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1.  Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: Disposition kinetics and pharmacology distinct from solvent-based paclitaxel 
Journal of Clinical Pharmacology  2014;54(10):1097-1107.
The aim of this study was to characterize population pharmacokinetics and the exposure–neutropenia relationship with nanoparticle albumin-bound (nab)-paclitaxel in patients with solid tumors. Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 patients with various solid tumors over the nab-paclitaxel dose range of 80–375 mg/m2. Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Pharmacokinetics of nab-paclitaxel were described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating paclitaxel was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325000 μg/h) was 40-fold greater than that for saturable elimination (8070 μg/h). Albumin was a significant covariate of paclitaxel elimination (P < .001), while total bilirubin, creatinine clearance, body size, age, sex, and tumor type had no significant or clinically relevant effect. The probability of experiencing a ≥50% reduction in neutrophils was best correlated to the duration above the drug concentration of 720 ng/mL. At a given exposure level, neutropenia development was positively correlated with increasing age but not significantly influenced by hepatic function, tumor type, sex, or dosing schedule. Covariate analyses supports exposure-matched dose adjustments in patients with moderate to severe hepatic impairment.
PMCID: PMC4302229  PMID: 24719309
pharmacokinetics; pharmacodynamics; neutropenia; nab-paclitaxel; covariates
2.  Ulcerative colitis with inflammatory polyposis in a teenage boy: A case report 
Ulcerative colitis in addition to inflammatory polyposis is common. The benign sequel of ulcerative colitis can sometimes mimic colorectal carcinoma. This report describes a rare case of inflammatory polyposis with hundreds of inflammatory polyps in ulcerative colitis which was not easy to distinguish from other polyposis syndromes. A 16-year-old Chinese male suffering from ulcerative colitis for 6 mo underwent colonoscopy, and hundreds of polyps were observed in the sigmoid, causing colonic stenosis. The polyps were restricted to the sigmoid. Although rectal inflammation was detected, no polyps were found in the rectum. A diagnosis of inflammatory polyposis and ulcerative colitis was made. The patient underwent total colectomy and ileal pouch anal anastomosis. The patient recovered well and was discharged on postoperative day 8. Endoscopic surveillance after surgery is crucial as ulcerative colitis with polyposis is a risk factor for colorectal cancer. Recognition of polyposis requires clinical, endoscopic and histopathologic correlation, and helps with chemoprophylaxis of colorectal cancer, as the drugs used postoperatively for colorectal cancer, ulcerative colitis and polyposis are different.
PMCID: PMC4299325  PMID: 25624746
Ulcerative colitis; Inflammatory polyposis; Teenager; Colorectal cancer
4.  Tricuspid regurgitation and right ventricular function after mitral valve surgery with or without concomitant tricuspid valve procedure 
To study the effect of mitral valve repair with or without concomitant tricuspid valve repair on functional tricuspid regurgitation and right ventricular function.
From 2001 to 2007, 1833 patients with degenerative mitral valve disease, a structurally normal tricuspid valve, and no coronary artery disease underwent mitral valve repair, and 67 underwent concomitant tricuspid valve repair. Right ventricular function (myocardial performance index and tricuspid annular plane systolic excursion) was measured before and after surgery using transthoracic echocardiography for randomly selected patients with tricuspid regurgitation grade 0, 1+, and 2+(100 patients for each grade) and 93 with grade 3+/4+, 393 patients in total.
In patients with mild (<3+) preoperative tricuspid regurgitation, mitral valve repair alone was associated with reduced tricuspid regurgitation and mild worsening of right ventricular function. Tricuspid regurgitation of 2+or greater developed in fewer than 20%, and right ventricular function had improved, but not to preoperative levels, at 3 years. In patients with severe (3+/4+) preoperative tricuspid regurgitation, mitral valve repair alone reduced tricuspid regurgitation and improved right ventricular function; however, tricuspid regurgitation of 2+ or greater returned and right ventricular function worsened toward preoperative levels within 3 years. Concomitant tricuspid valve repair effectively eliminated severe tricuspid regurgitation and improved right ventricular function. Also, over time, tricuspid regurgitation did not return and right ventricular function continued to improve to levels comparable to that of patients with lower grades of preoperative tricuspid regurgitation.
In patients with mitral valve disease and severe tricuspid regurgitation, mitral valve repair alone was associated with improved tricuspid regurgitation and right ventricular function. However, the improvements were incomplete and temporary. In contrast, concomitant tricuspid valve repair effectively and durably eliminated severe tricuspid regurgitation and improved right ventricular function toward normal, supporting an aggressive approach to important functional tricuspid regurgitation.
PMCID: PMC4215162  PMID: 23010580
6.  Evaluation and identification of microRNA-106 in the diagnosis of cancer: a meta-analysis 
Recently, extensive research has identified the non-invasive and cost-effective biomarker microRNA-106 (miR-106) in cancer detection. However, inconsistent results have prevented its usage in clinical. Therefore, we conducted this meta-analysis aimed to systematically determine diagnostic accuracy of miR-106 in distinguishing patients with cancer from cancer-free controls and further evaluate its value serving as a biomarker in clinical. We conducted a systematically literature search in databases (PubMed, web of science, Embase and the Cochrane Library) collecting relevant articles up to July 22th, 2014. The overall diagnostic accuracy of miR-106 was assessed by the following indexes: sensitivity, specificity, PLR, NLR and DOR. The SROC curve with AUC value was also generated for the assessment. Due to the significant heterogeneity, the random effects approach was chosen in our analysis and meta-regression was performed to explore the potential source of it. We also tested potential presence of publication bias using Deeks’ funnel plots test. Stata 12.0 statistical software was used for analysis in the present study. Overall, the 11 studies involving 756 cancer patients and 834 controls were considered eligible in our analysis. The results in our work showed that sensitivity of 0.57 (95% CI: 0.44-0.68) and specificity of 0.85 (95% CI: 0.72-0.92), with the under area AUC value of 0.75 (95% CI: 0.71-0.79) for miR-106 assay. Additionally, the combined PLR, NLR and DOR describing the discriminatory ability were 3.7 (95% CI: 2.2-6.2), 0.51 (95% CI: 0.42-0.62) and 7 (95% CI: 4-12) in the present analysis. The results in our meta-analysis showed that miR-106 had moderate accuracy in identifying cancer patients. Thus, further larger-scale prospective studies are needed to improve the diagnostic efficiency and explore the combination of miR-106 and other biomarkers with more pronounced accuracy.
PMCID: PMC4238492  PMID: 25419428
MicroRNA-106; cancer; meta-analysis; accuracy
7.  Apolipoprotein E Polymorphism and Colorectal Neoplasm: Results from a Meta-Analysis 
PLoS ONE  2014;9(7):e102477.
To investigate the relationship of Apolipoprotein E (APOE) gene polymorphism to colorectal neoplasia (CRN), we performed a systematic review and meta-analysis. Eligible studies were identified through a systematic literature review from PubMed, EMBASE, and the Science Citation Index up to February 2014. A combined analysis was performed, followed by a subgroup analyses stratified by the study design. We used data collected from 8 prospective studies involving respectively a total of 9243 participants and 4310 CRN cases which including 438 patients with colorectal adenoma (CRA), and 3873 patients with colorectal carcinoma (CRC). The pooled data from this meta-analysis indicated there was no significant association between APOE polymorphism and CRN (ε2: P = 0.51, OR 1.04 95% CI 0.93 to 1.16; ε4: P = 0.72, OR 0.98 95% CI 0.90 to 1.07). Interestingly, subgroup analysis demonstrated there was a significant decreased risk for proximal CRN in patients with APOE ε4 (P = 0.0007, OR 0.52 95% CI 0.35 to 0.76). Data showed no significant association between APOE genotype and overall CRN. However, compared with those carry APOE ε3 alleles, persons with APOE ε4 genotype have significant decreased risk suffering from proximal CRN but not from distal CRN.
PMCID: PMC4100903  PMID: 25029444
8.  Zn-Driven Discovery of a Hydrothermal Vent Fungal Metabolite Clavatustide C, and an Experimental Study of the Anti-Cancer Mechanism of Clavatustide B 
Marine Drugs  2014;12(6):3203-3217.
A naturally new cyclopeptide, clavatustide C, was produced as a stress metabolite in response to abiotic stress elicitation by one of the hydrothermal vent fluid components Zn in the cultured mycelia of Aspergillus clavatus C2WU, which were isolated from Xenograpsus testudinatus. X. testudinatus lives at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. The known compound clavatustide B was also isolated and purified. This is the first example of a new hydrothermal vent microbial secondary metabolite produced in response to abiotic Zn treatment. The structures were established by spectroscopic means. The regulation of G1-S transition in hepatocellular carcinoma cell lines by clavatustide B was observed in our previous study. The purpose of the present study was to verify these results in other types of cancer cell lines and elucidate the possible molecular mechanism for the anti-cancer activities of clavatustide B. In different human cancer cell lines, including pancreatic cancer (Panc-1), gastric cancer (MGC-803), colorectal cancer (SW-480), retinoblastoma (WERI-Rb-1) and prostate cancer (PC3), clavatustide B efficiently suppressed cell proliferations in a dose-dependent manner. Although different cancer cell lines presented variety in Max effect dose and IC50 dose, all cancer cell lines showed a lower Max effect dose and IC50 dose compared with human fibroblasts (hFB) (p < 0.05). Moreover, significant accumulations in G1 phases and a reduction in S phases (p < 0.05) were observed under clavatustide B treatment. The expression levels of 2622 genes including 39 cell cycle-associated genes in HepG2 cells were significantly altered by the treatment with 15 μg/mL clavatustide B after 48 h. CCNE2 (cyclin E2) was proved to be the key regulator of clavatustide B-induced G1-S transition blocking in several cancer cell lines by using real-time PCR.
PMCID: PMC4071572  PMID: 24879544
clavatustides; stress-driven discovery; hydrothermal vent; anti-cancer
9.  Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation 
Leukemia & lymphoma  2010;51(9):1711-1719.
Nuclear localization of non-phosphorylated, active β-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total β-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated β-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.
PMCID: PMC4000011  PMID: 20795789
Cytogenetics; DNA methylation; epigenetics; leukemia; Wnt pathway
10.  Neuritogenic Monoglyceride Derived from the Constituent of a Marine Fish for Activating the PI3K/ERK/CREB Signalling Pathways in PC12 Cells 
A neuritogenic monoglyceride, 1-O-(myristoyl) glycerol (MG), was isolated from the head of Ilisha elongate using a PC12 cell bioassay system, and its chemical structure was elucidated using spectroscopic methods. MG significantly induced 42% of the neurite outgrowth of PC12 cells at a concentration of 10 μM. To study the structure-activity relationships of MG, a series of monoglycerides was designed and synthesised. Bioassay results indicated that the alkyl chain length plays a key role in the neuritogenic activity of the monoglycerides. The groups that link the propane-1,2-diol and alkyl chain were also investigated. An ester linkage, rather than an amido one, was found to be optimal for neuritogenic activity. Therefore, 1-O-(stearoyl) glycerol (SG), which induces 57% of the neurite outgrowth of PC12 cells at 10 μM, was determined to be a lead compound for neuritogenic activity. We then investigated the mechanism of action of neurite outgrowth induced by SG on PC12 cells using protein specific inhibitors and Western blot analysis. The mitogen-activated kinase/ERK kinase (MEK) inhibitor U0126 and the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 significantly decreased neurite outgrowth. At the same time, SG increased phosphorylation of CREB in protein level. Thus, SG-induced neuritogenic activity depends on the activation of the extracellular-regulated protein kinase (ERK), cAMP responsive element-binding protein (CREB) and PI3K signalling pathways in PC12 cells.
PMCID: PMC3876105  PMID: 24351811
1-O-(myristoyl) glycerol; neuritogenic activity; Ilisha elongate; PC12 cells; 1-O-(stearoyl) glycerol; ERK
11.  Two Novel Hepatocellular Carcinoma Cycle Inhibitory Cyclodepsipeptides from a Hydrothermal Vent Crab-Associated Fungus Aspergillus clavatus C2WU 
Marine Drugs  2013;11(12):4761-4772.
Two novel cyclodepsipeptides containing an unusual anthranilic acid dimer and a d-phenyllactic acid residues, clavatustides A (1) and B (2), were identified from cultured mycelia and broth of Aspergillus clavatus C2WU isolated from Xenograpsus testudinatus, which lives at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. This is the first example of cyclopeptides containing an anthranilic acid dimer in natural products, and the first report of microbial secondary metabolites from the hydrothermal vent crab. Clavatustides A (1) and B (2) suppressed the proliferation of hepatocellular carcinoma (HCC) cell lines (HepG2, SMMC-7721 and Bel-7402) in a dose-dependent manner, and induced an accumulation of HepG2 cells in G1 phase and reduction of cells in S phase.
PMCID: PMC3877885  PMID: 24317468
cyclodepsipeptide; Aspergillus clavatus; hydrothermal vent; carcinoma cycle inhibitory
12.  Pretherapeutic Plasma Pro- and Anti- Inflammatory Mediators Are Related to High Risk of Oral Mucositis in Pediatric Patients with Acute Leukemia: A Prospective Cohort Study 
PLoS ONE  2013;8(5):e64918.
This prospective study evaluated clinical risk indicators as well as pro- and anti- inflammatory mediators at the time of malignancy diagnosis in relation to chemotherapy-related oral mucositis in pediatric population.
Patients (n = 104) under 18 years of age with primary malignancies and undergoing chemotherapy were included. Potential risk indicators were analyzed using binary logistic regression with oral mucositis as the outcome. In a subgroup (n = 35), plasma samples at the time of malignancy diagnosis were analyzed for inflammatory cytokines and an antimicrobial protein pro-LL-37 (hCAP18).
In the multivariable model, type of malignancy diagnosis was significantly associated with oral mucositis, with highest risk of oral mucositis in patients with acute leukemia compared to those with lymphoma or solid tumors. At the time of malignancy diagnosis, plasma from patients with acute leukemia displayed higher concentrations (P<0.05) of IL-6, IL-8, IL-10, and TNF-α and lower levels of pro-LL-37 (P<0.001).
The results imply that pretherapeutic high levels of inflammatory cytokines and low levels of pro-LL-37 in plasma might contribute to the high incidence of oral mucositis in patients with acute leukemia. These findings may add to our understanding of the predispositions to oral mucositis in children with malignancies.
PMCID: PMC3669020  PMID: 23741421
14.  Surveillance of Antimicrobial Susceptibility Patterns among Shigella Species Isolated in China during the 7-Year Period of 2005-2011 
Annals of Laboratory Medicine  2013;33(2):111-115.
Shigella is a frequent cause of bacterial dysentery in the developing world. Treatment with antibiotics is recommended for shigellosis, but the options are limited due to globally emerging resistance. This study was conducted to determine the frequency and pattern of antimicrobial susceptibility of Shigella in China.
We studied the antimicrobial resistance profiles of 308 Shigella spp. strains (260 S. flexneri, 40 S. sonnei, 5 S. boydii, and 3 S. dysenteriae) isolated from fecal samples of patients (age, from 3 months to 92 yr) presenting with diarrhea in different districts of Anhui, China. The antimicrobial resistance of strains was determined by the agar dilution method according to the CSLI guidelines.
The most common serogroup in the Shigella isolates was S. flexneri (n=260, 84.4%), followed by S. sonnei (n=40, 13.0%). The highest resistance rate was found for nalidixic acid (96.4%), followed by ampicillin (93.2%), tetracycline (90.9%), and trimethoprim/sulfamethoxazole (80.8%). Among the isolates tested, 280 (91.0%) were multidrug resistant (resistant to ≥2 agents). The most common resistance pattern was the combination of ampicillin, tetracycline, and trimethoprim/sulfamethoxazole (70.8%). Resistance to ampicillin and tetracycline were more common among S. flexneri than among S. sonnei isolates.
S. flexneri is predominant in Anhui, China, and its higher antimicrobial resistance rate compared with that of S. sonnei is a cause for concern. Continuous monitoring of resistance patterns is necessary to control the spread of resistance in Shigella. The recommendations for antimicrobial treatment must be updated regularly based on surveillance results.
PMCID: PMC3589635  PMID: 23482897
Antimicrobial susceptibility; Antimicrobial resistance; Shigella
15.  Electronically-measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation* 
Clinical transplantation  2010;25(2):E124-E131.
Non-adherence with immunosuppressive medications can result in allograft rejection and eventually allograft loss.
In a racially diverse population, we utilized microelectronic cap monitors to determine the association of adherence with a single immunosuppressive medication and kidney allograft outcomes post-transplantation. This prospective cohort study enrolled 243 patients from eight transplant centers to provide adherence and kidney allograft outcomes data. To determine the association of adherence with change in estimated glomerular filtration rate (eGFR), we fit mixed effects models with the outcome being change in eGFR over time. We also fit Cox proportional hazards models to determine the association of adherence with time to persistent 25% and 50% decline in eGFR.
The distribution of adherence post-transplant was as follows: 164 (68%), 49 (20%) and 30 (12%) had >85–100%, 50–85% and <50% adherence, respectively. 79 (33%) and 36 (15%) of the subjects experienced a persistent 25% decline in eGFR or allograft loss and 50% decline in eGFR or allograft loss during follow-up. Adherence was not associated with acute rejection or 25% decline or 50% decline in eGFR. In the adjusted and unadjusted model, adherence and black race were not associated with change in eGFR over time.
Non-adherence with a single immunosuppressive medication, was not associated with kidney allograft outcomes.
PMCID: PMC3566245  PMID: 20977496
kidney transplant; adherence; renal function
16.  Plasmid-Mediated Quinolone Resistance in Extended-Spectrum-β-Lactamase- and AmpC β-Lactamase-Producing Serratia marcescens in China 
We investigated the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants and examined the association of these determinants with extended-spectrum β-lactamases (ESBLs) and/or plasmid-mediated AmpC β-lactamases (pAmpCs) in Serratia marcescens isolates in China. In this study, the presence of PMQR determinants was significantly related to the coproduction of ESBLs and/or pAmpCs (CTX-M-14, SHV-5, DHA-1, and ACT-1), among which CTX-M-14 was the most common gene type.
PMCID: PMC3421568  PMID: 22664965
17.  Invasive ductal breast cancer metastatic to the sigmoid colon 
The most common sites of breast cancer metastasis are the bone, lung, liver and brain. However, colonic metastases from breast cancer are very rare in the clinic. We describe an unusual case of sigmoid colonic metastasis from invasive ductal breast cancer. With this report, we should increase the clinical awareness that any patient with a colorectal lesion and a history of malignancy should be considered to have a metastasis until proven otherwise. Early diagnosis is very important, which enables prompt initiation of systemic treatment, such as chemotherapy, endocrine therapy or both, thus avoiding unnecessary radical surgical resection and improving the prognosis.
PMCID: PMC3547804  PMID: 23181599
Breast cancer; Sigmoid colon; Metastasis; Invasive ductal cancer
18.  Emergence of serogroup C meningococcal disease associated with a high mortality rate in Hefei, China 
BMC Infectious Diseases  2012;12:205.
Neisseria meningitidis serogroup C has emerged as a cause of epidemic disease in Hefei. The establishment of serogroup C as the predominant cause of endemic disease has not been described.
We conducted national laboratory-based surveillance for invasive meningococcal disease during 2000–2010. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing.
A total of 845 cases of invasive meningococcal disease were reported. The incidence increased from 1.25 cases per 100,000 population in 2000 to 3.14 cases per 100,000 in 2003 (p < 0.001), and peaked at 8.43 cases per 100,000 in 2005. The increase was mainly the result of an increase in the incidence of serogroup C disease. Serogroup C disease increased from 2/23 (9%) meningococcal cases and 0.11 cases per 100,000 in 2000 to 33/58 (57%) cases and 1.76 cases per 100,000 in 2003 (p < 0.01). Patients infected with serogroup C had serious complications more frequently than those infected with other serogroups. Specifically, 161/493 (32.7%) cases infected with serogroup C had at least one complication. The case-fatality rate of serogroup C meningitis was 11.4%, significantly higher than for serogroup A meningitis (5.3%, p = 0.021). Among patients with meningococcal disease, factors associated with death in univariate analysis were age of 15–24 years, infection with serogroup C, and meningococcemia.
The incidence of meningococcal disease has substantially increased and serogroup C has become endemic in Hefei. The serogroup C strain has caused more severe disease than the previously predominant serogroup A strain.
PMCID: PMC3459715  PMID: 22943188
Neisseria meningitidis; Serogroup C strain; Incidence
19.  Paroxysmal Supraventricular Tachycardia in an Infant with Hand, Foot, and Mouth Disease 
Annals of Dermatology  2012;24(2):200-202.
An 11-month-old male infant was admitted to our hospital with fever, fussiness, poor feeding, vomiting, and tachypnea for two days prior. Physical examination revealed sporadic papules and vesicles occurring on his hands, feet, face, and perianal mucosa. Enterovirus 71 was identified from both throat swab and vesicle fluid using virus isolation techniques. The patient's heart rate fluctuated in a very narrow range from 180~210/beats/min regardless of his physiologic state. An electrocardiogram showed P-waves buried within or occurring just after regular, narrow, QRS complexes. The patient was diagnosed as having hand, foot, and mouth disease in combination with paroxysmal supraventricular tachycardia (PSVT). The child recovered well with symptomatic treatment, including intravenous administration of acyclovir, glucocorticoids, immunoglobulin, adenosine, and sotalol. PSVT was terminated within 36 hours of hospitalization. The skin lesions became crusted on the third day, and then proceeded to heal spontaneously. Here we report on this unusual case and review the associated literature.
PMCID: PMC3346912  PMID: 22577272
Electrocardiography; Hand; foot and mouth disease; Enterovirus 71; Paroxysmal supraventricular tachycardia
20.  Different sperm sources and parameters can influence intracytoplasmic sperm injection outcomes before embryo implantation*  
To evaluate the effects of sperm with different parameters and sources on the outcomes of intracytoplasmic sperm injection (ICSI), 1972 ICSI cycles were analyzed retrospectively. Groups 1 to 5 were composed of cycles using ejaculated sperm and were grouped according to sperm quantity, quality, and morphology into normal (288 cycles), or mild (329 cycles), moderate (522 cycles), severe (332 cycles), and extremely severe (171 cycles) oligozoospermia and/or asthenozoospermia and/or teratozoospermia (OAT) groups. Group 6 was composed of 250 cycles using testicular or epididymal sperm, and Group 7 consisted of 80 cycles using frozen-thawed sperm. We found that fertilization rates were gradually reduced from Groups 1 to 6, and reached statistical difference in Groups 5 and 6 (P<0.05). The high-quality embryo rate was higher in Group 1 than in Groups 2, 3, 5, 6, and 7 (P<0.05). No statistical differences were observed in the rates of embryo cleavage, clinical pregnancy, miscarriage, live-birth, premature birth, low birth weight, weeks of premature birth, average birth weight, or sex ratio for all seven groups (P>0.05). A total of nine cases of malformation were observed, with a malformation rate of 1.25% (9/719). In conclusion, different sperm sources and parameters can affect ICSI outcomes before embryo implantation. A full assessment of offspring malformation will require further study using a larger sample size.
PMCID: PMC3251746  PMID: 22205614
Intracytoplasmic sperm injection (ICSI); Sperm; Sperm source; Sperm parameters; Malformation
21.  Mutations in the ELANE Gene are Associated with Development of Periodontitis in Patients with Severe Congenital Neutropenia 
Journal of Clinical Immunology  2011;31(6):936-945.
Patients with severe congenital neutropenia (SCN) often develop periodontitis despite standard medical and dental care. In light of previous findings that mutations in the neutrophil elastase gene, ELANE, are associated with more severe neutropenic phenotypes, we hypothesized an association between the genotype of SCN and development of periodontitis.
Fourteen Swedish patients with SCN or cyclic neutropenia harboring different genetic backgrounds were recruited for periodontal examination. Peripheral blood, gingival crevicular fluid (GCF), and subgingival bacterial samples were collected. The levels of cytokines and antibacterial peptides were determined in GCF and plasma by multiplex immunoassay and immunoblotting, respectively. Subgingival bacterial samples were analyzed using 16S rDNA pyrosequencing.
ELANE mutations correlated with more severe periodontal status than the HAX1 or unknown mutations in patients with SCN. The subjects with mutant ELANE had higher levels of IL-1β in GCF. Using principal coordinate analysis of the subgingival microbiota, patients with ELANE mutations and reference subjects with periodontitis tended to cluster differently from patients with HAX1 or unknown mutations and non-periodontitis reference subjects.
This study demonstrates an association between ELANE mutations in SCN and the development of periodontitis with skewed subgingival microbiota, indicating a potential role of ELANE mutations in the pathogenesis of periodontitis.
PMCID: PMC3223588  PMID: 21796505
Kostmann neutropenia; neutrophil elastase 2; periodontal diseases; subgingival microflora
22.  Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies 
Cancer research  2009;69(21):8482-8490.
Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematological disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), while no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high risk MDS (≥RAEB2), but not in low risk MDS (
PMCID: PMC3081599  PMID: 19826047
del(5q); monosomy 5; CTNNA1; methylation; myelodysplastic syndrome; acute myelogenous leukemia; methylation; Progressive silencing; AML transformation
Oncogene  2010;29(17):2467-2476.
The tumor suppressor gene HYPERMETHYLATED IN CANCER 1 (HIC1), which encodes a transcriptional repressor, is epigenetically inactivated in various human cancers. Here, we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. We also show that mouse embryos lacking both Hic1 alleles manifest developmental defects spatially associated with misexpression of ephrin-A1, and that overexpression of ephrin-A1 is a feature of tumors arising in Hic1 heterozygous mice in which the remaining wild-type allele is epigenetically silenced. In breast cancer, we find that ephrin-A1 expression is common in vivo, but that in cell culture, expression of the EphA receptors is predominant. Restoration of HIC1 function in breast cancer cells leads to a reduction in tumor growth in vivo, an effect that can be partially rescued by co-overexpression of ephrin-A1. Interestingly, overexpression of ephrin-A1 in vitro triggers downregulation of EphA2 and EphA4 levels, resulting in an expression pattern similar to that seen in vivo. We conclude that Hic1 spatially restricts ephrin-A1 expression in development, and that upregulated expression of ephrin-A1 resulting from epigenetic silencing of HIC1 in cancer cells may be an important mechanism in epithelial malignancy.
PMCID: PMC3025282  PMID: 20154726
Hic1; Ephrin-A1; EphA2; EphA4
Oncogene  2010;29(25):3619-3629.
Aneurysmal bone cyst (ABC) is an aggressive, pediatric bone tumor characterized by extensive destruction of the surrounding bone. Though first described over 60 years ago, its molecular etiology remains poorly understood. Recent work revealed that ABCs harbor translocation of TRE17/USP6, leading to its transcriptional upregulation. TRE17 encodes a ubiquitin-specific protease (USP), and a TBC domain that mediates binding to the Arf6 GTPase. However, the mechanisms by which TRE17 overexpression contributes to tumor pathogenesis, and the role of its USP and TBC domains are unknown. ABCs are characterized by osteolysis, inflammatory recruitment, and extensive vascularization, processes in which matrix proteases play a prominent role. This led us to explore whether TRE17 regulates the production of matrix metalloproteinases (MMPs). In the current study, we demonstrate that TRE17 is sufficient to induce expression of MMP-9 and MMP-10, in a manner requiring its USP activity, but not its ability to bind Arf6. TRE17 induces transcription of MMP-9 through activation of NFκB, mediated in part by the GTPase RhoA and its effector kinase, ROCK. Furthermore, xenograft studies demonstrate that TRE17 induces formation of tumors that reproduce multiple features of ABC, including a high degree of vascularization, with an essential role for the USP domain. In sum, these studies reveal that TRE17 is sufficient to initiate tumorigenesis, identify MMPs as novel TRE17 effectors that likely contribute to ABC pathogenesis, and define the underlying signaling mechanism of their induction.
PMCID: PMC2892027  PMID: 20418905
TRE17/USP6; aneurysmal bone cyst; MMP-9; Arf6; NFκB; RhoA
AIM: To investigate the role of enhancer of zeste homologue 2 (EZH2) and STAT6 immunohistochemistry in the evaluation of clinical stages and prognosis of colorectal cancer (CRC).
METHODS: The expression patterns were examined by immunohistochemistry in both tumor and adjacent non-neoplastic tissues of 119 CRC patients who underwent operation during the time period from 2002 to 2004.
RESULTS: The positive rates of EZH2 and STAT6 in CRC cases were 69.7% (83 of 119) and 60.5% (72 of 119), respectively, and there was significant difference when compared with tumor adjacent non-neoplastic tissues (P < 0.05). In all CRC cases, patients with EZH2-positive, or STAT6-positive expression had lower survival rates than those with EZH2-negative or STAT6-negative expression (P = 0.002 and P = 0.005, respectively). Co-expression of EZH2 and STAT6 showed significantly higher levels in CRC cases of high clinical TNM stages (P = 0.001), and the expression of STAT6 was also correlated with lymph node metastasis and distant metastasis (P = 0.001 and P = 0.016, respectively). Multivariate analysis revealed that EZH2 expression was an independent prognostic indicator of CRC (P = 0.039).
CONCLUSION: EZH2 and STAT6 expressions have significant values in distinguishing clinical stages of CRC and predicting the prognosis of the patients.
PMCID: PMC2874149  PMID: 20480530
Colorectal Neoplasms; Enhancer of zeste homologue 2; STAT6; Immunohistochemistry

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