active metabolites. In the present study, we performed de novo transcriptome sequencing for the first time to produce a comprehensive dataset of I. indigotica.
A database of 36,367 unigenes (average length = 1,115.67 bases) was generated by performing transcriptome sequencing. Based on the gene annotation of the transcriptome, 104 unigenes were identified covering most of the catalytic steps in the general biosynthetic pathways of indole, terpenoid, and phenylpropanoid. Subsequently, the organ-specific expression patterns of the genes involved in these pathways, and their responses to methyl jasmonate (MeJA) induction, were investigated. Metabolites profile of effective phenylpropanoid showed accumulation pattern of secondary metabolites were mostly correlated with the transcription of their biosynthetic genes. According to the analysis of UDP-dependent glycosyltransferases (UGT) family, several flavonoids were indicated to exist in I. indigotica and further identified by metabolic profile using UPLC/Q-TOF. Moreover, applying transcriptome co-expression analysis, nine new, putative UGTs were suggested as flavonol glycosyltransferases and lignan glycosyltransferases.
This database provides a pool of candidate genes involved in biosynthesis of effective metabolites in I. indigotica. Furthermore, the comprehensive analysis and characterization of the significant pathways are expected to give a better insight regarding the diversity of chemical composition, synthetic characteristics, and the regulatory mechanism which operate in this medical herb.
PMCID: PMC3890716  PMID: 24308360
Isatis indigotica; Transcriptome sequencing; Biosynthetic pathways; Metabolite profile; Co-expression analysis

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