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1.  The Phosphodiesterase-4 (PDE4) Inhibitor Rolipram Decreases Ethanol Seeking and Consumption in Alcohol-preferring Fawn-Hooded Rats 
Background
Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapies. Since the cyclic AMP (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets. Phosphodiesterase 4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, represents as a key point in regulating intracellular cAMP levels. Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse.
Methods
Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (v/v) ethanol and 10% (w/v) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125, 0.025, or 0.05 mg/kg, s.c.); rolipram at higher doses (0.05, 0.1, and 0.2 mg/kg, s.c.) was tested to determine its impact on the intake of ethanol, sucrose, or water using the two-bottle choice drinking paradigm. Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity.
Results
Acute administration of rolipram dose-dependently reduced operant self-administration of 5% ethanol, but had no effect on 10% sucrose responding. Time-course assessment revealed significant decreases in ethanol consumption after rolipram (0.1, 0.2 mg/kg) treatment in continuous- and intermittent-access to ethanol at 5% or 10%, respectively. Moreover, chronic rolipram treatment time-dependently decreased 5% ethanol consumption and preference during treatment days and after the termination of rolipram administration. Rolipram at the highest doses (0.1 and 0.2 mg/kg) did decrease locomotor activity, but the effect lasted only 10 and 20 min, respectively, which did not likely alter long-term ethanol drinking.
Conclusions
These results suggest that PDE4 plays a role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.
doi:10.1111/j.1530-0277.2012.01845.x
PMCID: PMC4335658  PMID: 22671516
Cyclic AMP Signaling; Phosphodiesterase-4 (PDE4); Rolipram; FH/Wjd Rat; Ethanol Intake
2.  Blockage of the Upregulation of Voltage-Gated Sodium Channel Nav1.3 Improves Outcomes after Experimental Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(4):346-357.
Abstract
Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Nav1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Nav1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Nav1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Nav1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Nav1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Nav1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Nav1.3 expression in the brain may improve outcomes following TBI.
doi:10.1089/neu.2013.2899
PMCID: PMC3922240  PMID: 24313291
antisense oligodeoxynucleotides; intracerebroventicular administration; Nav1.3; traumatic brain injury; voltage-gated sodium channels
3.  Identification of Synaptosomal Proteins Binding to Monomeric and Oligomeric α-Synuclein 
PLoS ONE  2015;10(2):e0116473.
Monomeric α-synuclein (αSN) species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson’s disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes.
doi:10.1371/journal.pone.0116473
PMCID: PMC4319895  PMID: 25659148
4.  A molecular signature for the prediction of recurrence in colorectal cancer 
Molecular Cancer  2015;14(1):22.
Background
Several clinical and pathological factors have an impact on the prognosis of colorectal cancer (CRC), but they are not yet adequate for risk assessment. We aimed to identify a molecular signature that can reliably identify CRC patients at high risk for recurrence.
Results
Two hundred eighty-one CRC samples (stage II/III) were included in this study. A two-step gene expression profiling study was conducted. First, gene expression measurements from 81 fresh frozen CRC samples were obtained using Affymetrix Human Genome U133 Plus 2.0 Arrays. Second, a focused gene expression assay, including prognostic genes and genes of interest from literature reviews, was performed using 200 fresh frozen samples and a Taqman low-density array (TLDA) analysis. An optimal 31-gene expression classifier for the prediction of recurrence among patients with stage II/III CRC was developed using logistic regression analysis. This gene expression signature classified 58.5% of patients as low-risk and 41.5% as high-risk (P < 0.001). The signature was the strongest independent prognostic factor in the multivariate analysis. The five-year relapse-free survival (RFS) rates for the low-risk patients and the high-risk patients were 88.5% and 41.3% (P < 0.001), respectively.
Conclusion
We identified a 31-gene expression signature that is closely associated with the clinical outcome of stage II/III CRC patients.
doi:10.1186/s12943-015-0296-2
PMCID: PMC4320628  PMID: 25645394
Molecular signature; Gene expression; Colorectal cancer; Recurrence
5.  Neuroprotective Effect of Gui Zhi (Ramulus Cinnamomi) on Ma Huang- (Herb Ephedra-) Induced Toxicity in Rats Treated with a Ma Huang-Gui Zhi Herb Pair 
Herb Ephedra (Ma Huang in Chinese) and Ramulus Cinnamomi (Gui Zhi in Chinese) are traditional Chinese herbs, often used together to treat asthma, nose and lung congestion, and fever with anhidrosis. Due to the adverse effects of ephedrine, clinical use of Ma Huang is restricted. However, Gui Zhi extract has been reported to decrease spontaneous activity in rats and exert anti-inflammatory and neuroprotective effects. The present study explored the possible inhibitory effect of Gui Zhi on Ma Huang-induced neurotoxicity in rats when the two herbs were used in combination. All Ma Huang and Ma Huang-Gui Zhi herb pair extracts were prepared using methods of traditional Chinese medicine and were normalized based on the ephedrine content. Two-month-old male Sprague-Dawley rats (n = 6 rats/group) were administered Ma Huang or the Ma Huang-Gui Zhi herb pair extracts for 7 days (ephedrine = 48 mg/kg), and locomotor activity was measured. After 7 days, oxidative damage in the prefrontal cortex was measured. Gui Zhi decreased hyperactivity and sensitization produced by repeated Ma Huang administration and attenuated oxidative stress induced by Ma Huang. The results of this study demonstrate the neuroprotective potential of Gui Zhi in Ma Huang-induced hyperactivity and oxidative damage in the prefrontal cortex of rats when used in combination.
doi:10.1155/2015/913461
PMCID: PMC4321680
6.  Evaluation of a HIV Voluntary Opt-Out Screening Program in a Singapore Hospital 
PLoS ONE  2015;10(1):e0116987.
Background
Early diagnosis of human immunodeficiency virus (HIV) allows for appropriately timed interventions with improved outcomes, but HIV screening among asymptomatic persons and the general population in Singapore remains low. In 2008, Singapore’s Ministry of Health implemented HIV voluntary opt-out screening (VOS) for hospitalised adults. We evaluated the outcome of VOS and surveyed reasons for its low uptake in our institution.
Methods
We assessed the outcomes of the VOS programme from January 2010 to December 2013 at National University Hospital, a 1081-bed tertiary hospital in Singapore. We also examined reasons for opting-in and opting-out using an interviewer–administered structured questionnaire in a representative sample in January 2013.
Results
107,523 patients fulfilled VOS criteria and were offered HIV screening, of which 5215 (4.9%) agreed to testing. 4850 (93.1%) of those who opted-in had an HIV test done. Three (0.06%) tested positive for HIV. 238 patients (14.2%) were surveyed regarding reasons for opting-in or out of VOS. 21 (8.8%) had opted-in. Patients who opted-in were likely to be younger, more educated and reported having more regular sexual partners. Type of housing, number of casual sexual partners, sexual orientation, intravenous drug use, condom use and previous sexually transmitted infection were not associated with deciding to opt-in/out. Patients’ most common reasons for opting-out were: belief that they were at low risk (50.2%), belief that they were too old (26.8%), cost (6.9%) and aversion to venepuncture (6.5%). The most common reason for opting-in was desire to know their HIV status (47.6%).
Conclusion
The success of an HIV-VOS program is largely determined by test uptake. Our study showed that the majority of eligible VOS patients opted-out of HIV screening. Given the considerable cost and low yield of this programme, more needs to be done to better equip patients in self-risk assessment and opting in to testing.
doi:10.1371/journal.pone.0116987
PMCID: PMC4303265  PMID: 25611741
7.  Laryngeal schwannoma treated with a CO2 laser: A case report 
Oncology Letters  2015;9(3):1467-1469.
Laryngeal schwannoma is a rare benign tumor of the larynx, with a high recurrence rate. The present study reports the case of a 36-year-old male patient with a two-week history of hoarseness. Electronic laryngoscopy revealed that there was a submucosal mass at the level of the right supraglottic area. A computed tomography scan of the larynx showed an 8×11-mm expansile mass in the right supraglottic area. Histopathological examination diagnosed a schwannoma of the larynx. The tumor was removed by CO2 laser through an endoscopic transoral approach. One year later, the patient remained symptom-free and direct examination of the larynx showed no signs of recurrence. The aim of the present study is to highlight this rare disease and its management options to the otolaryngological community.
doi:10.3892/ol.2015.2858
PMCID: PMC4315079  PMID: 25663932
laryngeal schwannoma; CO2 laser; recurrence
8.  Full Endoscopic Transsphenoidal Surgery for Pituitary Adenoma-emphasized on Surgical Skill of Otolaryngologist 
The purpose is to summarize the experience in full endoscopic transsphenoidal resection of pituitary adenoma in 28 patients by rhinologist, and introduce the surgical skill of otolaryngologist, especially skills and cautions when operating inside nose. We removed pituitary adenoma in 28 patients via entirely endoscopic transsphenoidal approach with the help of special-designed instruments; we performed the procedure bloodlessly within limited time. The skill emphasized bilateral nostrils and four hands technique which was as delicate as possible not to scratch nasal mucosa or injure nasal frame. The special instruments included curette with suction, monopolar electrotome and bipolar coagulation forceps with suction, powered surgical equipments (Diamond Bur, Irrigation Tubing for Blades and Burs for nasal endoscopic surgery). Among 28 patients, there were 16 total resections, 8 subtotal resections, 3 partial resections, and 1 only biopsy due to excessive bleeding and hard nature. Of 19 patients with preoperative visual impairment, 12 patients had postoperative improvement in visual acuity and visual field. All the procedures were finished within 60 to 90 min. Complications seldom occurred except transient diabetes insipidus, especially no nasal-related signs or complications but 1 had epistaxis. The full endoscopic transsphenoidal surgery is a promising approach for pituitary adenoma resection. Multidisciplinary collaboration will lead to optimal cure for the patients. New technique and special-designed instruments can facilitate greatly this procedure.
doi:10.1007/s12070-011-0317-4
PMCID: PMC3918297  PMID: 24533411
Nasal endoscopy; Pituitary adenoma; Complication; Surgical skill
9.  FOXM1 Promotes Lung Adenocarcinoma Invasion and Metastasis by Upregulating SNAIL 
The forkhead box M1 (FOXM1) transcription factor is one of the key genes inducing tumor invasion and metastasis by an unknown mechanism. In this study, we set out to investigate the effects of FOXM1 overexpression on metastatic human lung adenocarcinoma and the underlying mechanism. FOXM1 expression was analyzed in 78 frozen lung adenocarcinoma tissue samples using an Affymetrix microarray and a 155-paraffin-embedded lung adenocarcinoma tissue microarray with immunohistochemical detection. FOXM1 was found to be overexpressed in lung adenocarcinoma, particularly in metastatic patients, compared to non-metastatic patients. Knockdown of FOXM1 by a specific siRNA significantly suppressed EMT progression, migration and invasion of lung adenocarcinoma cells in vitro, and tumor growth and metastasis in vivo, whereas restored expression of FOXM1 had the opposite effect. FOXM1 binds directly to the SNAIL promoter through two specific binding sites and constitutively transactivates it. Collectively, our findings indicate that FOXM1 may play an important role in advancing lung adenocarcinoma progression. Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting lung adenocarcinoma metastasis. Inhibition of FOXM1-SNAIL signaling may present an ideal target for future treatment.
doi:10.7150/ijbs.10634
PMCID: PMC4279094  PMID: 25561901
Lung adenocarcinoma; Invasion; Metastasis; FOXM1; SNAIL
10.  Reduction of Acute Rejection by Bone Marrow Mesenchymal Stem Cells during Rat Small Bowel Transplantation 
PLoS ONE  2014;9(12):e114528.
Background
Bone marrow mesenchymal stem cells (BMMSCs) have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats.
Methods
Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control), isogeneically transplanted rats (BN-BN) and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg) cells were assessed at each time point.
Results
Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th)1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL)-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ while upregulating IL-10 and transforming growth factor (TGF)-β expression and increasing Treg levels.
Conclusion
BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation.
doi:10.1371/journal.pone.0114528
PMCID: PMC4266507  PMID: 25500836
11.  BCL6 is a negative prognostic factor and exhibits pro-oncogenic activity in ovarian cancer 
Background: Dysregulation of BCL6 plays critical oncogenic roles and facilitates tumorigenesis in various malignancies. However, whether the aberrant expression of BCL6 in ovarian carcinoma is associated with malignancy, metastasis or prognosis remains unknown. Our study aimed to investigate the expression of BCL6 in ovarian carcinoma and its possible correlation with clinicopathological features as well as patient survival to reveal its biological effects in ovarian tumor progression. Methods: Immunochemistry analysis was performed in 105 cases of ovarian carcinoma covering the histological types of serous, endometrioid and clear cell. Spearman analysis was used to calculate the correlation between pathological parameters and the expression of BCL6. Kaplan–Meier method and Cox proportional hazards analysis were used to analyze the disease-specific survival (DSS) and disease-free survival (DFS). We also assessed whether overexpression and knockdown of BCL6 influence in vitro cell proliferation, cell cycle progression, as well as tumor cell invasion and migration. Results: The expression of BCL6 was higher in all three major kinds of ovarian cancer in comparison with paratumorous epithelium. BCL6 expression was tightly correlated with FIGO staging, lymph node metastasis and recurrence. Higher expression of BCL6 led to a significantly poorer DSS and DFS and multivariate analysis revealed that BCL6 was an independent risk factor of DSS and DFS. Enforced overexpression of BCL6 in ovarian tumor cells stimulated proliferation by inducing G1–S transition, and promoted tumor cell invasion and migration. Conversely, RNA interference–mediated silencing BCL6 expression inhibited proliferation by altered cell cycle progression and reduced the ability of the cells to migrate, and invade the extracellular matrix in culture. Conclusions: Our study suggests that the inappropriate activation of BCL6 predicts poor prognosis and promotes tumor progression in ovarian carcinoma. Targeting BCL6 could be a novel therapeutic choice for treating ovarian carcinoma patients.
PMCID: PMC4300693  PMID: 25628935
BCL6; ovarian carcinoma; prognosis; proliferation; invasion
12.  Radiobiological effect induced by different activities of 125I seed brachytherapy in a hepatocellular carcinoma model 
Background: Iodine 125 (125I) seed irradiation is an effective non-surgical treatment for unresectable hepatocellular carcinoma (HCC) patients. However, the safety and tolerability of 125I seed sequential irradiation therapy remain unclear, there is no unified standard of brachytherapy radiation dose, and further study on the basic radiobiology of continuous rate irradiation is necessary. Methods: Forty Kunming-mice (KM-mice, China) were injected with suspensions of human hepatocellular carcinoma cells (H22) to create an animal model and mimic 125I seed implantation. The survival rates of mice, curative effect, pathological impairments including apoptosis and necrosis were investigated. The mice were randomly divided into four groups, A, B, C and D. In group A, 0.78 mCi 125I seeds were implanted into the tumor focus. In groups B and C, 0.58 mCi and 0.38 mCi 125I seeds were inserted at the same location, respectively. Group D was a control group, without any treatment. After 28 days of therapy, the survival rates and the tumor size were measured, and pathological impairments was measured by light or electron microscopy. Results: The tumor volume inhibition rate was 68.21% ± 3.21%, 51.38% ± 4.96%, and 35.71% ± 2.79% after 0.78 mCi, 0.58 mCi, and 0.38 mCi 125I seeds irradiation, respectively. However, radiation-related side effects were also observed in the high-dose group. Pathological results showed that radiation effect was closely associated with radiation dose, as the increase of radiation dose, an increase in apoptosis and necrosis was detected. Significant cellular impairments were noted by pathological analysis under electron microscopy. Conclusions: Our results demonstrate that the Kunming-mouse is an ideal animal to study 125I brachytherapy, and the curative effect was closely associated with radiation dose. High-dose of brachytherapy may effectively increase apoptosis and necrosis in liver cells in KM-mice. A dose of 0.58 mCi 125I radioactive particles may be a safe, effective and minimally invasive therapeutic option for liver cancer.
PMCID: PMC4307476  PMID: 25664029
125I seed; hepatocellular carcinoma; apoptosis; animal experimentation
13.  Efficacy and safety of herbal medicines in treating gastric ulcer: A review 
World Journal of Gastroenterology : WJG  2014;20(45):17020-17028.
Gastric ulcer is a common disorder of the digestive system. Current therapeutic regimens largely rely on Western medicine. However, numerous studies have demonstrated that herbal medicines can effectively treat gastric ulcer in humans and various animal models via divergent mechanisms. This review updates the efficacy and safety of herbal medicines in treating gastric ulcer, and the mechanisms of their action in humans and animal models. Studies have demonstrated that the efficacy of herbal medicines is comparable or superior to that of drugs such as omeprazole or cimetidine in humans and animal models, and herbal medicines display fewer adverse effects. The mechanisms by which herbal medicines benefit gastric ulcer include stimulation of mucous cell proliferation, anti-oxidation, and inhibition of gastric acid secretion and H(+)/K(+)-ATPase activity. Some herbal medicines also exhibit antimicrobial properties. Utilization of herbal medicines could be a valuable alternative to treat gastric ulcer in humans effectively, with few adverse effects.
doi:10.3748/wjg.v20.i45.17020
PMCID: PMC4258570  PMID: 25493014
Herbal medicines; Gastric ulcer; Mechanism of action
14.  Chlorogenic acid suppresses interleukin-1β-induced inflammatory mediators in human chondrocytes 
We investigated the anti-inflammatory properties of chlorogenic acid (CGA) in interleukin-1β-induced chondrocytes. The nitric oxide (NO) and prostaglandin E2 (PGE2) were detected by Griess and Enzyme-linked immunosorbent assay (ELISA) respectively. Quantitative real-time PCR and western blot were performed to measure the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2. Our results indicate that CGA inhibited the production of NO and PGE2 as well as the expression of iNOS and COX-2 in chondrocytes. Our data suggest that CGA possess potential value in the treatment of OA.
PMCID: PMC4314010
Chlorogenic acid; inducible NO synthase; cyclooxygenase; chondrocyte
15.  Associations between the C3435T polymorphism of the ABCB1 gene and drug resistance in epilepsy: a meta-analysis 
Objective: A meta-analysis was performed to comprehensively evaluate the correlations between the C3435T polymorphism of ABCB1 (the ATP-binding cassette, subfamily B, member 1 transporter gene) and drug resistance in epilepsy. Methods: Inclusion and exclusion criteria and a strategy for searching original literature were developed and utilized to search Chinese and non-Chinese databases. Research reports discussing correlations between the ABCB1 C3435T polymorphism and patient responses to anti-epileptic drug (AED) therapy were collected. Comparisons and comprehensive quantitative analyses were conducted using an allele model (C vs. T), and a genotype model (CC vs. CT+TT). In addition, subgroup analyses were performed that divided the included studies according to the race of the study subjects (Asian or Caucasian), based on the geographical region in which each study was conducted. Results: The meta-analysis included a total of 23 publications that examined a total of 3,912 drug-resistant epileptic patients and 4,419 epileptic patients for whom drug treatment was effective. The included studies did not exhibit publication bias. Statistical analyses revealed that the C3435T polymorphism was not significantly correlated with drug resistance in epilepsy. The random-effects model comparing the C and T alleles produced an odds ratio (OR) of 1.10 with a 95% confidence interval (CI) of 0.98-1.25 and P = 0.46. Subgroup analyses suggested that in Caucasian population there are significant differences between resistance group (RN) and control group (N) in both allele model (C vsT: OR = 1.13; 95% CI: 1.03-1.25) and genotype model (CC vsCT+TT: OR = 1.27; 95% CI: 1.08-1.50). Conclusion: The ABCB1 C3435T polymorphism is associated with drug resistance in epilepsy in Caucasian population.
PMCID: PMC4276158  PMID: 25550900
Epilepsy; gene polymorphism; ATP-binding cassette; subfamily B; member 1 transporter gene (ABCB1); drug resistance; meta-analysis
16.  Primary hepatic non-Hodgkin’s lymphoma with rectal cancer: A case report 
Oncology Letters  2014;9(1):324-326.
Primary hepatic non-Hodgkin’s lymphoma (NHL) is an extremely rare disease that is commonly neglected as a possible diagnosis. The present study reports the case of a middle-aged male with chronic hepatitis B in which primary hepatic NHL and rectal cancer occurred simultaneously. A large solitary tumor in the left lobe of the liver was incidentally detected on routine examination prior to the laparoscopic resection of the rectal cancer. Laparoscopic resection of the rectal cancer and a liver biopsy were performed simultaneously. The pathology revealed that the hepatic tumor was NHL and that the rectal cancer was adenocarcinoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, therefore, primary hepatic lymphoma (PHL) was diagnosed. PHL associated with rectal adenocarcinoma is extremely rare and to the best of our knowledge, has never been reported. At present, the cause and most effective therapy for the condition remain unclear.
doi:10.3892/ol.2014.2673
PMCID: PMC4247066  PMID: 25435985
non-Hodgkin’s lymphoma; liver; primary liver lymphoma; rectal cancer
17.  Modulation of Mcl-1 expression reduces age-related cochlear degeneration 
Neurobiology of aging  2013;34(11):2647-2658.
Mcl-1 is an anti-apoptotic member of the Bcl-2 family that modulates apoptosis-related signaling pathways and promotes cell survival. We have previously demonstrated a reduction of Mcl-1 expression in aging cochleae. To investigate whether restoring Mcl-1 expression would reduce aging-related cochlear degeneration, we developed a rat model of Mcl-1 overexpression. A plasmid encoding human Mcl-1/enhanced green fluorescent protein was applied to the round window of the cochlea. This in vivo treatment transfected both the sensory and supporting cells of the cochlear sensory epithelium and enhanced Mcl-1 expression at both the mRNA and the protein level. The upregulation of Mcl-1 expression reduced the progression of age-related cochlear dysfunction and sensory cell death. Furthermore, the transfection of Mcl-1 exerted its protective effect by suppressing cochlear apoptosis at the mitochondrial level. This study demonstrates that the genetic modulation of Mcl-1 expression reduces the progression of age-related cochlear degeneration.
doi:10.1016/j.neurobiolaging.2013.05.012
PMCID: PMC3742618  PMID: 23790646
Mcl-1; gene delivery; cochlea; aging; intervention; hair cells; rat
18.  Comparison of carotid and lower limb atherosclerotic lesions in both previously known and newly diagnosed type 2 diabetes mellitus 
Aims/Introduction
To compare carotid and lower limb atherosclerotic lesions, and examine if carotid atherosclerotic lesions are in line with lower limb atherosclerotic lesions, and can reflect generalized atherosclerosis in inpatients with type 2 diabetes.
Materials and Methods
This was an observational study carried out in 867 Chinese inpatients with type 2 diabetes, including 573 previously known and 294 newly diagnosed patients. Ultrasonographic assessments of intima-media thickness (IMT), plaques, and stenosis in the carotid and lower limb arteries were evaluated. Atherosclerotic lesions between the carotid and lower limb arteries were compared in both previously known and newly diagnosed diabetes, respectively.
Results
In both the known (77.3% vs 49.4%, P < 0.001) and the newly diagnosed diabetes (55.4% vs 29.9%, P < 0.001), the prevalence of atherosclerotic plaques was significantly higher in the lower limb arteries than in the carotid arteries. Likewise, the prevalence of stenosis was also significantly higher (P < 0.001) in the lower limb arteries (16.9%) than in the carotid arteries (4.2%) in the established diabetes patients. However, there was no significant difference in the mean IMT between common carotid and common femoral arteries in both the previously known (0.90 ± 0.24 mm vs 0.89 ± 0.20 mm, P = 0.675) and the newly diagnosed diabetes patients (0.86 ± 0.22 mm vs 0.85 ± 0.16 mm, P = 0.436).
Conclusions
Carotid plaques might underestimate generalized plaques in inpatients with type 2 diabetes, as shown by its significantly lower prevalence compared with that of the lower extremity arteries. A combined carotid and lower limb ultrasound examination can improve the detection of atherosclerotic lesions in inpatients with type 2 diabetes.
doi:10.1111/jdi.12204
PMCID: PMC4234239  PMID: 25422776
Atherosclerosis; Diabetes; Epidemiology
19.  Preparation and Pharmacokinetic Study of Aprepitant–Sulfobutyl Ether-β-Cyclodextrin Complex 
AAPS PharmSciTech  2013;15(1):121-130.
Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved treatment for chemotherapy-induced nausea and vomiting and for post-operative nausea and vomiting. However, it has poor water solubility. This study was performed to optimize the capsule formulation of an inclusion complex of APR with sulfobutyl ether-β-cyclodextrin (SBE-β-CD), and to evaluate its water solubility, dissolution rate, and bioavailability. The complex was prepared through the saturated-aqueous solution method and then characterized by Fourier transform infrared spectroscopy, x-ray powder diffraction, and differential scanning calorimetry. Subsequently, a pharmacokinetic study was performed using liquid chromatography–tandem mass spectrometry. Emend, which features an innovative formulation that incorporates drug nanoparticles with high bioavailability, was used as a reference for comparison with the optimized formulation. As a result, the dissolution rates and extent of release of the test formulation in various media were enhanced relative to those of Emend. The bioavailability of the drug complex was comparable to that of Emend. In summary, the SBE-β-CD complexation could provide a practical and cost-effective option for enhancing the solubility and bioavailability of APR according to our research.
doi:10.1208/s12249-013-0044-0
PMCID: PMC3909173  PMID: 24166668
aprepitant; bioavailability; dissolution rate; inclusion complex; sulfobutyl ether-β-cyclodextrin
20.  Expression of vaspin in the joint and the levels in the serum and synovial fluid of patients with osteoarthritis 
The aim of this study was to determine the expression of vaspin in the joint and investigate the distribution between paired serum and synovial fluid (SF) in osteoarthritis (OA) patients, and serum in healthy controls. The gene expression of vaspin was measured by quantitative real-time polymerase chain reaction (qPCR) in the OA joint tissues. The vaspin protein expression in the cartilage, synovium and osteophyte from OA patients who required total knee replacement (TKR) were detected by immunohistochemistry (IHC). Levels of vaspin in serum and SF were analyzed by enzyme-linked immunosorbent assay (ELISA), including 26 OA patients and 23 healthy controls. All the joint tissues including cartilage, synovium, meniscus, infrapatellar fat pad and osteophyte from OA patients expressed vaspin messenger RNA (mRNA), and the expression of vaspin protein was observed in OA cartilage, synovium and osteophyte. Furthermore, serum vaspin was reduced in OA patients compared to healthy controls, and serum vaspin levels from OA patients exceed those in the paired SF. Serum or SF vaspin were not related to age, gender, or body mass index (BMI). These results suggest that vaspin may be involved in the pathophysiology of OA and may have local effects in the joint during the process of OA.
PMCID: PMC4238502  PMID: 25419381
Vaspin; osteoarthritis; serum; synovial fluid; joint
21.  Right atrial cardiac rhabdomyoma with premature foramen ovale restriction: A case report 
Oncology Letters  2014;8(6):2553-2556.
Fetal cardiac rhabdomyoma is the most common cardiac tumor in fetuses. However, this benign tumor can cause hemodynamic repercussions and intrauterine fetal mortality. The present study reports a case of rare fetal cardiac rhabdomyoma located in the right atrium, accompanied by premature restriction of the foramen ovale and moderate pericardial effusion, as determined by tomographic ultrasound imaging (TUI). Fetal mortality subsequently occurred late in the second trimester of pregnancy and the diagnosis was confirmed by pathology. The present study discusses the occurrence and diagnosis of this rare abnormality. TUI mode with spatio-temporal image correlation offline imaging provides the physician with clear views of abnormal intracardiac structures in the beating heart. With improvements in sonographic technology, the diagnosis of fetal cardiac rhabdomyoma may be easier and more accurate in the clinical arena.
doi:10.3892/ol.2014.2605
PMCID: PMC4214446  PMID: 25364426
atrial cardiac rhabdomyoma; intrauterine fetal mortality; foramen ovale restriction; postnatal tuberous sclerosis complex; fetal echocardiography; tomographic ultrasound imaging
22.  A peptide probe for the detection of neurokinin-1 receptor by disaggregation enhanced fluorescence and magnetic resonance signals 
Scientific Reports  2014;4:6487.
We report a novel peptide probe for the detection of neurokinin-1 receptor using disaggregation-caused signal enhancement. The probe was obtained via the aggregation of a modified substance P in a terpyridine-Fe (II) complex with Gd (III)-DOTA into well-defined nanostructures, which effectively weaken ligand fluorescence and slow the exchange rate of inner-sphere water molecules. This probe disaggregates upon binding to the neurokinin-1 receptor and activates the contrast agents to generate a fluorescent signal that positively enhances magnetic resonance imaging contrast and allows for the detection of overexpressed receptors on tumor cells and the identification of lung cancer using serum samples.
doi:10.1038/srep06487
PMCID: PMC4180826  PMID: 25270511
23.  Rpb3 promotes hepatocellular carcinoma through its N-terminus 
Oncotarget  2014;5(19):9256-9268.
The expression of RNA polymerase II subunit 3 (Rpb3) was found frequent up-regulation in Hepatocellular carcinoma (HCC) tumors. Significant associations could also be drawn between increased expressions of Rpb3 and advance HCC staging and shorter disease-free survival of patients. Overexpression of Rpb3 increased HCC cell proliferation, migratory rate and tumor growth in nude mice, whereas suppression of Rpb3 using shRNA inhibited these effects. For mechanism study, we found that Rpb3 bound directly to Snail, downregulated E-cadherin, induced HCC cells epithelial-mesenchymal transition (EMT). In particular, N-terminus of Rpb3 blocked Rpb3 binding to Snail, inhibited Rpb3-high-expression HCC cells proliferation, migration, tumor growth in nude mice, and also inhibited DEN-induced liver tumorigenesis. Furthermore, N-terminus of Rpb3 did not inhibit normal liver cells or Rpb3-low-expression HCC cells proliferation. These findings suggest that N-terminus of Rpb3 selectively inhibits Rpb3-high-expression HCC cells proliferation. N-terminus of Rpb3 may be useful in treating patients diagnosed with Rpb3-high-expression HCC.
PMCID: PMC4253432  PMID: 25211001
Hepatocellular carcinoma; liver tumorigenesis; Proliferation; Rpb3
24.  Prognostic value of Ki67 expression in HR-negative breast cancer before and after neoadjuvant chemotherapy 
Background: Immunohistochemical (IHC) expression of Ki67 has been identified as a prognostic and predictive marker in hormone receptor (HR)-positive breast cancer, however, there is little evidence of the association of Ki67 with prognosis in HR-negative patients. We aimed to assess the benefit of Ki67 assessment in HR-negative breast cancers after neoadjuvant chemotherapy (NAC). Methods: In the present study, a total of 183 HR-negative breast cancer patients with Stage II to III that treated with anthracycline and/or taxane-based neoadjuvant chemotherapy between 2004 and 2011 were retrospectively analyzed. Endocrine therapy and trastuzumab was not administered to any patients in this study. Clinical and pathological features of the patients with breast cancer were retrieved from the hospital records. Predictive factors for NAC response and survival were analyzed. Results: Of the 183 patients, 122 (66.6%) were HR- HER2+, and 61 (33.3%) were triple-negative. The clinical response rates were similar across breast cancer subtype. Patients whose tumors contained high Ki67 expression effectively responded to NAC. Ki67 labeling index was a predictive marker for pathologic complete response (pCR). Ki67 expression showed a positive correlation with HER2 status, tumor size, lymph node status, lymphovascular invasion and tumor grade. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free survival (DFS), but no correlation of Ki-67 expression with overall survival (OS) was observed. Conclusions: Our results suggest that Ki67 expression in HR-negative breast cancer may improve the assessment of pathological response after NAC, and Ki67 score in residual tumor was an independent prognosticator for DFS in the HR-negative breast cancer patients.
PMCID: PMC4230098  PMID: 25400769
Breast cancer; Ki67; neoadjuvant chemotherapy; prognosis
25.  HIV-related Burkitt lymphoma with florid granulomatous reaction: an unusual case with good outcome 
Burkitt lymphoma (BL) is a highly aggressive subtype of non-Hodgkin lymphomas (NHL). Lymphoma related granulomatous reaction rarely occurs in sporadic BL. Herein, we describe the first case of HIV related Burkitt lymphoma with florid granulomatous reaction. A 41-year-old HIV-positive Chinese male presented lymphadenopathy in the right cervical region for 3 months. The enlarged lymph node biopsies revealed the presence of prominent granulomas of varying size with Langhans giant cells, leading to the misdiagnosis of tuberculous lymphadenitis in other hospital. Subsequently, the case was sent to us for consultation. The morphology, immunophenotype, special staining, interphase FISH analysis and blood tests confirmed a diagnosis of HIV related Burkitt lymphoma with granulomatous reaction. Without radiotherapy and chemotherapy, the patient was alive and well with no evidence of lymphoma during the observation period of 24 months. The case suggested that lymphoma with florid granulomatous reaction can easily be misdiagnosed as benign lesions since the large number of epithelioid granulomas could obscure the primary lesion. Moreover, the granulomatous reaction may be an indicator for favorable prognosis in HIV related Burkitt lymphoma.
PMCID: PMC4230138  PMID: 25400794
Human immunodeficiency virus related Burkitt lymphoma; granulomatous reaction; prognosis

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