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1.  Prognostic factors and survival in patients with gastric stump cancer 
AIM: To elucidate the clinicopathological characteristics and prognostic factors of gastric stump cancer (GSC).
METHODS: The clinical data for 92 patients with GSC were collected at Fudan University Shanghai Cancer Center. The prognostic factors were analyzed with Cox proportional hazard models.
RESULTS: GSC tended to occur within 25 years following the primary surgery, when the initial disease is benign, whereas it primarily occurred within the first 15 years post-operation for gastric cancer. Patients with regular follow-up after primary surgery had a better survival rate. The multivariate Cox regression analysis revealed that Borrmann type I/II (HR = 3.165, 95%CI: 1.055-9.500, P = 0.040) and radical resection (HR = 1.780, 95%CI: 1.061-2.987, P = 0.029) were independent prognostic factors for GSC. The overall 1-, 3-, and 5-year survival rates of the 92 patients were 78.3%, 45.6% and 27.6%, respectively. The 1-, 3-, and 5-year survival rates of those undergoing radical resection were 79.3%, 52.2%, and 37.8%, respectively. The 5-year survival rates for stages I, II, III, and IV were 85.7%, 47.4%, 16.0%, and 13.3%, respectively (P = 0.005).
CONCLUSION: The appearance of GSC occurs sooner in patients with primary malignant cancer than in patients with a primary benign disease. Therefore, close follow-up is necessary. The overall survival of patients with GSC is poor, and curative resection can improve their prognosis.
PMCID: PMC4323464
Gastric stump cancer; Clinicopathological characteristics; Prognosis
2.  Characterization and Propagation of Tumor Initiating Cells Derived from Colorectal Liver Metastases: Trials, Tribulations and a Cautionary Note 
PLoS ONE  2015;10(2):e0117776.
Tumor initiating cells (TIC) are increasingly being put forward as a potential target for intervention within colorectal cancer. Whilst characterisation and outgrowth of these cells has been extensively undertaken in primary colorectal cancers, few data are available describing characteristics within the metastatic setting. Tissue was obtained from patients undergoing surgical resection for colorectal liver metastases, and processed into single cell suspension for assessment. Tumor initiating cells from liver metastases were characterised using combinations of EPCAM, Aldehyde dehydrogenase activity, CD133 and CD26. CD133 expression was significantly lower in patients who had received chemotherapy, but this was accounted for by a decrease observed in the male patient cohort only. ALDHhigh populations were rare (0.4 and 0.3% for EPCAM+/ALDHhigh/CD133- and EPCAM+/ALDHhigh/CD133+ populations respectively) and below the limits of detection in 28% of samples. Spheroid outgrowth of metastatic tumor cells across all samples could not be readily achieved using standard spheroid-formation techniques, thus requiring further method validation to reliably propagate cells from the majority of tissues. Spheroid formation was not enhanced using additional growth factors or fibroblast co-culture, but once cells were passaged through NOD-SCID mice, spheroid formation was observed in 82% samples, accompanied by a significant increase in CD26. Order of spheroid forming ability was ALDHhigh>CD133>CD26. Samples sorted by these markers each had the ability to reform ALDHhigh, CD133 and CD26 positive populations to a similar extent, suggestive of a high degree of plasticity for each population. Ex vivo TIC models are increasingly being utilised to assess efficacy of therapeutic interventions. It is therefore essential that such investigations use well-characterised models that are able to sustain TIC populations across a large patient cohort in order that the inherent heterogeneity observed in cancer populations is maintained.
PMCID: PMC4319830  PMID: 25658706
3.  Anesthesia for stem cell transplantation in autistic children: A prospective, randomized, double-blind comparison of propofol and etomidate following sevoflurane inhalation 
The objective of the present study was to comparatively investigate the feasibility and safety of etomidate and propofol use following sevoflurane inhalation in autistic children during the intrathecal transplantation of stem cells. The patients selected were 60 autistic children with American Society of Anesthesiologists physical status I, who were aged between two and 12 years and scheduled for stem cell transplantation. The children received an inhalation induction of 8% sevoflurane, followed by intravenous injection of etomidate (0.2 mg/kg) in group E and propofol (2 mg/kg) in group P (n=30/group). Supplemental doses of 0.1 mg/kg etomidate or 1 mg/kg propofol were used until a deep sedation was obtained. The heart rate (HR), mean arterial pressure, oxygen saturation, respiratory rate, Ramsay sedation score (RSS) and recovery time were monitored continuously. Following anesthesia, blood pressure and HR measurements were significantly decreased in group P compared with the baseline (P<0.01) and group E values at the same time-points (P<0.05). The occurrence of adverse effects, such as respiratory depression, bradycardia, hypotension and pain on injection, was significantly higher in group P than that in group E, whereas the incidence of myoclonus in group E was significantly higher than that in group P (P<0.01). No significant differences in anesthesia induction, surgery duration, recovery time, RSS and physician satisfaction were observed between the two groups. In conclusion, sevoflurane-etomidate combinations resulted in more stable hemodynamic responses and relatively fewer adverse effects compared with propofol injection following sevoflurane inhalation and may therefore be more suitable for the induction of short-term anesthesia in autistic children during stem cell transplantation.
PMCID: PMC4316962  PMID: 25667673
sevoflurane; propofol; etomidate; autism; stem cell transplantation
4.  Burkholderia pseudomallei Sequence Type 562 in China and Australia 
Emerging Infectious Diseases  2015;21(1):166-168.
PMCID: PMC4285272  PMID: 25531912
Melioidosis; Burkholderia pseudomallei; MLST; bacteria; China; Australia
5.  Molecular ferroelectrics: where electronics meet biology 
In the last several years, we have witnessed significant advances in molecular ferroelectrics, with ferroelectric properties of molecular crystals approaching those of barium titanate. In addition, ferroelectricity has been observed in biological systems, filling an important missing link in bioelectric phenomena. In this perspective, we will present short historical notes on ferroelectrics, followed by overview on the fundamentals of ferroelectricity. Latest development in molecular ferroelectrics and biological ferroelectricity will then be highlighted, and their implications and potential applications will be discussed. We close by noting molecular ferroelectric as an exciting frontier between electronics and biology, and a number of challenges ahead are also noted.
PMCID: PMC3836842  PMID: 24018952
6.  Metagenomics of Ancient Fermentation Pits Used for the Production of Chinese Strong-Aroma Liquor 
Genome Announcements  2014;2(5):e01045-14.
The complex microbiota of pit mud of solid-state fermentation reactors used for the production of Chinese liquor is responsible for producing one of the oldest distillates in the world. We apply a deep-sequencing approach to characterize the microbiota from pits that have been in use for up to 440 years.
PMCID: PMC4208321  PMID: 25342677
7.  Hybrid optofluidic integration 
Lab on a chip  2013;13(20):10.1039/c3lc50818h.
Complete integration of microfluidic and optical functions in a single lab-on-chip device is one goal of optofluidics. Here, we demonstrate the hybrid integration of a PDMS-based fluid handling layer with a silicon-based optical detection layer in a single optofluidic system. The optical layer consists of a liquid-core antiresonant reflecting optical waveguide (ARROW) chip that is capable of single particle detection and interfacing with optical fiber. Integrated devices are reconfigurable and able to sustain high pressures despite the small dimensions of the liquid-core waveguide channels. We show the combination of salient sample preparation capabilities—particle mixing, distribution, and filtering—with single particle fluorescence detection. Specifically, we demonstrate fluorescent labelling of λ-DNA, followed by flow-based single-molecule detection on a single device. This points the way towards amplification-free detection of nucleic acids with low-complexity biological sample preparation on a chip.
PMCID: PMC3818110  PMID: 23969694
8.  Profiling the microRNA Expression in Human iPS and iPS-derived Retinal Pigment Epithelium 
Cancer Informatics  2014;13(Suppl 5):25-35.
The purpose of this study is to characterize the microRNA (miRNA) expression profiles of induced pluripotent stem (iPS) cells and retinal pigment epithelium (RPE) derived from induced pluripotent stem cells (iPS-RPE). MiRNAs have been demonstrated to play critical roles in both maintaining pluripotency and facilitating differentiation. Gene expression networks accountable for maintenance and induction of pluripotency are linked and share components with those networks implicated in oncogenesis. Therefore, we hypothesize that miRNA expression profiling will distinguish iPS cells from their iPS-RPE progeny. To identify and analyze differentially expressed miRNAs, RPE was derived from iPS using a spontaneous differentiation method. MiRNA microarray analysis identified 155 probes that were statistically differentially expressed between iPS and iPS-RPE cells. Up-regulated miRNAs including miR-181c and miR-129–5p may play a role in promoting differentiation, while down-regulated miRNAs such as miR-367, miR-18b, and miR-20b are implicated in cell proliferation. Subsequent miRNA–target and network analysis revealed that these miRNAs are involved in cellular development, cell cycle progression, cell death, and survival. A systematic interrogation of temporal and spatial expression of iPS-RPE miRNAs and their associated target mRNAs will provide new insights into the molecular mechanisms of carcinogenesis, eye differentiation and development.
PMCID: PMC4218680  PMID: 25392691
microRNA; induced pluripotent stems cells; retinal pigment epithelium; cancer
9.  Structure-guided Inhibitor Design Expands the Scope of Analog-Sensitive Kinase Technology 
ACS chemical biology  2013;8(9):1931-1938.
Engineered analog-sensitive (AS) protein kinases have emerged as powerful tools for dissecting phospho-signaling pathways, for elucidating the cellular function of individual kinases, and for deciphering unanticipated effects of clinical therapeutics. A crucial and necessary feature of this technology is a bioorthogonal small molecule that is innocuous towards native cellular systems but can potently inhibit the engineered kinase. In order to generalize this method we sought a molecule capable of targeting divergent AS-kinases. Here we employ X-ray crystallography and medicinal chemistry to unravel the mechanism of current inhibitors and use these insights to design the most potent, selective and general AS-kinase inhibitors reported to date. We use large-scale kinase inhibitor profiling to characterize the selectivity of these molecules as well as examine the consequences of potential off-target effects in chemical genetic experiments. The molecules reported here will serve as powerful tools in efforts to extend AS-kinase technology to the entire kinome and the principles discovered may help in the design of other engineered enzyme/ligand pairs.
PMCID: PMC3938192  PMID: 23841803
10.  Seroprevalence of Merkel Cell Polyomavirus in the General Rural Population of Anyang, China 
PLoS ONE  2014;9(9):e106430.
Despite the probably causal link between Merkel cell polyomavirus (MCPyV) infection and Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy, little is known about the seroepidemiology of MCPyV among healthy adults in China.
Serum antibodies against MCPyV were evaluated by multiplex serology in a population-based study of 5548 adults (including 1587 heterosexual couples) aged 25–65 years who were enrolled from rural Anyang, China in 2007–2009. Univariate and multivariate logistic regression analyses were performed to assess the risk factors for the seropositivity of MCPyV.
The seroprevalence for MCPyV was 61.0%. MCPyV seropositivity was significantly higher in males than in females (64.5% vs. 57.7%, P<0.001), and for both genders, showed a trend of increase with age (Male: Ptrend<0.001; Female: Ptrend<0.001). Furthermore, among antibody positives, antibody levels of MCPyV increased with advancing age (Ptrend = 0.017). MCPyV seropositivity of one spouse was significantly associated with that of the other partner (Adjusted OR = 1.32, 95% CI: 1.07–1.62). However, there was no association between sexual behaviors and the seropositivity of MCPyV.
High seroprevalence of MCPyV was observed in healthy Chinese individuals. Serological evidence suggests that nonsexual horizontal spread of MCPyV can occur among family members, and further research in this regard is needed.
PMCID: PMC4153645  PMID: 25184447
11.  TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro 
Cellular and Molecular Immunology  2014;11(5):477-494.
Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors (TLRs) recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 (rBCSP31) to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-α, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases (MAPKs) by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-κB in macrophages. In addition, continuous exposure (>24 h) of RAW264.7 cells to rBCSP31 significantly enhanced IFN-γ-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4+ T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2−/− and TLR4−/− mice was lower than that from C57BL/6 macrophages, and the activation of NF-κB and MAPKs was attenuated in macrophages from TLR2−/− and TLR4−/− mice. In addition, CD4+ T cells from C57BL/6 mice immunized with rBCSP31 produced higher levels of IFN-γ and IL-2 compared with CD4+ T cells from TLR2−/− and TLR4−/− mice. Macrophages from immunized C57BL/6 mice produced higher levels of IL-12p40 than those from TLR2−/− and TLR4−/− mice. Furthermore, immunization with rBCSP31 provided better protection in C57BL/6 mice than in TLR2−/− and TLR4−/− mice after B. abortus 2308 challenge. These results indicate that rBCSP31 is a TLR2 and TLR4 agonist that induces cytokine production, upregulates macrophage function and induces the Th1 immune response.
PMCID: PMC4197203  PMID: 24769793
BCSP31; Brucella abortus; cytokine; macrophage; Th1 immune response; TLR
12.  Developmental Changes of TGF-β1 and Smads Signaling Pathway in Intestinal Adaption of Weaned Pigs 
PLoS ONE  2014;9(8):e104589.
Weaning stress caused marked changes in intestinal structure and function. Transforming growth factor-β1 (TGF-β1) and canonical Smads signaling pathway are suspected to play an important regulatory role in post-weaning adaptation of the small intestine. In the present study, the intestinal morphology and permeability, developmental expressions of tight junction proteins and TGF-β1 in the intestine of piglets during the 2 weeks after weaning were assessed. The expressions of TGF-β receptor I/II (TβRI, TβRII), smad2/3, smad4 and smad7 were determined to investigate whether canonical smads signaling pathways were involved in early weaning adaption process. The results showed that a shorter villus and deeper crypt were observed on d 3 and d 7 postweaning and intestinal morphology recovered to preweaning values on d 14 postweaning. Early weaning increased (P<0.05) plasma level of diamine oxidase (DAO) and decreased DAO activities (P<0.05) in intestinal mucosa on d 3 and d 7 post-weaning. Compared with the pre-weaning stage (d 0), tight junction proteins level of occludin and claudin-1 were reduced (P<0.05) on d 3, 7 and 14 post-weaning, and ZO-1 protein was reduced (P<0.05) on d 3 and d 7 post-weaning. An increase (P<0.05) of TGF-β1 in intestinal mucosa was observed on d 3 and d 7 and then level down on d 14 post-weaning. Although there was an increase (P<0.05) of TβR II protein expression in the intestinal mucosa on d3 and d 7, no significant increase of mRNA of TβRI, TβRII, smad2/3, smad4 and smad7 was observed during postweaning. The results indicated that TGF-β1 was associated with the restoration of intestinal morphology and barrier function following weaning stress. The increased intestinal endogenous TGF-β1 didn't activate the canonical Smads signaling pathway.
PMCID: PMC4149345  PMID: 25170924
13.  Analysis of Lymph Node Metastasis Correlation with Prognosis in Patients with T2 Gastric Cancer 
PLoS ONE  2014;9(8):e105112.
To investigate the correlated factors for lymph node metastasis and prognosis for patients with T2 gastric cancer.
A total of 442 patients with T2 gastric cancer who underwent gastrectomy from January 1996 to December 2009 were evaluated. The clinicopathological parameters were analyzed for lymph node metastasis and prognosis, including gender, age, tumor size, tumor location, histological type, depth of invasion, vascular tumor emboli, nervous invasion, resection type, and pathological stage.
The rate of lymph node metastasis was 45.9%. Univariate analysis showed that depth of invasion, tumor size, and vascular tumor emboli were associated with lymph node metastasis. Logistic regression demonstrated that depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. The 5-year survival rate was 64.0%. Multivariate analysis showed that tumor size, tumor location, resection type, and pathological stage were independent prognostic factors. Based on tumor size, there were significant differences of 5-year survival between small size tumor (<6 cm) and large size tumor (≥6 cm) according to stage IIA (P = 0.006). Based on tumor location, there were significant differences of 5-year survival among different tumor location according to stage IB. Based on resection type, there were significant differences of overall 5-year survival between curative surgery and palliative surgery according to stage IIB (P = 0.015) and IIIA (P = 0.001).
Depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. Tumor size, tumor location, resection type, and pathological stage were independent prognostic factors.
PMCID: PMC4138144  PMID: 25136920
14.  Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer 
Cancer discovery  2013;3(8):894-907.
Hereditary breast cancers stem from germline mutations in susceptibility genes such as BRCA1, BRCA2 and PALB2, whose products function in the DNA damage response and redox regulation. Autophagy is an intracellular waste disposal and stress mitigation mechanism important for alleviating oxidative stress and DNA damage response activation; it can either suppress or promote cancer, but its role in breast cancer is unknown. Here we show that, similar to Brca1 and Brca2, ablation of Palb2 in mouse mammary gland resulted in tumor development with long latency and the tumors harbored mutations in Trp53. Interestingly, impaired autophagy, due to monoallelic loss of the essential autophagy gene Becn1, reduced Palb2-associated mammary tumorigenesis in Trp53-wild type but not conditionally null background. These results indicate that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, p53 is a barrier to cancer development, whereas autophagy facilitates cell survival and tumorigenesis.
PMCID: PMC3740014  PMID: 23650262
15.  Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination 
Nature structural & molecular biology  2010;17(10):1247-1254.
Inherited mutations in human PALB2 are associated with a predisposition to breast and pancreatic cancers. The tumor-suppressing capability of PALB2 is thought to be based on its ability to enable BRCA2 function in homologous recombination. However, the biochemical properties of PALB2 are unknown. Here we show that human PALB2 binds DNA, preferentially D-loop structures, and directly interacts with the RAD51 recombinase to strongly stimulates strand invasion, a vital step of homologous recombination. Such stimulation occur by reinforcing biochemical mechanisms as PALB2 alleviates the inhibitory role of RPA and stabilizes the RAD51 filament. Moreover, PALB2 can function synergistically with a BRCA2 chimera (termed piccolo) to further promote strand invasion. Finally, we show that PALB2-deficient cells are sensitive to PARP inhibitors. Collectively, our studies provide the first biochemical insights into the homologous recombination mediator functions of PALB2 with piBRCA2 in DNA double-strand break repair.
PMCID: PMC4094107  PMID: 20871615
RAD51; PALB2; BRCA2; homologous recombination
16.  Diversity of Francisella tularensis Subsp. holarctica Lineages, China 
Emerging Infectious Diseases  2014;20(7):1191-1194.
We analyzed 10 isolates of Francisella tularensis subspecies holarctica from China and assigned them to known clades by using canonical single-nucleotide polymorphisms. We found 4 diverse subtypes, including 3 from the most basal lineage, biovar japonica. This result indicates unprecedented levels of diversity from a single region and suggests new models for emergence.
PMCID: PMC4073844  PMID: 24963721
Francisella tularensis subsp. holarctica; phylogeography; SNP; canSNP; China; bacteria; tularemia; lineage
17.  Structural, biochemical and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer 
Science translational medicine  2013;5(216):216ra177.
Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small-cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (∼10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib and afatinib). The basis of this primary resistance is poorly understood.  We study a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients; and find that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered ATP-binding pocket and the inserted residues form a wedge at the end of the C-helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro; and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C-helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology and their response to EGFR TKIs.
PMCID: PMC3954775  PMID: 24353160
lung cancer; non-small-cell lung cancer; epidermal growth factor receptor; EGFR; erlotinib; gefitinib; afatinib; exon 20 insertion; x-ray crystallography
18.  Expression of leucine aminopeptidase 3 (LAP3) correlates with prognosis and malignant development of human hepatocellular carcinoma (HCC) 
Leucine aminopeptidases (LAPs) were associated with tumor cell proliferation, invasion and/or angiogenesis. LAP3 is one important member of this family. However, its clinical significance and biological function in hepatocellular carcinoma (HCC) remains unknown. In the present study, we demonstrated that LAP3 expression was significantly up-regulated in HCC tissues as well as cells and was closely correlated with lower differentiation, positive lymph node metastasis and high Ki-67 expression, indicating a poor prognosis. Then cell viability assays, flow cytometry assays, wound-healing assays and matrigel invasion assays were performed to demonstrate that LAP3 promoted HCC cells proliferation by regulating G1/S checkpoint in cell cycle and advanced HCC cells migration. Furthermore, we discovered that knockdown LAP3 will enhance the sensitivity of HCC cells to cisplatin, thus promoting the cell death of HCC cells. Collectively, our results indicated that up-regulated expression of LAP3 might contribute to the proliferation and metastasis of HCC. Our data gains greater insight into the cancer-promoting role of LAP3 and its functions in HCC cells, possibly providing potential therapeutic strategies for clinical trials.
PMCID: PMC4128986  PMID: 25120751
Hepatocellular carcinoma (HCC); LAP3; prognosis; proliferation; migration
19.  The Distribution and Common Amino Acid Polymorphisms of Human Papillomavirus (HPV)-31 Variants in 2700 Women from Northern China 
PLoS ONE  2014;9(6):e99141.
To investigate the distribution of Human papillomavirus (HPV)-31 A, B and C variants as well as the common amino acid polymorphisms in Chinese women, all 14 HPV-31 positive cervical exfoliated cell specimens identified from a descriptive study including ∼2700 women from Northern China were analyzed. HPV-31 positive specimens were identified by Mass Spectrometry and the fragments of partial Long Control Region, E6 and E7 were amplified and directly sequenced or cloned into vector and then sequenced to confirm the variant information. HPV-31 prevalence in Northern Chinese female population was 0.52%. Six different sequences represented all 14 isolates, and these isolates were subsequently classified into variant lineage A (9), B (0) and C (5) by phylogenetic analysis. Five common amino acid polymorphism sites (2 in E6 and 3 in E7) and a novel non-synonymous mutation were detected in the current study. Our investigation suggested that HPV-31 was much less detected in Chinese women population than that in western countries. A and C variants were commonly detected while B variants were rarely detected in this population.
PMCID: PMC4047102  PMID: 24901850
20.  Biomechanical and Histological Evaluation of Roughened Surface Titanium Screws Fabricated by Electron Beam Melting 
PLoS ONE  2014;9(4):e96179.
Various fabrication methods are used to improve the stability and osseointegration of screws within the host bone. The aim of this study was to investigate whether roughened surface titanium screws fabricated by electron beam melting can provide better stability and osseointegration as compared with smooth titanium screws in sheep cervical vertebrae.
Roughened surface titanium screws, fabricated by electron beam melting, and conventional smooth surface titanium screws were implanted into sheep for 6 or 12 weeks (groups A and B, respectively). Bone ingrowth and implant stability were assessed with three-dimensional imaging and reconstruction, as well as histological and biomechanical tests.
No screws in either group showed signs of loosening. Fibrous tissue formation could be seen around the screws at 6 weeks, which was replaced with bone at 12 weeks. Bone volume/total volume, bone surface area/bone volume, and the trabecular number were significantly higher for a define region of interest surrounding the roughened screws than that surrounding the smooth screws at 12 weeks. Indeed, for roughened screws, trabecular number was significantly higher at 12 weeks than at 6 weeks. On mechanical testing, the maximum pullout strength was significantly higher at 12 weeks than at 6 weeks, as expected; however, no significant differences were found between smooth and roughened screws at either time point. The maximum torque to extract the roughened screws was higher than that required for the smooth screws.
Electron beam melting is a simple and effective method for producing a roughened surface on titanium screws. After 12 weeks, roughened titanium screws demonstrated a high degree of osseointegration and increased torsional resistance to extraction over smooth titanium screws.
PMCID: PMC4005762  PMID: 24788866
21.  Structure and ubiquitination-dependent activation of Tank-Binding Kinase 1 
Cell reports  2013;3(3):10.1016/j.celrep.2013.01.033.
Upon stimulation by pathogen-associated inflammatory signals, the atypical IκB kinase TBK1 induces type-I interferon expression and modulates NF-κB signaling. Here we describe the 2.4 Å-resolution crystal structure of nearly full-length TBK1 in complex with specific inhibitors. The structure reveals a novel dimeric assembly, created by an extensive network of interactions among the kinase, ubiquitin-like (ULD) and scaffold/dimerization (SDD) domains. An intact TBK1 dimer undergoes K63-linked polyubiquitination on Lysine 30 and Lysine 401, and these modifications are required for TBK1 activity. The ubiquitination sites and dimer contacts are conserved in the close homolog IKKε, but not in the canonical IκB kinase IKKβ, which assembles in an unrelated manner. The multidomain architecture of TBK1 provides a structural platform for integrating ubiquitination with kinase activation and IRF3 phosphorylation. The structure of TBK1 will facilitate studies of the atypical IκB kinases in normal and disease physiology and will further development of more specific inhibitors that may be useful as anti-cancer or anti-inflammatory agents.
PMCID: PMC3863638  PMID: 23453972
22.  Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER) 
Lancet  2013;381(9880):1835-1843.
c-Jun, a nuclear transcription factor, is preferentially expressed in cancer. The study drug Dz13, a deoxyribozyme targeting c-jun mRNA inhibits the growth of a range of tumors, including basal cell carcinoma (BCC) in murine models.
The primary objectives of this first-in-class, first-in-human trial (DISCOVER) Phase I trial (ACTRN12610000162011) were to determine the safety and tolerability of Dz13 in patients with BCC. A secondary objective was to assess Dz13 pharmacokinetics, changes in protein expression and cell markers in the tissue following single intratumoral injection.
Nine patients with nodular BCC were recruited from Royal Prince Alfred Hospital, Sydney, Australia between 2010 and 2011 and enrolled in three escalating dose groups of three patients. Each patient received a single intratumoral injected dose of Dz13 (10, 30 or 100µg) and was monitored over four weeks. The highest dose used in the trial (100µg), is at the upper limit of solubility of the formulation for a 50µl injection and was the highest concentration used in the preclinical mouse tumor studies 1. At each follow up visit, complete physical examination, blood and urine tests, electrocardiogram and pharmacokinetic/pharmacodynamic analyses were performed. BCCs were surgically removed 14 days post-Dz13 injection and compared with the pre-injection biopsy.
All nine patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the BCC of all nine of nine participants treated with Dz13. The DNAzyme increased Caspase-3, -8, -9, and p53, reduced Bcl-2 and MMP-9, and stimulated inflammatory and immune cell infiltration in the tumors. Moreover, five of the nine patients had a reduction in histological tumor depth.
Dz13 is safe, well tolerated, inhibits its target, and shows no detectable systemic exposure following single intratumoral injection.
PMCID: PMC3951714  PMID: 23660123
23.  The expression and clinical significance of miR-132 in gastric cancer patients 
Diagnostic Pathology  2014;9:57.
Background and objective
miR-132 plays a role in regulating neuronal morphology and cellular excitability. Little is known about the effects of miR-132 in cancer. The aim of this study is to evaluate the expression of miR-132 and its clinical significance in gastric cancer.
Cancerous tissues and corresponding normal tissues from 79 patients with gastric cancer were examined for the expression of miR-132 using quantitative PCR and the association between miR-132 expression levels and clinicopathological factors and prognosis was analyzed.
In 79 clinical samples of gastric cancer patients, miR-132 expression levels in cancer tissues were significantly higher than those in the corresponding normal tissues (P = 0.001). Higher expression levels of miR-132 were associated with more frequent lymph node metastasis (P = 0.033), more lymphatic tumor emboli (P = 0.007), and more advanced stage (P = 0.016). Additionally, expression of miR-132 was an independent prognostic factor for overall survival (P = 0.020).
miR-132 could serve as an efficient prognostic factor for gastric cancer patients.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3975191  PMID: 24621117
Gastric cancer; Prognosis; Biological markers
24.  Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population*  
Objective: A study in a Caucasian population has identified two single-nucleotide polymorphisms (SNPs) in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population. Methods: We performed a similar association study using families with three individuals (one autistic child and two unaffected parents). A family-based transmission disequilibrium test (TDT) was used to analyze the results. Results: There were significant associations between autism and the two SNPs of ZNF533 gene (rs11885327: χ 2=4.5200, P=0.0335; rs1964081: χ 2=4.2610, P=0.0390) and the SNP of DOCK4 gene (rs2217262: χ 2=5.3430, P=0.0208). Conclusions: Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.
PMCID: PMC3955913  PMID: 24599690
Autism; ZNF533; DOCK4; IMMP2L; Northeastern Chinese Han population; Single-nucleotide polymorphism
25.  Prediction of tumor recurrence after curative resection in gastric carcinoma based on bcl-2 expression 
There are currently no reliable predictive factors for gastric cancer recurrence. The aim of this study was to evaluate the relationship between bcl-2 expression and risk of gastric cancer recurrence.
From January 1996 to December 2007, 449 gastric cancer patients who underwent curative resection were retrospectively studied. The expression levels of bcl-2 were examined by immunohistochemistry. Logistic regression was performed to identify independent risk factors for overall recurrence of gastric cancer.
151 patients (33.6%) experienced recurrences. The median time to recurrence was 17.0 months, 113 (74.8%) patients had recurrences within 2 years. Peritoneal recurrence was the most prevalent pattern, followed by hematogenous metastasis in which the liver was the most common site. Depth of invasion, lymph node metastases, and negative expression of bcl-2 were independent risk factors for overall recurrence. The overall survival time of recurrent patients was 22.7 months. The median survival time after recurrence was 6.7 months.
The depth of invasion, lymph node metastases and expression of bcl-2 are independent factors for predicting gastric cancer recurrence.
PMCID: PMC3996074  PMID: 24555747
Gastric cancer; recurrence; clinicopathological factors; bcl-2

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