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1.  Overweight as a Prognostic Factor for Triple-Negative Breast Cancers in Chinese Women 
PLoS ONE  2015;10(6):e0129741.
Obesity is associated with poorer outcomes in patients with hormone receptor-positive breast cancers, but this association is not well established for women with triple-negative breast cancers (TNBC). Here, we investigated the prognostic effects of body mass index (BMI) on clinical outcomes in patients with TNBC.
We identified 1106 patients with TNBC who met the inclusion criteria and were treated between January 2002 and June 2012. Clinical and biological features were collected to evaluate the relation between BMI and breast cancer-specific survival (BCSS) and overall survival (OS) after controlling for other clinically significant variables.
Of 1106 patients, 656 (59.3%) were normal weight (BMI ≤24) and 450 patients (40.7%) were overweight(BMI>24). Median follow-up time was 44.8 months. Breast cancer specific death was observed in 140 patients. After adjusting for clinicopathologic risk factors, overweight was associated with OS (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 1.04-2.06, P =0.028) but not BCSS (HR: 1.34, 95% CI: 0.90–2.01, P =0.15)in all the patients with TNBC. When stratified with menopausal status, overweight was associated with BCSS and OS (HR: 2.27, 95% CI: 1.11-4.63, P = 0.024 and HR: 2.16, 95% CI: 1.21-3.87, P = 0.010, respectively) in premenopausal women. BMI was not associated with BCSS or OS in postmenopausal women.
Overweight is an independent prognostic factor of OS in all women with TNBC, and menopause status may be a mitigating factor. Among premenopausal women, overweight women are at a greater risk of poor prognosis than normal weight women. If validated, these findings should be considered in developing preventive programs.
PMCID: PMC4479880  PMID: 26107623
3.  Clinicopathologic Characteristics of Oestrogen Receptor-Positive/Progesterone Receptor-Negative/Her2-Negative Breast Cancer According to a Novel Definition of Negative Progesterone Receptor Status: A Large Population-Based Study from China 
PLoS ONE  2015;10(5):e0125067.
A lack of progesterone receptor (PgR) expression in oestrogen receptor-positive (ER+) tumours is associated with worse survival. PgR status is usually defined as positive or negative using 1% positive nuclei as a cut-off point. In this study, we aimed to assess the clinicopathologic characteristics of ER+/PgR-/HER2- tumours by comparing them with ER+/PgR+/HER2- tumours using a PgR cut-off point of 20% as a divisive criterion.
We analysed 1,522 patients with primary breast cancer who had undergone surgery at the Cancer Center of Fudan University between 2012 and 2014. Age, grade, tumour size, lymph node status and lymphovascular invasion were assessed. Multinomial logistic regression, linear regression and chi-square test models were applied to assess associations between ER, PR and clinical features.
ER+/PgR-/HER2- tumours showed poorer clinicopathologic characteristics relative to ER+/PgR+/HER2- tumours using a PgR threshold of 20% instead of 1%. The clinicopathologic characteristics did not differ between tumours with purely negative PgR expression and tumours with a PgR percentage ranging from 1% to 19%. The prognostic significance of PR expression appeared more pronounced in patients under a high Ki-67 status than those under a low Ki-67 status.
Based on these findings, we propose the use of a novel threshold of 20% to define PgR status. Nevertheless, the impact of this new criterion on patient management and clinical treatment requires additional study.
PMCID: PMC4418610  PMID: 25938238
4.  Comparative Analysis of Anther Transcriptome Profiles of Two Different Rice Male Sterile Lines Genotypes under Cold Stress 
Rice is highly sensitive to cold stress during reproductive developmental stages, and little is known about the mechanisms of cold responses in rice anther. Using the HiSeq™ 2000 sequencing platform, the anther transcriptome of photo thermo sensitive genic male sterile lines (PTGMS) rice Y58S and P64S (Pei’ai64S) were analyzed at the fertility sensitive stage under cold stress. Approximately 243 million clean reads were obtained from four libraries and aligned against the oryza indica genome and 1497 and 5652 differentially expressed genes (DEGs) were identified in P64S and Y58S, respectively. Both gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted for these DEGs. Functional classification of DEGs was also carried out. The DEGs common to both genotypes were mainly involved in signal transduction, metabolism, transport, and transcriptional regulation. Most of the DEGs were unique for each comparison group. We observed that there were more differentially expressed MYB (Myeloblastosis) and zinc finger family transcription factors and signal transduction components such as calmodulin/calcium dependent protein kinases in the Y58S comparison group. It was also found that ribosome-related DEGs may play key roles in cold stress signal transduction. These results presented here would be particularly useful for further studies on investigating the molecular mechanisms of rice responses to cold stress.
PMCID: PMC4463707  PMID: 25993302
cold stress; transcriptome; RNA-Seq; anther; PTGMS rice
5.  Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase 
Oncotarget  2015;6(12):10030-10044.
Prostate cancer is the most commonly diagnosed non-cutaneous cancer and one of the leading causes of cancer death for North American men. Whereas localized prostate cancer can be cured, there is currently no cure for metastatic prostate cancer. Here we report a novel approach that utilizes designed chimeric transcription activator-like effectors (dTALEs) to control prostate cancer metastasis. Transfection of dTALEs of DNA methyltransferase or demethylase induced artificial, yet active locus-specific CpG and subsequent histone modifications. These manipulations markedly altered expression of endogenous CRMP4, a metastasis suppressor gene. Remarkably, locus-specific CpG demethylation of the CRMP4 promoter in metastatic PC3 cells abolished metastasis, whereas locus-specific CpG methylation of the promoter in non-metastatic 22Rv1 cells induced metastasis. CRMP4-mediated metastasis suppression was found to require activation of Akt/Rac1 signaling and down-regulation of MMP-9 expression. This proof-of-concept study with dTALEs for locus-specific epigenomic manipulation validates the selected CpG methylation of CRMP4 gene as an independent biomarker for diagnosis and prognosis of prostate cancer metastasis and opens up a novel avenue for mechanistic research on cancer biology.
PMCID: PMC4496338  PMID: 25888628
prostate cancer; metastasis; transcription activator-like effectors (TALEs); CRMP4; epigenetic manipulation
6.  Acupuncture Therapy for Sudden Sensorineural Hearing Loss: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2015;10(4):e0125240.
Acupuncture has commonly been used in China, either alone or in combination with Western medicine, to treat sudden sensorineural hearing loss (SSHL). The purpose of this systematic review is to assess the efficacy and safety of acupuncture therapy for patients with SSHL.
We searched PubMed, the Cochrane Library, Embase, China National Knowledge Internet (CNKI), Database for Chinese Technical Periodicals (VIP), and Chinese Biomedical literature service system (SinoMed) to collect randomized controlled trials of acupuncture for SSHL published before July 2014. A meta-analysis was conducted according to the Cochrane systematic review method using RevMan 5.2 software. The evidence level for each outcome was assessed using the GRADE methodology.
Twelve trials involving 863 patients were included. A meta-analysis showed that the effect of manual acupuncture combined with Western medicine comprehensive treatment (WMCT) was better than WMCT alone (RR 1.33, 95%CI 1.19–1.49) and the same as the effect of electroacupuncture combined with WMCT (RR 1.33, 95%CI 1.19–1.50). One study showed a better effect of electroacupuncture than of WMCT (RR 1.34, 95%CI 1.24–1.45). For mean changes in hearing over all frequencies, the meta-analysis showed a better effect with the combination of acupuncture and WMCT than with WMCT alone (MD 10.85, 95%CI 6.84–14.86). However, the evidence levels for these interventions were low or very low due to a high risk of bias and small sample sizes in the included studies.
There was not sufficient evidence showing that acupuncture therapy alone was beneficial for treating SSHL. However, interventions combining acupuncture with WMCT had more efficacious results in the treatment of SSHL than WMCT alone. Electroacupuncture alone might be a viable alternative treatment besides WMCT for SSHL. However, given that there were fewer eligible RCTs and limitations in the included trials, such as methodological drawbacks and small sample sizes, large-scale RCTs are required to confirm the current findings regarding acupuncture therapy for SSHL.
PMCID: PMC4412536  PMID: 25919000
7.  Application of technical strategies for surgical management of adult intrinsic pontine gliomas: a retrospective series 
Object: The authors retrospectively analyzed the surgical treatment of adult intrinsic pontine gliomas in their department, and to enhance the understanding of technical strategies to treat this disease. Methods: 7 patients with intrinsic pontine gliomas were recruited for this study, between January 2011 and June 2013. All patients underwent preoperative MRI and Diffusion Tensor Imaging Fiber Tracking (DTI-FT). In addition, multimodal Intraoperative Neuromonitoring (IOM) and Intraoperative Neuronavigation were also applied during microsurgery. Results: 7 patients with intrinsic pontine gliomas were treated at the West China Hospital of Sichuan University. Mean age, mean duration of symptoms prior to diagnosis, and mean duration of follow-up average time were 38.0 years, 2.0 months, and 23.4 months, respectively. The main presentations were progressive cranial nerve deficits and long tract signs. Total resection was achieved in 3 patients, subtotal resection in 2, and partial resection in 2. Postoperative pathological examination revealed: astrocytoma (WHO II) in 4 cases, anaplastic oligoastrocytoma (AO, WHO III) in one case, and anaplastic astrocytoma (AA, WHO III) in two cases. Postoperative radiotherapy were administered to all patients, and 4 patients with astrocytoma (WHO II) rejected chemotherapy. After 11-39 months of follow-up, patient symptoms were resolved or stable without aggravation except one patient died because of rapidly progressive glioma at 11 months after operation. MRI in other patients showed residual tumor size to be unchanged or without obviously recurrence. Conclusion: Combining preoperative MRI with preoperative DTI-FT, surgery can be better assessed and the operation for adult intrinsic pontine gliomas can be maximally and safely resected with the aid of Multimodal IOMs and Intraoperative Navigation during microsurgery.
PMCID: PMC4483872  PMID: 26131091
Adult intrinsic pontine gliomas; diffusion tensor imaging fiber tracking (DTI-FT); multimodal intraoperative neuromonitoring (IOM); intraoperative neuronavigation
8.  In Vivo Effect of Quaternized Chitosan-Loaded Polymethylmethacrylate Bone Cement on Methicillin-Resistant Staphylococcus epidermidis Infection of the Tibial Metaphysis in a Rabbit Model 
Antimicrobial Agents and Chemotherapy  2014;58(10):6016-6023.
Infection of open tibial fractures with contamination remains a challenge for orthopedic surgeons. Local use of antibiotic-impregnated polymethylmethacrylate (PMMA) beads and blocks is a widely used procedure to reduce the risk of infection. However, the development of antibiotic-resistant organisms make the management of infection more difficult. Our in vitro study demonstrated that quaternized chitosan (hydroxypropyltrimethyl ammonium chloride chitosan [HACC])-loaded PMMA bone cement exhibits strong antibacterial activity toward antibiotic-resistant bacteria. Therefore, the present study aimed to investigate the in vivo antibacterial activity of quaternized chitosan-loaded PMMA. Twenty-four adult female New Zealand White rabbits were used in this study. The right proximal tibial metaphyseal cavity was prepared, 107 CFU of methicillin-resistant Staphylococcus epidermidis was inoculated, and PMMA-only, gentamicin-loaded PMMA (PMMA-G), chitosan-loaded PMMA (PMMA-C), or HACC-loaded PMMA (PMMA-H) bone cement cylinders were inserted. During the follow-up period, the infections were evaluated using X rays on days 21 and 42 and histopathological and microbiological analyses on day 42 after surgery. Radiographic indications of bone infections, including bone lysis, periosteal reactions, cyst formation, and sequestral bone formation, were evident in the PMMA, PMMA-G, and PMMA-C groups but not in the PMMA-H group. The radiographic scores and gross bone pathological and histopathological scores were significantly lower in the PMMA-H group than in the PMMA, PMMA-G, and PMMA-C groups (P < 0.05). Explant cultures also indicated significantly less bacterial growth in the PMMA-H group than in the PMMA, PMMA-G, and PMMA-C groups (P < 0.01). We concluded that PMMA-H bone cement can inhibit the development of bone infections in this animal model inoculated with antibiotic-resistant bacteria, thereby demonstrating its potential application for treatment of local infections in open fractures.
PMCID: PMC4187961  PMID: 25070107
9.  A special healing pattern in stable metaphyseal fractures 
Acta Orthopaedica  2015;86(2):238-242.
Background and purpose
Metaphyseal fractures heal in a rapid fashion that is different from the bone shaft healing process. Animal studies have focused on diaphyseal fractures. We investigated the metaphyseal fracture-healing process in rabbits.
Animals and methods
60 rabbits (divided into 12 groups) underwent proximal tibial osteotomy, anatomical reduction, and fixation with screws. After surgery, the proximal tibiae were harvested at different time points for histology.
No obvious osteonecrosis or bone resorption were found 2 weeks after surgery. From day 5 to week 5, woven bone or new trabeculae formed. From week 2, remodeling into lamellar bone started and reached a peak at week 6. These 3 stages overlapped. Histomorphometry showed that the structure changed as a unimodal curve.
The healing process of metaphyseal fractures appears to differ from the commonly studied healing process in diaphyseal fractures. It is rapid, and can be divided into 4 histological stages: cellular activation and differentiation, formation of woven bone, transformation of woven bone into lamellar bone, and further remodeling.
PMCID: PMC4404778  PMID: 25582035
10.  Liver transplantation for recurrent posthepatectomy malignant hepatic angiomyolipoma: A case report 
Hepatic angiomyolipomas (AMLs) are typically benign tumors containing varying amounts of smooth muscle cells, adipose tissue, and vessels, and are commonly found in the kidney and occasionally in the liver. The preoperative diagnosis of hepatic AML is primarily made from imaging and fine-needle aspiration biopsy results, though limited experience for such diagnoses can result in misdiagnosis. Some uncommon features of hepatic AML have been reported in the literature without an objective or qualitative consensus. As the majority of cases are benign, conservative treatment of AMLs is recommended. However, in rare cases, liver transplantation has been implemented. Only five cases of malignant hepatic AML have been reported. We report a rare case of recurrent posthepatectomy malignant hepatic AML that was misdiagnosed as liver cancer in a 37-year-old woman, which was treated by liver transplantation. The imaging and pathologic findings are presented in order to provide a more concise description to aid in future diagnoses.
PMCID: PMC4375604  PMID: 25834347
Angiomyolipoma; Hepatectomy; Malignant; Liver transplantation; Recurrence
11.  Antitumor Activities of Ethyl Acetate Extracts from Selaginella doederleinii Hieron In Vitro and In Vivo and Its Possible Mechanism 
The antitumor activities of ethyl acetate extracts from Selaginella doederleinii Hieron (SD extracts) in vitro and in vivo and its possible mechanism were investigated. HPLC method was developed for chemical analysis. SD extracts were submitted to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay on different cells, flow cytometry, and RT-PCR analysis using HepG2 cell and antitumor activity in vivo using H-22 xenograft tumor mice. Six biflavonoids from SD extracts were submitted to molecular docking assay. The results showed that SD extracts had considerable antitumor activity in vitro and in vivo without obvious toxicity on normal cells and could induce cell apoptosis. The mechanisms of tumorigenesis and cell apoptosis induced by SD extracts may be associated with decreasing the ratio of bcl-2 and bax mRNA level, activating caspase-3, suppressing survivin, and decreasing the gene expression of COX-2, 5-LOX, FLAP, and 12-LOX mRNA. The main active component in SD extracts is biflavonoids and some exhibited strong interactions with COX-2, 5-LOX, 12-LOX, and 15-LOX. These results offering evidence of possible mechanisms of SD extracts suppress cell proliferation and promote apoptosis and provide the molecular theoretical basis of clinical application of S. doederleinii for cancer therapy.
PMCID: PMC4381860  PMID: 25866543
12.  Synchronous splenectomy and hepatectomy for patients with hepatocellular carcinoma and hypersplenism: A case-control study 
AIM: To investigate whether the use of synchronous hepatectomy and splenectomy (HS) is more effective than hepatectomy alone (HA) for patients with hepatocellular carcinoma (HCC) and hypersplenism.
METHODS: From January 2007 to March 2013, 84 consecutive patients with HCC and hypersplenism who underwent synchronous hepatectomy and splenectomy in our center were compared with 84 well-matched patients from a pool of 268 patients who underwent hepatectomy alone. The short-term and long-term outcomes of the two groups were analyzed and compared.
RESULTS: The mean time to recurrence was 21.11 ± 12.04 mo in the HS group and 11.23 ± 8.73 mo in the HA group, and these values were significantly different (P = 0.001). The 1-, 3-, 5-, and 7-year disease-free survival rates for the patients in the HS group and the HA group were 86.7%, 70.9%, 52.7%, and 45.9% and 88.1%, 59.4%, 43.3%, and 39.5%, respectively (P = 0.008). Platelet and white blood cell counts in the HS group were significantly increased compared with the HA group one day, one week, one month and one year postoperatively (P < 0.001). Splenectomy and micro-vascular invasion were significant independent prognostic factors for disease-free survival. Gender, tumor number, and recurrence were independent prognostic factors for overall survival.
CONCLUSION: Synchronous hepatectomy and hepatectomy potentially improves disease-free survival rates and alleviates hypersplenism without increasing the surgical risks for patients with HCC and hypersplenism.
PMCID: PMC4342911  PMID: 25741142
Hepatocellular carcinoma; Hypersplenism; Splenectomy; Hepatectomy; Case-control study
13.  Arthroscopic treatment of bony loose bodies in the subacromial space 
Graphical abstract
•The multiple bony loose bodies were found in the subacromial.•Arthroscopic removal is a good option to treat the loose body in the subacromial space.•The bony loose bodies may be associated with synovial cartilage metaplasia.•MRI can easily diagnosis bony loose bodies in the subacromial space.
Multiple bony loose bodies in the subacromial space caused form cartilage or bone cells and continue to grow.
Presentation of case
A 58-year-old man with two-year history of swelling and pain of the right shoulder. He had no history of tuberculosis and rheumatoid arthritis. Magnetic resonance (MR) images showed some bony loose bodies in the subacromial space. The removal of loose bodies and bursa debridement were performed arthroscopically. Histological diagnosis of them was synovitis with fibrous bodies.
Extra-articular loose bodies is extremely rare, especially in the subacromial space, which maybe originated in the proliferative synovial bursa. Most authors recommend open removal to relive the pain, but there were choice to apply arthroscopy to remove them.
The mechanism of formation of bony loose bodies is not clear, may be associated with synovial cartilage metaplasia. Arthroscopic removal of loose bodies and bursa debridement is a good option for treatment of the loose body in the subacromial space, which can receive good function.
PMCID: PMC4446658  PMID: 25958049
Shoulder; Bony loose bodies; Synovitis; Arthroscopy; Subacromial space; Bursitis
14.  Large animal models of human cauda equina injury and repair: evaluation of a novel goat model 
Neural Regeneration Research  2015;10(1):60-64.
Previous animal studies of cauda equina injury have primarily used rat models, which display significant differences from humans. Furthermore, most studies have focused on electrophysiological examination. To better mimic the outcome after surgical repair of cauda equina injury, a novel animal model was established in the goat. Electrophysiological, histological and magnetic resonance imaging methods were used to evaluate the morphological and functional outcome after cauda equina injury and end-to-end suture. Our results demonstrate successful establishment of the goat experimental model of cauda equina injury. This novel model can provide detailed information on the nerve regenerative process following surgical repair of cauda equina injury.
PMCID: PMC4357118  PMID: 25788921
nerve regeneration; spinal cord injury; goat; animal model; radiography; magnetic resonance imaging; diffusion tensor imaging; fiber bundle; diagnosis; injury; physiology; neuroimaging; NSFC grants; neural regeneration
15.  Natural history of sensory nerve recovery after cutaneous nerve injury following foot and ankle surgery 
Neural Regeneration Research  2015;10(1):99-103.
Cutaneous nerve injury is the most common complication following foot and ankle surgery. However, clinical studies including long-term follow-up data after cutaneous nerve injury of the foot and ankle are lacking. In the current retrospective study, we analyzed the clinical data of 279 patients who underwent foot and ankle surgery. Subjects who suffered from apparent paresthesia in the cutaneous sensory nerve area after surgery were included in the study. Patients received oral vitamin B12 and methylcobalamin. We examined final follow-up data of 17 patients, including seven with sural nerve injury, five with superficial peroneal nerve injury, and five with plantar medial cutaneous nerve injury. We assessed nerve sensory function using the Medical Research Council Scale. Follow-up immediately, at 6 weeks, 3, 6 and 9 months, and 1 year after surgery demonstrated that sensory function was gradually restored in most patients within 6 months. However, recovery was slow at 9 months. There was no significant difference in sensory function between 9 months and 1 year after surgery. Painful neuromas occurred in four patients at 9 months to 1 year. The results demonstrated that the recovery of sensory function in patients with various cutaneous nerve injuries after foot and ankle surgery required at least 6 months.
PMCID: PMC4357126  PMID: 25788928
nerve regeneration; natural history; cutaneous nerve injury; foot and ankle; sural nerve; superficial peroneal nerve; medial plantar nerve; neurosensory function; neural regeneration
16.  Circulating miRNAs in cancer: from detection to therapy 
Since the discovery of circulating microRNAs (miRNAs) in body fluids, an increasing number of studies have focused on their potential as non-invasive biomarkers and as therapeutic targets or tools for many diseases, particularly for cancers. Because of their stability, miRNAs are easily detectable in body fluids. Extracellular miRNAs have potential as biomarkers for the prediction and prognosis of cancer. Moreover, they also enable communication between cells within the tumor microenvironment, thereby influencing tumorigenesis. In this review, we summarize the progresses made over the past decade regarding circulating miRNAs, from the development of detection methods to their clinical application as biomarkers and therapeutic tools for cancer. We also discuss the advantages and limitations of different detection methods and the pathways of circulating miRNAs in cell-cell communication, in addition to their clinical pharmacokinetics and toxicity in human organs. Finally, we highlight the potential of circulating miRNAs in clinical applications for cancer.
PMCID: PMC4269921  PMID: 25476853
17.  Specific-detection of clinical samples, systematic functional investigations, and transcriptome analysis reveals that splice variant MUC4/Y contributes to the malignant progression of pancreatic cancer by triggering malignancy-related positive feedback loops signaling 
MUC4 plays important roles in the malignant progression of human pancreatic cancer. But the huge length of MUC4 gene fragment restricts its functional and mechanism research. As one of its splice variants, MUC4/Y with coding sequence is most similar to that of the full-length MUC4 (FL-MUC4), together with alternative splicing of the MUC4 transcript has been observed in pancreatic carcinomas but not in normal pancreas. So we speculated that MUC4/Y might be involved in malignant progression similarly to FL-MUC4, and as a research model of MUC4 in pancreatic cancer. The conjecture was confirmed in the present study.
MUC4/Y expression was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) using gene-specific probe in the clinic samples. The effects of MUC4/Y were observed by serial in vitro and in vivo experiments based on stable over-expressed cell model. The underlying mechanisms were investigated by sequence-based transcriptome analysis and verified by qRT-PCR, Western blot and enzyme-linked immunosorbent assays.
The detection of clinical samples indicates that MUC4/Y is significantly positive-correlated with tumor invasion and distant metastases. Based on stable forced-expressed pancreatic cancer PANC-1 cell model, functional studies show that MUC4/Y enhances malignant activity in vitro and in vivo, including proliferation under low-nutritional-pressure, resistance to apoptosis, motility, invasiveness, angiogenesis, and distant metastasis. Mechanism studies indicate the novel finding that MUC4/Y triggers malignancy-related positive feedback loops for concomitantly up-regulating the expression of survival factors to resist adverse microenvironment and increasing the expression of an array of cytokines and adhesion molecules to affect the tumor milieu.
In light of the enormity of the potential regulatory circuitry in cancer afforded by MUC4 and/or MUC4/Y, repressing MUC4 transcription, inhibiting post-transcriptional regulation, including alternative splicing, or blocking various pathways simultaneously may be helpful for controlling malignant progression. MUC4/Y- expression model is proven to a valuable tool for the further dissection of MUC4-mediated functions and mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0309-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4236435  PMID: 25367394
MUC4/Y; Alternative splicing; Pancreatic neoplasms; Cell movement; Angiogenesis; Neoplasm metastasis; Gene expression regulation; Signal transduction
18.  Effects of Ixeris Chinensis (Thunb.) Nakai Boiling Water Extract on Hepatitis B Viral Activity and Hepatocellular Carcinoma 
Hepatitis B virus (HBV) infection and hepatocellular carcinoma are major diseases that affect the Taiwanese population. Therefore, the development of an alternative herbal medicine that can effectively treat these diseases is a research target. In this study, we tested Ixeris Chinensis (Thunb.) Nakai boiling water extract (ICTN BWE) in vitro and analysed its effects on the HBV and liver cancer.
Materials and Methods
We used a human liver cancer cell line (Hep3B, a cell line that continuously secretes HBV particles into a medium) as an experimental model for the screening of various ICTN BWE concentrations and their effects on the HBV in vitro.
Our results showed that 75 µg/mL ICTN BWE downregulated the relative expression of the hepatitis B virus surface antigens (HBsAg) to 77.1%. Using the human liver cancer cell lines HuH-7 and HepG2, and 3-(4,5-dimethylthiazol-zyl)-2,5-diphenyl tetrazolium bromide (MTT) and tumour clonogenic assays, we then showed that ICTN BWE inhibits hepatocellular carcinoma growth.
Fluorescent microscopy of DAPI(4′,6-Diamidino-2-phenylindole)-stained nuclei and DNA fragmentation assays confirmed the inhibitory effects of ICTN BWE on liver tumour cell growth through induction of apoptosis.
PMCID: PMC3957264  PMID: 24653576
herbal medicine; Ixeris Chinensis (Thunb.) Nakai; antihepatocellular carcinoma; apoptosis; antihepatitis B virus
19.  Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction 
BMC Cancer  2014;14:738.
Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. However the anti-tumor effect of NK cells decreases during pancreatic cancer progression. The regulatory pathways by which NK cells facilitate tumor immune escape are unclear, therefore our purpose was to investigate the roles of the contributory factors.
NK cells isolated from fresh healthy peripheral blood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE and human pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cell function was determined by Flow cytometric analysis of surface receptors and cytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, and Enzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDO and COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR. Statistical differences between data groups were determined by independent t-tests using SPSS 19.0 software.
Our results showed that NK cell function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, as demonstrated by lower expressions of activating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxic granules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-α and IFN-γ); and reduced cytotoxicity against myelogenous leukemia K562 cells. Further investigations revealed that MMP-9 and IDO may be implicated in SW1990 cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockade by TIMP-1 and/or 1-MT could partially restore NK function.
Taken together, elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates NK cell dysfunction. Our findings could contribute to the development of NK cell-based immunotherapy in patients with pancreatic cancer.
PMCID: PMC4287420  PMID: 25274283
Pancreatic cancer; Natural killer cell dysfunction; MMP-9; IDO
20.  Low immediate postoperative platelet count is associated with hepatic insufficiency after hepatectomy 
World Journal of Gastroenterology : WJG  2014;20(33):11871-11877.
AIM: To investigate the relationship between low immediate postoperative platelet count and perioperative outcome after liver resection in patients with hepatocellular carcinoma (HCC).
METHODS: In a cohort of 565 consecutive hepatitis B-related HCC patients who underwent major liver resection, the characteristics and clinical outcomes after liver resection were compared between patients with immediate postoperative platelet count < 100 × 109/L and patients with platelet count ≥ 100 × 109/L. Risk factors for postoperative hepatic insufficiency were evaluated by multivariate analysis.
RESULTS: Patients with a low immediate postoperative platelet count (< 100 × 109/L) had more grade III-V complications (20.5% vs 12.4%, P = 0.016), and higher rates of postoperative liver failure (6.8% vs 2.6%, P = 0.02), hepatic insufficiency (31.5% vs 21.2%, P < 0.001) and mortality (6.8% vs 0.5%, P < 0.001), compared to patients with a platelet count ≥ 100 × 109/L. The alanine aminotransferase levels on postoperative days 3 and 5, and bilirubin on postoperative days 1, 3 and 5 were higher in patients with immediate postoperative low platelet count. Multivariate analysis revealed that immediate postoperative low platelet count, rather than preoperative low platelet count, was a significant independent risk factor for hepatic insufficiency.
CONCLUSION: A low immediate postoperative platelet count is an independent risk factor for hepatic insufficiency. Platelets can mediate liver regeneration in the cirrhotic liver.
PMCID: PMC4155380  PMID: 25206294
Thrombocytopenia; Hepatic insufficiency; Hepatocellular carcinoma; Hepatectomy; Hepatitis B
21.  AAV-Mediated Lysophosphatidylcholine Acyltransferase 1 (Lpcat1) Gene Replacement Therapy Rescues Retinal Degeneration in rd11 Mice 
The retinal degeneration 11 (rd11) mouse is a newly discovered, naturally occurring animal model with early photoreceptor dysfunction and rapid rod photoreceptor degeneration followed by cone degeneration. The rd11 mice carry a spontaneous mutation in the lysophosphatidylcholine acyltransferase 1 (Lpcat1) gene. Here, we evaluate whether gene replacement therapy using the fast-acting tyrosine-capsid mutant AAV8 (Y733F) can arrest retinal degeneration and restore retinal function in this model.
The AAV8 (Y733F)-smCBA-Lpcat1 was delivered subretinally to postnatal day 14 (P14) rd11 mice in one eye only. At 10 weeks after injection, treated rd11 mice were examined by visually-guided behavior, electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT), and then killed for morphologic and biochemical examination.
Substantial scotopic and photopic ERG signals were maintained in treated rd11 eyes, whereas untreated eyes in the same animals showed extinguished signals. The SD-OCT (in vivo) and light microscopy (in vitro) showed a substantial preservation of the outer nuclear layer in most parts of the treated retina only. Almost wild-type LPCAT1 expression in photoreceptors with strong rod rhodopsin and M/S cone opsin staining, and normal visually-guided water maze behavioral performances were observed in treated rd11 mice.
The results demonstrate that the tyrosine-capsid mutant AAV8 (Y733F) vector is effective for treating rapidly degenerating models of retinal degeneration and, moreover, is more therapeutically effective than AAV2 (Y444, 500, 730F) vector with the same promoter-cDNA payload. To our knowledge, this is the first demonstration of phenotypic rescue by gene therapy in an animal model of retinal degeneration caused by Lpcat1 mutation.
This is a comprehensive morphologic, biochemical, electrophysiologic and behavioral analysis of tyrosine capsid mutant AAV8 (Y733F) or triple mutant AAV2 (Y444, 500, 730F)-mediated photoreceptor rescue in rd11 mice, a naturally occurring retinal degeneration model caused by Lpcat1 mutation.
PMCID: PMC3968931  PMID: 24557352
rd11; gene therapy; mice; Lpcat1; AAV
22.  Effect of low-dose tacrolimus with mycophenolate mofetil on renal function following liver transplantation 
World Journal of Gastroenterology : WJG  2014;20(32):11356-11362.
AIM: To determine whether low-dose tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is a safe approach to decrease the incidence of chronic kidney disease (CKD) in liver transplantation (LT) recipients.
METHODS: We analyzed the medical records of 689 patients who underwent LT between March 1999 and December 2012 in a single Chinese center. Immunosuppression was initiated with a calcineurin inhibitor (TAC or CSA) and prednisone with or without MMF. CKD is defined by the glomerular filtration rate (GFR), estimated by an abbreviated Modification of Diet in Renal Disease formula, < 60 mL/min per 1.73 m2 for at least 3 consecutive months after LT. Individuals with TAC trough concentrations ≤ 8 ng/mL at 3 mo after LT were defined as the low-dose group. The incidence of CKD within 5 years was compared between the TAC group and the CSA group, as well as between four subgroups (low-dose and high-dose TAC groups with or without MMF).
RESULTS: No difference regarding the occurrence of pre-LT renal dysfunction or that of post-LT rejection was found between the TAC and CSA groups or between the four subgroups. With a definition of GFR < 60 mL/min per 1.73 m2, the overall incidence of CKD was significantly higher in the CSA group than in the TAC group. The incidence of CKD in the low-dose TAC + MMF group (7.7%) was significantly lower than that observed in the low-dose TAC group (15.9%), high-dose TAC group (24.6%) and high-dose TAC + MMF group (18.5%). The cumulative 1-, 3- and 5-year incidence rates of CKD were 12.7%, 14.5% and 16.7%, respectively. The cumulative 5-year survival rates were 61.7% and 82.2% in patients with or without CKD, respectively.
CONCLUSION: In LT patients, the choice of immunosuppressive therapy appears to affect renal function and patient survival.
PMCID: PMC4145776  PMID: 25170222
Liver transplantation; Chronic kidney disease; Calcineurin inhibitor; Mycophenolate mofetil
23.  Clinical study on postoperative recurrence in patients with pN0 esophageal squamous cell carcinoma 
Despite increasingly radical surgery for esophageal carcinoma, many patients still develop tumor recurrence after operation. This study was designed to analyze the clinical and pathologic influencing factors of early recurrence in patients with histological node-negative (pN0 stage) esophageal squamous cell carcinoma (ESCC) after radical esophagectomy.
A retrospective study on 112 consecutive pN0 stage ESCC patients who underwent esophagectomy with lymphadenectomy by the same surgical team from January 2004 to December 2010. There were 92 male and 20 female patients, aging from 36 to 80 years with a mean age of 60.3 years. The Cox proportional hazards model was used to determine the independent risk factors for recurrence within 3 years after the operation.
Recurrence was recognized in 45 patients (40.2%) within 3 years after operation. The median time to tumor recurrence was 17.4 months. Locoregional recurrence was found in 38 patients (33.9%) and hematogenous metastasis in 7 patients (6.3%). However, locoregional recurrence accounted for 84.4% of all relapse patients. Recurrence closely correlated with tumor location, grade of differentiation, primary tumor stage (pT) and pathologic stage (χ2 = 6.380 to 18.837, p < 0.05). The Cox multivariate analysis showed that upper/middle thoracic location (OR = 1.092, p = 0.049) and pT3-4a stage (OR = 3.296, p = 0.017) were independent risk factors for postoperative locoregional recurrence.
Locoregional recurrence was the most common recurrence pattern of patients with pN0 ESCC within 3 years after operation. Upper/middle thoracic location and pT3-4a stage were independent risk factors for locoregional recurrence of pN0 ESCC after radical esophagectomy.
PMCID: PMC4200175  PMID: 25164541
Esophagus neoplasms; Lymph node dissection; Recurrence and metastasis
24.  Risk factors associated with early and late HAT after adult liver transplantation 
World Journal of Gastroenterology : WJG  2014;20(30):10545-10552.
AIM: To identify risk factors that might contribute to hepatic artery thrombosis (HAT) after liver transplantation (LT).
METHODS: The perioperative and follow-up data of a total of 744 liver transplants, performed from February 1999 to July 2010, were retrospectively reviewed. HAT developed in 20 patients (2.7%). HAT was classified as early (occurring in fewer than 30 d post LT) or late (occurring more than 30 d post LT). Early HAT developed in 14 patients (1.9%). Late HAT developed in 6 patients (0.8%). Risk factors associated with HAT were analysed using the χ2 test for univariate analysis and logistic regression for multivariate analysis.
RESULTS: Lack of ABO compatibility, recipient/donor weight ratio ≥ 1.15, complex arterial reconstruction, duration time of hepatic artery anastomosis > 80 min, duration time of operation > 10 h, dual grafts, number of units of blood received intraoperatively ≥ 7, number of units of fresh frozen plasma (FFP) received intraoperatively ≥ 6, postoperative blood transfusion and postoperative FFP use were significantly associated with early HAT in the univariate analysis (P < 0.1). After logistic regression, independent risk factors associated with early HAT were recipient/donor weight ratio ≥ 1.15 (OR = 4.499), duration of hepatic artery anastomosis > 80 min (OR = 5.429), number of units of blood received intraoperatively ≥ 7 (OR = 4.059) and postoperative blood transfusion (OR = 6.898). Graft type (whole/living-donor/split), duration of operation > 10 h, retransplantation, rejection reaction, recipients with diabetes preoperatively and recipients with a high level of blood glucose or diabetes postoperatively were significantly associated with late HAT in the univariate analysis (P < 0.1). After logistic regression, the independent risk factors associated with early HAT were duration of operation > 10 h (OR = 6.394), retransplantation (OR = 21.793) and rejection reactions (OR = 16.936).
CONCLUSION: Early detection of these risk factors, strict surveillance protocols by Doppler ultrasound and prophylactic anticoagulation for recipients at risk might be determined prospectively.
PMCID: PMC4130865  PMID: 25132774
Liver transplantation; Hepatic artery thrombosis; Risk factors; Complication; Blood transfusion
25.  MicroRNA-122 Triggers Mesenchymal-Epithelial Transition and Suppresses Hepatocellular Carcinoma Cell Motility and Invasion by Targeting RhoA 
PLoS ONE  2014;9(7):e101330.
The loss of microRNA-122 (miR-122) expression is strongly associated with increased invasion and metastasis, and poor prognosis of hepatocellular carcinoma (HCC), however, the underlying mechanisms remain poorly understood. In the present study, we observed that miR-122 over-expression in HCC cell lines Sk-hep-1 and Bel-7402 triggered the mesenchymal-epithelial transition (MET), as demonstrated by epithelial-like morphological changes, up-regulated epithelial proteins (E-cadherin, ZO-1, α-catenin, occludin, BVES, and MST4), and down-regulated mesenchymal proteins (vimentin and fibronectin). The over-expression of miRNA-122 also caused cytoskeleton disruption, RhoA/Rock pathway inactivation, enhanced cell adhesion, and suppression of migration and invasion of Sk-hep-1 and Bel-7402 cells, whereas, these effects could be reversed through miR-122 inhibition. Additional studies demonstrated that the inhibition of wild-type RhoA function induced MET and inhibited cell migration and invasion, while RhoA over-expression reversed miR-122-induced MET and inhibition of migration and invasion of HCC cells, suggesting that miR-122 induced MET and suppressed the migration and invasion of HCC cells by targeting RhoA. Moreover, our results demonstrated that HNF4α up-regulated its target gene miR-122 that subsequently induced MET and inhibited cell migration and invasion, whereas miR-122 inhibition reversed these HNF4α-induced phenotypes. These results revealed functional and mechanistic links among the tumor suppressors HNF4α, miR-122, and RhoA in EMT and invasive and metastatic phenotypes of HCC. Taken together, our study provides the first evidence that the HNF4α/miR-122/RhoA axis negatively regulates EMT and the migration and invasion of HCC cells.
PMCID: PMC4081555  PMID: 24992599

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