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1.  C-terminal kinesin motor KIFC1 participates in facilitating proper cell division of human seminoma 
Oncotarget  2017;8(37):61373-61384.
C-terminus kinesin motor KIFC1 is known for centrosome clustering in cancer cells with supernumerary centrosomes. KIFC1 crosslinks and glides on microtubules (MT) to assist normal bipolar spindle formation to avoid multi-polar cell division, which might be fatal. Testis cancer is the most common human cancer among young men. However, the gene expression profiles of testis cancer is still not complete and the expression of the C-terminus kinesin motor KIFC1 in testis cancer has not yet been examined. We found that KIFC1 is enriched in seminoma tissues in both mRNA level and protein level, and is specifically enriched in the cells that divide actively. Cell experiments showed that KIFC1 may be essential in cell division, but not essential in metastasis. Based on subcellular immuno-florescent staining results, we also described the localization of KIFC1 during cell cycle. By expressing ΔC-FLAG peptide in the cells, we found that the tail domain of KIFC1 might be essential for the dynamic disassociation of KIFC1, and the motor domain of KIFC1 might be essential for the degradation of KIFC1. Our work provides a new perspective for seminoma research.
PMCID: PMC5617430
KIFC1; kinesin-14; seminoma; testis cancer; cell division
2.  Chiral platinum (II)-4-(2,3-dihydroxypropyl)- formamide oxo-aporphine (FOA) complexes promote tumor cells apoptosis by directly targeting G-quadruplex DNA in vitro and in vivo 
Oncotarget  2017;8(37):61982-61997.
Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(–)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells. Moreover, our in vivo studies showed that complex 6 can effectively inhibit tumor growth in the BEL-7404 and BEL-7402 xenograft mouse models and is less toxic than 5-fluorouracil and cisplatin. The effective inhibition of tumor growth is attributed to its interactions with 53BP1, TRF1, c-myc, TRF2, and hTERT. Thus, complex 6 can serve as a novel lead compound and a potential drug candidate for anticancer chemotherapy.
PMCID: PMC5617480
chiral platinum(II) complex; oxoaporphine; G-quadruplex DNA; telomerase; antitumor activity
3.  Lactobacillus paracasei GMNL-32 exerts a therapeutic effect on cardiac abnormalities in NZB/W F1 mice 
PLoS ONE  2017;12(9):e0185098.
Systemic lupus erythematosus (SLE) is a disease that mostly affects women. Accelerated atherosclerosis is a high-risk factor associated with SLE patients. SLE associated with cardiovascular disease is one of the most important causes of death. In this study, we demonstrated that Lactobacillus paracasei GMNL-32 (GMNL-32), a probiotic species, exhibits anti-fibrosis and anti-apoptotic effects on the cardiac tissue of NZB/WF1 mice. Female NZB/W F1 mice, a well-known and commonly used lupus-prone mouse strain, were treated with or without GMNL-32 administration for 12 weeks. Oral administration of GMNL-32 to NZB/WF1 mice significantly increased the ventricular thickness when compared to that of NZB/WF1 mice. Administration of GMNL-32 significantly attenuated the cardiac cell apoptosis that was observed in exacerbate levels in the control NZB/WF1 mice. Further, the cellular morphology that was slightly distorted in the NZB/WF1 was effectively alleviated in the treatment group mice. In addition, GMNL-32 reduced the level of Fas death receptor-related pathway of apoptosis signaling and enhanced anti-apoptotic proteins. These results indicate that GMNL-32 exhibit an effective protective effect on cardiac cells of SLE mice. Thus, GMNL-32 may be a potential therapeutic strategy against SLE associated arthrosclerosis.
PMCID: PMC5608316  PMID: 28934296
4.  Objective and Perceived Weight: Associations with Risky Adolescent Sexual Behavior 
Studies have shown that obesity is associated with increased sexual risk-taking, particularly among adolescent females, but the relationships between obesity, perceived weight and sexual risk behaviors are poorly understood.
Integrative data analysis was performed that combined baseline data from the 1994–1995 National Longitudinal Study of Adolescent Health (from 17,606 respondents in grades 7–12) and the 1997 National Longitudinal Survey of Youth (from 7,752 respondents aged 12–16). Using six sexual behaviors measured in both data sets (age at first intercourse, various measures of contraceptive use and number of partners), cluster analysis was conducted that identified five distinct behavior clusters. Multivariate ordinal logistic regression analysis examined associations between adolescents’ weight status (categorized as underweight, normal-weight, overweight or obese) and weight perception and their cluster membership.
Among males, being underweight, rather than normal-weight, was negatively associated with membership in increasingly risky clusters (odds ratio, 0.5), as was the perception of being overweight, as opposed to about the right weight (0.8). However, being overweight was positively associated with males’ membership in increasingly risky clusters (1.3). Among females, being obese, rather than normal-weight, was negatively correlated with membership in increasingly risky clusters (0.8), while the perception of being overweight was positively correlated with such membership (1.1).
Both objective and subjective assessments of weight are associated with the clustering of risky sexual behaviors among adolescents, and these behavioral patterns differ by gender.
PMCID: PMC5028289  PMID: 27608419
5.  Association between four SNPs in IL-4 and the risk of gastric cancer in a Chinese population 
Gastric cancer (GC) is the 5th most prevalent cancer. The etiology of GC is still poorly understood. We performed a case-control study in a Chinese population to investigate the association of rs2243248 (-1098 G/T), rs2227284 (-33 C/T), rs2243250 (-589 T/C) and rs2070874 (-107 T/C) polymorphisms and haplotypes with the development of gastric cancer in a Chinese population. A total of 362 patients with gastric cancer and 384 controls were recruited between December 2013 and December 2015. Genotyping of rs2243248 (-1098 G/T), rs2227284 (-33 C/T), rs2243250 (-589 T/C) and rs2070874 (-107 T/C) was performed in a 384-well plate format on the sequenom MassARRAY platform, and analyzed by MALDI-TOF MS. The TC and CC genotypes of rs2243250 (-589 T/C) were associated with an increased risk of gastric cancer when compared with the TT genotype, with adjusted ORs (95% CI) of 1.52 (1.07-2.15) and 2.13 (1.30-3.51), respectively. The TTTT haplotype revealed a reduced risk of gastric cancer (OR=0.65, 95% CI=0.45-0.94). No linkage disequilibrium was found among IL-4 rs2243248, rs2227284, rs2243250 and rs2070874. In summary, our findings support a significant association of IL-4 rs2243250 polymorphism with the risk of gastric cancer in the Chinese population, and IL-4 haplotype contributes to the development of this disease.
PMCID: PMC5636916
IL-4; polymorphism; haplotype; gastric cancer
6.  Unilateral stimulation of the lateral division of the dorsal telencephalon induces synaptic plasticity in the bilateral medial division of zebrafish 
Scientific Reports  2017;7:9096.
This study was aimed to evaluate the synaptic plasticity in projections from the dorsal lateral region (Dl) to the bilateral dorsal medial region (Dm) of the zebrafish telencephalon. The results showed that unilateral electrical stimulation of the Dl evokes a negative field potential (FP) in both the contralateral and ipsilateral side of the Dm. We tested synaptic plasticity, including high-frequency stimulation-induced LTP (HFS-LTP) and low-frequency stimulation-induced LTD (LFS-LTD). We demonstrated that HFS-induced bilateral LTP is NMDAR-dependent by the application of an NMDAR antagonist, DL-AP5 (30 μM, suprafused for 10 min), which blocked the HFS-induced LTP in both the contralateral and ipsilateral Dm. In addition, LTP was restored after DL-AP5 was washed out by continuous aCSF suprafusion. These results suggested that the potentiation is NMDAR-dependent. Either LFS (1 Hz for 20 min) or applying the mGluR agonist, DHPG (40 μM, suprafused for 10 min) successfully induced bilateral LTD for at least 1 h. Furthermore, both the contralateral fEPSP and LTP vanished after ablation of the anterior commissure. In conclusion, the results of the present study suggested that the projection between the Dl and contralateral Dm in the telencephalon of zebrafish is via the anterior commissure and possesses synaptic plasticity.
PMCID: PMC5567264  PMID: 28831099
7.  Schistosoma japonicum attenuates dextran sodium sulfate-induced colitis in mice via reduction of endoplasmic reticulum stress 
World Journal of Gastroenterology  2017;23(31):5700-5712.
To elucidate the impact of Schistosoma (S.) japonicum infection on inflammatory bowel disease by studying the effects of exposure to S. japonicum cercariae on dextran sodium sulfate (DSS)-induced colitis.
Infection was percutaneously established with 20 ± 2 cercariae of S. japonicum, and colitis was induced by administration of 3% DSS at 4 wk post infection. Weight change, colon length, histological score (HS) and disease activity index (DAI) were evaluated. Inflammatory cytokines, such as IL-2, IL-10 and IFN-γ, were tested by a cytometric bead array and real-time quantitative polymerase chain reaction (RT-PCR). Protein and mRNA levels of IRE1α, IRE1β, GRP78, CHOP, P65, P-P65, P-IκBα and IκBα in colon tissues were examined by Western blot and RT-PCR, respectively. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells, cleaved-caspase 3 expression and Bcl2/Bax were investigated to assess the apoptosis in colon tissues.
Mice infected with S. japonicum cercariae were less susceptible to DSS. Mice infected with S. japonicum cercariae and treated with DSS showed decreased weight loss, longer colon, and lower HS and DAI compared with mice treated with DSS alone. A substantial decrease in Th1/Th2/Th17 response was observed after infection with S. japonicum. Endoplasmic reticulum (ER) stress and the nuclear factor-kappa B (NF-κB) pathway were reduced in mice infected with S. japonicum cercariae and treated with DSS, along with ameliorated celluar apoptosis, in contrast to mice treated with DSS alone.
Exposure to S. japonicum attenuated inflammatory response in a DSS-induced colitis model. In addition to the Th1/Th2/Th17 pathway and NF-κB pathway, ER stress was shown to be involved in mitigating inflammation and decreasing apoptosis. Thus, ER stress is a new aspect in elucidating the relationship between helminth infection and inflammatory bowel disease (IBD), which may offer new therapeutic methods for IBD.
PMCID: PMC5569284
Endoplasmic reticulum stress; Schistosoma japonicum; Colitis
8.  Suppression of diabetic retinopathy with GLUT1 siRNA 
Scientific Reports  2017;7:7437.
To investigate the effect of glucose transporter-1 (GLUT1) inhibition on diabetic retinopathy, we divided forty-eight mice into scrambled siRNA, diabetic scrambled siRNA, and GLUT1 siRNA (intravitreally injected) groups. Twenty-one weeks after diabetes induction, we calculated retinal glucose concentrations, used electroretinography (ERG) and histochemical methods to assess photoreceptor degeneration, and conducted immunoblotting, leukostasis and vascular leakage assays to estimate microangiopathy. The diabetic scrambled siRNA and GLUT1 siRNA exhibited higher glucose concentrations than scrambled siRNA, but GLUT1 siRNA group concentrations were only 50.05% of diabetic scrambled siRNA due to downregulated GLUT1 expression. The diabetic scrambled siRNA and GLUT1 siRNA had lower ERG amplitudes and ONL thicknesses than scrambled siRNA. However, compared with diabetic scrambled siRNA, GLUT1 siRNA group amplitudes and thicknesses were higher. Diabetic scrambled siRNA cones were more loosely arranged and had shorter outer segments than GLUT1 siRNA cones. ICAM-1 and TNF-α expression levels, adherent leukocyte numbers, fluorescence leakage areas and extravasated Evans blue in diabetic scrambled siRNA were higher than those in scrambled siRNA. However, these parameters in the GLUT1 siRNA were lower than diabetic scrambled siRNA. Together, these results demonstrate that GLUT1 siRNA restricted glucose transport by inhibiting GLUT1 expression, which decreased retinal glucose concentrations and ameliorated diabetic retinopathy.
PMCID: PMC5547104  PMID: 28785055
9.  Electrophysiological evidence for pre-attention information processing improvement in patients with central hemiplegic after peripheral nerve rewiring: a pilot study 
Scientific Reports  2017;7:6888.
Central neurologic injury (CNI) causes dysfunctions not only in limbs but also in cognitive ability. We applied a novel peripheral nerve rewiring (PNR) surgical procedure to restore limb function. Here, we conducted a prospective study to develop estimates for the extent of preattentive processes to cognitive function changes in CNI patients after PNR. Auditory mismatch negativity (MMN) was measured in CNI patients who received the PNR surgery plus conventional rehabilitation treatment. During the 2-year follow-up, the MMN was enhanced with increased amplitude in the PNR plus rehabilitation group compared to the rehabilitation-only group as the experiment progressed, and progressive improvement in behavioural examination tests was also observed. Furthermore, we found a significant correlation between the changes in Fugl-Meyer assessment scale scores and in MMN amplitudes. These results suggested that PNR could affect the efficiency of pre-attention information processing synchronously with the recovery of motor function in the paralyzed arm of the in chronic CNI patients. Such electroencephalographic measures might provide a biological approach with which to distinguish patient subgroups after surgery, and the change in MMN may serve as an objective auxiliary index, indicating the degree of motor recovery and brain cognitive function.
PMCID: PMC5537276  PMID: 28761096
10.  Benchmarking Health-Related Quality of Life Data from a Clinical Setting 
Health-related quality of life (HRQoL) is an important clinical outcome, yet there is little guidance for its interpretation in clinical settings. One approach would use benchmarking to contextualize HRQoL results.
To construct a nationally representative HRQoL benchmark for use with a clinical sample.
Research Design
Cross-sectional analysis of HRQoL scores from: 1) the 2011 Medical Expenditures Panel Survey (MEPS), a representative sample of the noninstitutionalized US population, and 2) outpatient academic and community cardiology clinics within a large health system in 2012–2013.
The 2011 MEPS includes 21,959 adults who completed the HRQoL measures; 414 reported visiting a cardiologist. Of 1,945 outpatient index visits during the study period that were not for outpatient cardiac catheterization, 1,434 patients completed the HRQoL measures.
Main Measures
The primary outcome was the Short Form-6D (SF-6D). The secondary outcomes were the Mental Component Summary score and the Physical Component Summary score.
The local cardiology clinic sample was 42% female with a mean Charlson Comorbidity Index (CCI) score of 1.74. The MEPS subsample of cardiology patients more closely matched the local cardiology clinic sample (43% female, mean CCI score of 1.57) than the entire MEPS sample (52% female, mean CCI score of 0.62). SF-6D scores for the local cardiology clinic sample were significantly better, statistically and clinically, in 4 of 5 age strata than the MEPS subsample of cardiology patients.
HRQoL benchmarks can be created from current public datasets. Subgroups in national samples may provide more valid benchmarks for clinical populations.
PMCID: PMC5516952  PMID: 28557518
Quality measurement/Benchmarking; Quality of life; Epidemiology/Statistics
11.  Measuring Nonspecific Factors in Treatment: Item Banks that Assess the Healthcare Experience and Attitudes from the Patient's Perspective 
Nonspecific factors that accompany healthcare treatments, such as patients’ attitudes and expectations, are important parts of the experience of care and can influence outcomes. However, no precise, concise, and generalizable instruments to measure these factors exist. We report on the development and calibration of new item banks, titled the Healing Encounters and Attitudes Lists (HEAL), that assess nonspecific factors across a broad range of treatments and conditions.
The instrument development methodology of the Patient-Reported Outcomes Measurement Information System (PROMIS®) was used. Patient focus groups and clinician interviews informed our HEAL conceptual model. Literature searches of 8 databases yielded over 500 instruments and resulted in an initial item pool of several thousand items. After qualitative item analysis, including cognitive interviewing, 296 items were included in field testing. The calibration sample included 1657 respondents, 1400 obtained through an internet panel and 257 from conventional and integrative medicine clinics. Following exploratory and confirmatory factor analyses, the HEAL item banks were calibrated using item response theory (IRT).
The final HEAL item banks were Patient-Provider Connection (57 items), Healthcare Environment (25 items), Treatment Expectancy (27 items), Positive Outlook (27 items), and Spirituality (26 items). Short forms were also developed from each item bank. A 6-item short form, Attitudes toward Complementary and Alternative Medicine (CAM) was also created.
HEAL item banks provided substantial information across a broad range of each construct. HEAL item banks showed initial evidence of predictive and concurrent validity, suggesting they are suitable for measuring nonspecific factors in treatment.
PMCID: PMC4865446  PMID: 26563249
12.  Health Care Use, Health Behaviors, and Medical Conditions Among Individuals in Same-Sex and Opposite-Sex Partnerships 
Medical care  2016;54(6):547-554.
Prior research documents disparities between sexual minority and nonsexual minority individuals regarding health behaviors and health services utilization. However, little is known regarding differences in the prevalence of medical conditions.
To examine associations between sexual minority status and medical conditions.
Research Design
We conducted multiple logistic regression analyses of the Medical Expenditure Panel Survey (2003–2011). We identified individuals who reported being partnered with an individual of the same sex, and constructed a matched cohort of individuals in opposite-sex partnerships.
A total of 494 individuals in same-sex partnerships and 494 individuals in opposite-sex partnerships.
Measures of health risk (eg, smoking status), health services utilization (eg, physician office visits), and presence of 15 medical conditions (eg, cancer, diabetes, arthritis, HIV, alcohol disorders).
Same-sex partnered men had nearly 4 times the odds of reporting a mood disorder than did opposite-sex partnered men [adjusted odds ratio (aOR) = 3.96; 95% confidence interval (CI), 1.85–8.48]. Compared with opposite-sex partnered women, same-sex partnered women had greater odds of heart disease (aOR =2.59; 95% CI, 1.19–5.62), diabetes (aOR= 2.75; 95% CI, 1.10–6.90), obesity (aOR =1.92; 95% CI, 1.26–2.94), high cholesterol (aOR = 1.89; 95% CI, 1.03–3.50), and asthma (aOR=1.90; 95% CI, 1.02–1.19). Even after adjusting for sociodemographics, health risk behaviors, and health conditions, individuals in same-sex partnerships had 67% increased odds of past-year emergency department utilization and 51% greater odds of ≥3 physician visits in the last year compared with opposite-sex partnered individuals.
A combination of individual-level, provider-level, and system-level approaches are needed to reduce disparities in medical conditions and health care utilization among sexual minority individuals.
PMCID: PMC5137194  PMID: 26974678
sexual orientation; health disparities; health care utilization; minority health
13.  Sodium perchlorate in the space group Pnma. Corrigendum 
Erratum to Acta Cryst. (2006), E62, i150–i151.
In the paper by Zhang et al. [Acta Cryst. (2006), E62, i150–i151], the sodium cation was assigned incorrectly.
PMCID: PMC5458325
14.  Marked response to nab-paclitaxel in EGFR mutated lung neuroendocrine carcinoma 
Medicine  2017;96(21):e6985.
Lung cancer is the leading cause of cancer-related death in the world. Tyrosine kinase inhibitors (TKIs), which target mutated epidermal growth factor receptor (EGFR), have been the first-line treatment of late-stage lung adenocarcinoma harboring EGFR mutation. EGFR mutations are mostly identified in lung adenocarcinoma. However, it is rarely seen in lung neuroendocrine carcinoma, and treatment strategies remain under reported.
Patient concerns:
Here, we describe a 54-year-old Chinese man diagnosed with lung adenocarcinoma (cT4N3M1b, stage IV) with neuroendocrine differentiation and L858R mutation on exon 21. He developed progressive disease in liver 4 months later, and the biopsy of liver metastases showed neuroendocrine carcinoma maintained the same EGFR mutation.
Lung adenocarcinoma and neuroendocrine carcinoma were identified by biopsy.
After a combined treatment with nab-paclitaxel and erlotinib, the patient achieved partial remission.
The patient's overall survival was 27 months.
This case highlights that EGFR mutated lung neuroendocrine carcinoma is not responsive to single-agent EGFR-TKI. However, combined application with nab-paclitaxel can improve its efficacy and prolong the patient's survival.
PMCID: PMC5457885  PMID: 28538405
epidermal growth factor receptor; lung neuroendocrine carcinoma; nab-paclitaxel; tyrosine kinase inhibitor
15.  Clinical Validity of PROMIS® Depression, Anxiety, and Anger across Diverse Clinical Samples 
To evaluate the responsiveness to change of the PROMIS® negative affect measures (Depression, Anxiety, and Anger) using longitudinal data collected in six chronic health conditions.
Study Design and Setting
Individuals with major depressive disorder (MDD), back pain, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), and cancer completed PROMIS negative affect instruments as computerized adaptive test (CAT) or as fixed-length short form (SF) at baseline and a clinically-relevant follow-up interval. Participants also completed global ratings of health. Linear mixed effects models and standardized response means (SRM) were estimated at baseline and follow-up.
903 individuals participated (back pain, n = 218; cancer, n = 304; CHF, n = 60; COPD, n = 125; MDD, n = 196). All three negative affect instruments improved significantly for treatments of depression and pain. Depression improved for CHF patients (anxiety and anger not administered), while anxiety improved significantly in COPD groups (stable and exacerbation). Response to treatment was not assessed in cancer. Subgroups of patients reporting better or worse health showed a corresponding positive or negative average SRM for negative affect across samples.
This study provides evidence that the PROMIS negative affect scores are sensitive to change in intervention studies in which negative affect is expected to change. These results inform the estimation of meaningful change and enable comparative effectiveness research.
PMCID: PMC4928679  PMID: 26931289
PROMIS; Depression; Anxiety; Anger; Chronic Conditions; Item Bank
16.  Evaluation of the correlation of vasculogenic mimicry, ALDH1, KAI1 and microvessel density in the prediction of metastasis and prognosis in colorectal carcinoma 
BMC Surgery  2017;17:47.
Metastasis and recurrence are the most common reasons for treatment failure of colorectal carcinoma (CRC). Vasculogenic mimicry (VM, blood supply formation often seen in highly aggressive tumors), Aldehyde dehydrogenase 1 (ALDH1, a biomarker of cancer stem cells), KAI1 (a suppressor gene of tumor metastasis) are all valuable factors for metastasis and prognosis in diverse human cancers. However, the correlation of VM, ALDH1, KAI1 and microvessel density (MVD) in CRC is unclear. In this study, we analyzed the correlations among VM, ALDH1, KAI1 and MVD, as well as their respective correlations with clinicopathological parameters and survival in CRC.
The level of VM, ALDH1, KAI1 and MVD in 204 whole tissue samples of CRC were examined by immunhistochemistry. Clinical data was also collected.
Levels of VM, ALDH1 and MVD were significantly higher, and levels of KAI1 significantly lower, in CRC tissues than in normal colorectal tissues. Levels of VM, ALDH1 and MVD were positively associated with invasion of depth, lymph node metastasis (LNM), distant metastasis and tumor-node-metastasis (TNM) stages, and negatively with patients’ overall survival (OS). Levels of KAI1 was negatively correlated with invasion of depth, LNM, distant metastasis and TNM stages, and the KAI1 positive expression subgroup had significantly longer OS than did the KAI1- subgroup. In multivariate analysis, high levels of VM, ALDH1 and KAI1, as well as TNM stages were independently correlated with lower OS in patients with CRC.
VM, MVD and the expression of ALDH1 and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets for CRC.
PMCID: PMC5399824  PMID: 28431527
CRC; VM; ALDH1; KAI1; MVD; Prognosis
17.  Reduction in the copy number and expression level of the recurrent human papillomavirus integration gene fragile histidine triad (FHIT) predicts the transition of cervical lesions 
PLoS ONE  2017;12(4):e0175520.
Cervical cancer is the second most common cancer and the third leading cause of cancer death in females worldwide, especially in developing countries. High risk human papillomavirus (HR-HPV) infection causes cervical cancer and precancerous cervical intraepithelial neoplasia (CIN). Integration of the HR-HPV genome into the host chromatin is an important step in cervical carcinogenesis. The detection of integrated papillomavirus sequences-PCR (DIPS-PCR) allowed us to explore HPV integration in the human genome and to determine the pattern of this integration. We performed DIPS-PCR for 4 cell lines including 3 cervical cancer cell lines and 40 tissue samples. Overall, 32 HR-HPV integration loci were detected in the clinical samples and the HeLa and SiHa cell lines. Among all the integration loci, we identified three recurrent integration loci: 3p14.2 (3 samples), 13q22.1 (2 samples and a SiHa cell line) and 8q24 (1 sample and a HeLa cell line). To further explore the effect of HR-HPV integration in the 3p14.2 locus, we used fluorescence in situ hybridization (FISH) to determine the copy number of the 3p14.2 locus and immunohistochemistry (IHC) to determine the protein expression levels of the related FHIT gene in the clinical samples. Both the 3p14.2 locus copy number and FHIT protein expression levels showed significant decreases when CIN transitioned to cervical cancer. HPV copy number was also evaluated in these clinical samples, and the copy number of HPV increased significantly between CIN and cervical cancer samples. Finally, we employed receiver operating characteristic curve (ROC curve) analysis to evaluate the potential of all these indexes in distinguishing CIN and cervical cancer, and the HPV copy number, FHIT copy number and FHIT protein expression levels have good diagnostic efficiencies.
PMCID: PMC5393568  PMID: 28414756
18.  The Long Noncoding RNA NEAT1 Exerts Antihantaviral Effects by Acting as Positive Feedback for RIG-I Signaling 
Journal of Virology  2017;91(9):e02250-16.
Hantavirus infection, which causes zoonotic diseases with a high mortality rate in humans, has long been a global public health concern. Over the past decades, accumulating evidence suggests that long noncoding RNAs (lncRNAs) play key regulatory roles in innate immunity. However, the involvement of host lncRNAs in hantaviral control remains uncharacterized. In this study, we identified the lncRNA NEAT1 as a vital antiviral modulator. NEAT1 was dramatically upregulated after Hantaan virus (HTNV) infection, whereas its downregulation in vitro or in vivo delayed host innate immune responses and aggravated HTNV replication. Ectopic expression of NEAT1 enhanced beta interferon (IFN-β) production and suppressed HTNV infection. Further investigation suggested that NEAT1 served as positive feedback for RIG-I signaling. HTNV infection activated NEAT1 transcription through the RIG-I–IRF7 pathway, whereas NEAT1 removed the transcriptional inhibitory effects of the splicing factor proline- and glutamine-rich protein (SFPQ) by relocating SFPQ to paraspeckles, thus promoting the expression of RIG-I and DDX60. RIG-I and DDX60 had synergic effects on IFN production. Taken together, our findings demonstrate that NEAT1 modulates the innate immune response against HTNV infection, providing another layer of information about the role of lncRNAs in controlling viral infections.
IMPORTANCE Hantaviruses have attracted worldwide attention as archetypal emerging pathogens. Recently, increasing evidence has highlighted long noncoding RNAs (lncRNAs) as key regulators of innate immunity; however, their roles in hantavirus infection remain unknown. In the present work, a new unexplored function of lncRNA NEAT1 in controlling HTNV replication was found. NEAT1 promoted interferon (IFN) responses by acting as positive feedback for RIG-I signaling. This lncRNA was induced by HTNV through the RIG-I–IRF7 pathway in a time- and dose-dependent manner and promoted HTNV-induced IFN production by facilitating RIG-I and DDX60 expression. Intriguingly, NEAT1 relocated SFPQ and formed paraspeckles after HTNV infection, which might reverse inhibitive effects of SFPQ on the transcription of RIG-I and DDX60. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA NEAT1 in host innate immunity after HTNV infection. In summary, our findings provide additional insights regarding the role of lncRNAs in controlling viral infections.
PMCID: PMC5391460  PMID: 28202761
long noncoding RNA; NEAT1; Hantaan virus; RIG-I; DDX60; beta interferon; SFPQ; interferons; innate immunity
19.  A novel PHD-finger protein 14/KIF4A complex overexpressed in lung cancer is involved in cell mitosis regulation and tumorigenesis 
Oncotarget  2017;8(12):19684-19698.
The plant homeodomain (PHD) finger-containing proteins have been implicated in many human diseases including cancer. In this study, we found that PHF14, a newly identified PHD finger protein, is highly expressed in lung cancer. The high expression level of PHF14 was associated with adenocarcinoma and poor survival in lung cancer patients. Knocking down PHF14 suppressed cancer cell growth and carcinogenesis, while over-expressing PHF14 promoted cell proliferation. During cell division, PHF14 directly bound to and co-localized with KIF4A (a nuclear motor protein involved in lung carcinogenesis) to form a functional complex. Similarly to the effect of KIF4A depletion, silencing PHF14 in several cell lines caused cell mitotic defects, prolonged M phase, and inhibited cell proliferation. What's more, these two proteins had a synergistic effect on cell proliferation and were significantly co-overexpressed in lung cancer tissues. Our data provide new insights into the biological significance of PHD finger proteins and imply that PHF14 may be a potential biomarker for lung cancer.
PMCID: PMC5386714  PMID: 28160558
PHF14; KIF4A; lung carcinogenesis; mitosis; biomarker
20.  Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome 
Chinese Medical Journal  2017;130(6):703-709.
Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases.
Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided.
In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations.
This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated.
PMCID: PMC5358421  PMID: 28303854
GATA binding protein 3; Genetic Anticipation; Hypoparathyroidism-deafness-renal Dysplasia Syndrome
21.  PIG3 promotes NSCLC cell mitotic progression and is associated with poor prognosis of NSCLC patients 
Non-small cell lung cancer (NSCLC) is the most commonly diagnosed type of lung cancer that is associated with poor prognosis. In this study we explored the potential role of p53-induced gene 3 (PIG3) in the progression of NSCLC.
Immunohistochemistry was used to determine the expression levels of PIG3 in 201 NSCLC patients. We performed in vitro studies and silenced endogenous PIG3 by using specific siRNAs that specific target PIG3. Immunofluorescent staining was performed to determine the effect of PIG3 on mitotic progression in NSCLC cells. The growth rates of microtubules were determined by microtubule nucleation analysis. Cell proliferation and chemosensitivity were analyzed by CCK8 assays. Annexin V staining and β-galactosidase activity analysis were used to evaluate PIG3 deficiency-related apoptosis and senescence, respectively.
PIG3 expression levels negatively correlated with overall survival and disease-free survival of NSCLC patients. Knock down of PIG3 resulted in repressed proliferation of NSCLC cells and increased aberrant mitosis, which included misaligning and lagging chromosomes, and bi- or multi-nucleated giant cells. In addition, PIG3 contributed to mitotic spindle assembly by promoting microtubule growth. Furthermore, loss of PIG3 sensitized NSCLC cells to docetaxel by enhancing docetaxel-induced apoptosis and senescence.
Our results indicate that PIG3 promotes NSCLC progression and therefore suggest that PIG3 may be a potential prognostic biomarker and novel therapeutic target for the treatment of NSCLC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-017-0508-2) contains supplementary material, which is available to authorized users.
PMCID: PMC5336678  PMID: 28259183
Non-small cell lung cancer (NSCLC); p53-induced gene 3 (PIG3); Mitotic progression; Microtubule assembly; Chemoresistance
22.  Evaluation of the correlation of vasculogenic mimicry, ALDH1, KiSS-1, and MACC1 in the prediction of metastasis and prognosis in ovarian carcinoma 
Diagnostic Pathology  2017;12:23.
Recurrence and metastasis are the usual manifestations of treatment failure of epithelial ovarian carcinoma (EOC). Vasculogenic mimicry (VM; blood supply development often seen in highly aggressive cancers), aldehyde dehydrogenase 1 (ALDH1, cancer stem cell biomarker), KiSS-1 (suppressor of tumor metastasis), and metastasis associated in colon cancer-1 (MACC1) are all useful predictive factors for metastasis and prognosis in various cancers. In this study, we analyzed associations among VM, ALDH1, KiSS-1, and MACC1 in EOC, and their respective correlations with clinicopathological characteristics and survival in EOC.
Positive rates of VM, ALDH1, KiSS-1, and MACC1 in 207 whole EOC tissue samples were detected by immunohistochemistry. Patients’ clinical data were also collected.
Levels of VM, ALDH1, and MACC1 were significantly higher, and levels of KiSS-1 significantly lower, in EOC tissues than in benign ovary tumors. Levels of VM, ALDH1, KiSS-1, and MACC1 were associated significantly with tumor/lymph node/metastasis (LNM) grade, implantation, and International Federation of Gynecology and Obstetrics (FIGO) stage, and with patients’ overall survival (OS); whereas the KiSS-1+ subgroup had significantly longer OS than did the KiSS-1− subgroup. In multivariate analysis, high VM, ALDH1 or MACC1 levels, FIGO stage, implantation and low KiSS-1 levels were independently associated with shorter OS in patients with EOC.
VM and expressions of ALDH1, KiSS-1, and MACC1 represent promising markers for metastasis and prognosis, and potential therapeutic targets for EOC.
PMCID: PMC5335811  PMID: 28253891
Epithelial ovarian carcinoma; VM; ALDH1; KiSS-1; MACC1; Prognosis
23.  Adsorptive Granulocyte and Monocyte Apheresis in the Treatment of Ulcerative Colitis: The First Multicenter Study in China 
Gut and Liver  2016;11(2):216-225.
Patients with active ulcerative colitis (UC) have elevated levels of activated myeloid-derived leukocytes as a source of inflammatory cytokines. The selective depletion of these leukocytes by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn should alleviate inflammation, promote remission and enhance drug efficacy. However, studies have reported contrasting efficacy outcomes based on patients’ baseline demographic variables. This study was undertaken to understand the demographic features of GMA responders and nonresponders.
This was a multicenter study in China involving four institutions and 34 patients with active UC. Baseline conventional medications were continued without changing the dosage. The treatment efficacy was evaluated based on the endoscopic activity index and the Mayo score.
Thirty of the 34 patients completed all 10 GMA treatment sessions. The overall efficacy rate was 70.59%. The receiver operating characteristic analysis showed that the area under the curve was approximately 0.766 for a Mayo score of ≤5.5 with 0.273 specificity and 0.857 sensitivity (Youden index, 0.584) for GMA responders. No GMA-related serious adverse events were observed.
The overall efficacy of GMA in patients with active UC who were taking first-line medications or were corticosteroid refractory was encouraging. Additionally, GMA was well tolerated and had a good safety profile.
PMCID: PMC5347645  PMID: 27843131
Colitis, ulcerative; Mayo score; Myeloid lineage leucocytes; Adsorptive granulocyte/monocyte apheresis; Receiver operating characteristic curve
24.  Identification and characterization of microsatellite markers in Pinus kesiya var. langbianensis (Pinaceae)1 
Applications in Plant Sciences  2017;5(2):apps.1600126.
Premise of the study:
Microsatellite primers were developed in Pinus kesiya var. langbianensis (Pinaceae), a species native to southwestern China, to investigate its genetic diversity and population structure in order to provide information for the conservation and management of this species.
Methods and Results:
Using next-generation sequencing, a total of 2349 putative simple sequence repeat primer pairs were designed. Eighteen polymorphic markers in 60 individuals belonging to four populations of P. kesiya var. langbianensis were identified and characterized with two to 11 alleles per locus. The observed and expected heterozygosity ranged from 0.000 to 0.800 and 0.000 to 0.840, respectively. Each of these loci cross-amplified in the closely related species P. massoniana, P. densata, P. tabuliformis, and P. yunnanensis, with one to seven alleles per locus.
The new markers are promising tools to study the population genetics of P. kesiya var. langbianensis and related species.
PMCID: PMC5315380
microsatellite; next-generation sequencing; Pinaceae; Pinus kesiya var. langbianensis; population genetics
25.  Association between Genetic Variants of Transforming Growth Factor-β1 and Susceptibility of Pneumoconiosis: A Meta-analysis 
Chinese Medical Journal  2017;130(3):357-364.
Transforming growth factor-beta 1 (TGF-β1) and gene variants have been extensively studied in various human diseases. For example, TGF-β1 polymorphisms were associated with fibrosis and pneumoconiosis, but the data remained controversial. The aim of this meta-analysis was to assess the association between TGF-β1 −509 C>T [rs1800469], +869 T>C [rs1800470], and +915 G>C [rs1800471] polymorphisms and pneumoconiosis.
A comprehensive literature search was conducted through searching in PubMed, Embase, the Chinese Biomedical Database, and the Wei Pu (Chinese) Database by the end of April 2016. Eleven publications with 21 studies were included in this meta-analysis, covering a total of 4333 patients with pneumoconiosis and 3478 controls. Study quality was assessed, and heterogeneity and publication bias were measured. All statistical analyses were performed using STATA version 12.0 (StataCorp, College Station, TX, USA) software.
The data showed significant associations between TGF-β1 −509 C>T polymorphism and the risk of pneumoconiosis development (T vs. C, odds ratio [OR] = 1.35, 95% confidence interval [CI]: 1.00–1.81, P = 0.046); between TGF-β1 +915 G>C polymorphism and the pneumoconiosis risk (C vs. G, OR = 1.69, 95% CI: 1.19–2.40, P = 0.004; CG vs. GG, OR = 1.79, 95% CI: 1.23–2.60, P = 0.002; CC+CG vs. GG, OR = 1.80, 95% CI: 1.24–2.61, P = 0.002). In addition, the subgroup analysis of ethnicity versus pneumoconiosis types indicated a significant association of silicosis among Asian populations but not that of coal workers’ pneumoconiosis in Caucasian populations. In contrast, no significant association was exhibited between TGF-β1 +869 T>C polymorphism and risk of pneumoconiosis.
The polymorphisms of both TGF-β1 −509 C>T and +915 G>C are associated with increased risk of pneumoconiosis.
PMCID: PMC5308020  PMID: 28139521
Meta analysis; Pneumoconiosis; Polymorphism; Transforming Growth Factor-beta1

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