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1.  Targeted Nanogel Conjugate for Improved Stability and Cellular Permeability of Curcumin: Synthesis, Pharmacokinetics, and Tumor Growth Inhibition 
Molecular Pharmaceutics  2014;11(9):3112-3122.
Curcumin (CUR) is a unique natural compound with promising anticancer and anti-inflammatory activities. However, the therapeutic efficacy of curcumin was challenged in clinical trials, mostly due to its low bioavailability, rapid metabolism, and elimination. We designed a nanodrug form of curcumin, which makes it stable and substantially enhances cellular permeability and anticancer activity at standard oral administration. Curcumin was conjugated as an ester to cholesteryl-hyaluronic acid (CHA) nanogel that is capable of targeted delivery to CD44-expressing drug-resistant cancer cells. CHA-CUR nanogels demonstrated excellent solubility and sustained drug release in physiological conditions. It induced apoptosis in cancer cells, suppressing the expression of NF-κB, TNF-α, and COX-2 cellular targets similar to free curcumin. Pharmacokinetic/pharmacodynamic (PK/PD) studies also revealed improved circulation parameters of CHA-CUR at oral, i.p. and i.v. administration routes. CHA-CUR showed targeted tumor accumulation and effective tumor growth inhibition in human pancreatic adenocarcinoma MiaPaCa-2 and aggressive orthotropic murine mammary carcinoma 4T1 animal models. CHA-CUR treatment was well-tolerated and resulted in up to 13-fold tumor suppression, making this nanodrug a potential candidate for cancer prevention and therapeutic treatment.
PMCID: PMC4151794  PMID: 25072100
Curcumin; nanogel−drug conjugate; NF-κB inhibition; PK/PD parameters; animal cancer models
2.  Severe Pediatric Adenovirus 7 Disease in Singapore Linked to Recent Outbreaks across Asia 
Emerging Infectious Diseases  2015;21(7):1192-1196.
During November 2012–July 2013, a marked increase of adenovirus type 7 (Ad7) infections associated with severe disease was documented among pediatric patients in Singapore. Phylogenetic analysis revealed close genetic links with severe Ad7 outbreaks in China, Taiwan, and other parts of Asia.
PMCID: PMC4480382  PMID: 26079293
Human adenovirus; viruses; Ad7; outbreak; Asia; China; Singapore; Malaysia; invasive disease; death; mechanical ventilation
3.  Genetic ME–a visualization application for merging and editing pedigrees for genetic studies 
BMC Research Notes  2015;8:241.
In order to study the genetics of diseases more accurately and effectively, one often collects large families. Different members of a large family may provide differing information about the structure and make-up of their pedigree. Thus, software is needed to facilitate reconciliation of pedigrees collected independently from multiple informants from a single large family to create a unified pedigree that is based on the best composite information available.
Our implementation demonstrates that Genetic ME performs merging in terms of adding, replacing and combining information from two pedigrees. Through a tracking process, all of the changes made to the data set for the individuals can be traced back to their original source material. A new pedigree structure can be easily visualized while reconciling disparate information from multiple pedigrees.
We developed the Genetic Merging & Editing (Genetic ME) program, an open source Java application built on top of CraneFoot and Ghostscript, to support comparing, editing and merging of pedigrees collected from multiple sources in a visually-oriented manner.
Genetic ME constitutes an ideal addition to software packages for reconciling pedigree information from multiple sources. Genetic ME provides a friendly graphical user interface, traces the changes made by users, and produces viewable merged pedigree structures able to be further used by other popular analysis programs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-015-1131-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4478623  PMID: 26076732
Algorithms; Human; Java; Pedigree; Software
4.  A chromatin activity based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing 
Nature communications  2014;5:5733.
Immune cells develop endotoxin tolerance (ET) after prolonged stimulation. ET increases the level of a repression mark H3K9me2 in the transcriptional-silent chromatin specifically associated with pro-inflammatory genes. However, it is not clear what proteins are functionally involved in this process. Here we show that a novel chromatin activity based chemoproteomic (ChaC) approach can dissect the functional chromatin protein complexes that regulate ET-associated inflammation. Using UNC0638 that binds the enzymatically active H3K9-specific methyltransferase G9a/GLP, ChaC reveals that G9a is constitutively active at a G9a-dependent mega-dalton repressome in primary endotoxin-tolerant macrophages. G9a/GLP broadly impacts the ET-specific reprogramming of the histone code landscape, chromatin remodeling, and the activities of select transcription factors. We discover that the G9a-dependent epigenetic environment promotes the transcriptional repression activity of c-Myc for gene-specific co-regulation of chronic inflammation. ChaC may be also applicable to dissect other functional protein complexes in the context of phenotypic chromatin architectures.
PMCID: PMC4360912  PMID: 25502336
5.  Toll-like receptor 2 promotes T helper 17 cells response in hepatitis B virus infection 
Purpose: Innate and adaptive immune responses play vital roles in initiating and maintaining the immunological homeostasis in both physiological and pathological processes. However, the expression and function of the important cells and molecules as well as their interaction in hepatitis B virus (HBV) infection has not been well elucidated. The aim of the current study was to determine the pattern of Toll-like receptor 2 (TLR2) in T cells in HBV infection and the function of TLR2 in regulation of T helper 17 (Th17) cells response. Methods: Thirty-four patients with HBV infection (ten acute and twenty-four chronic) were enrolled. HBV-specific and -nonspecific Th17 cells and TLR2 expression in T cells were analyzed by flow cytometry. The function of TLR2 agonist for induction of IL-17 production was also determined. Results: HBV-specific and -nonspecific IL-17 secretion in CD4+ (Th17 cells) and CD8+ T cells was significantly elevated in chronic HBV infection. Viral-specific TLR2 expression in CD4+, CD8+, and Th17 cells was also remarkably increased in patients with chronic hepatitis B. Moreover, TLR2 agonist Pam3Csk4 directly activated Th17 cells response without antigen stimulation in HBV infection. Conclusion: TLR2, which traditionally associated with innate immunity, might also promote Th17 cells response in HBV infection. The function of TLRs in regulation of adaptive immune response in HBV infection, which might play an important role in persistent HBV infection.
PMCID: PMC4509216  PMID: 26221271
Hepatitis B virus; Toll-like receptor; T helper 17 cells; immunoregulation
6.  Postsecondary Pathways and Persistence for STEM versus non-STEM Majors: Among College Students with an Autism Spectrum Disorder 
Little is known about postsecondary pathways and persistence among college students with an Autism Spectrum Disorder (ASD). This study analyzed data from the National Longitudinal Transition Study-2, 2001–2009, a nationally representative sample of students in special education with an ASD who progressed from high school to postsecondary education. Findings suggest that most college students with an ASD enrolled in a 2-year community college at some point in their postsecondary careers (81%). Those in science, technology, engineering and mathematics (STEM) fields were more likely to persist in a 2-year community college and were twice as likely to transfer from a 2-year community college to a 4-year university than their peers in the non-STEM fields. College persistence rates varied by gender, race, parent education level, and college pathway and major. Educational policy implications are discussed.
PMCID: PMC4005068  PMID: 24158680
Autism Spectrum Disorder; postsecondary pathway; 2-year community colleges; 4-year universities; persistence; science; technology; engineering; mathematics (STEM)
7.  Early activated hepatic stellate cell-derived molecules reverse acute hepatic injury 
AIM: To test whether hepatic stellate cells (HSCs) at different activation stages play different roles in acetaminophen (APAP)-induced acute liver injury (ALI).
METHODS: HSCs were isolated from mouse liver and cultured in vitro. Morphological changes of initiation HSCs [HSCs (5d)] and perpetuation HSCs [HSCs (p3)] were observed by immunofluorescence and transmission electron microscopy. The protective effects of HSC-derived molecules, cell lysates and HSC-conditioned medium (HSC-CM) were tested in vivo by survival and histopathological analyses. Liver injury was determined by measuring aminotransferase levels in the serum and by histologic examination of tissue sections under a light microscope. Additionally, to determine the molecular mediators of the observed protective effects of initiation HSCs, we examined HSC-CM using a high-density protein array.
RESULTS: HSCs (5d) and HSCs (p3) had different morphological and phenotypic traits. HSCs (5d) presented a star-shaped appearance with expressing α-SMA at non-uniform levels between cells. However, HSCs (p3) evolved into myofibroblast-like cells without lipid droplets and expressed a uniform and higher level of α-SMA. HSC-CM (5d), but not HSC-CM (p3), provided a significant survival benefit and showed a dramatic reduction of hepatocellular necrosis and panlobular leukocyte infiltrates in mice exposed to APAP. However, this protective effect was abrogated at higher cell masses, indicating a therapeutic window of effectiveness. Furthermore, the protein array screen revealed that HSC-CM (5d) was composed of many chemokines and growth factors that correlated with inflammatory inhibition and therapeutic activity. When compared with HSC-CM (p3), higher levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-1γ, hepatocyte growth factor, interleukin-10, and matrix metalloproteinase-2, but lower levels of stem cell factor and Fas-Ligand were observed in HSC-CM (5d).
CONCLUSION: These data indicated that initiation HSCs and perpetuation HSCs were different in morphology and protein expression, and provided the first experimental evidence of the potential medical value of initiation HSC-derived molecules in the treatment of ALI.
PMCID: PMC4394079  PMID: 25892868
Hepatic stellate cells; Acute liver injury; Initiation and perpetuation
8.  Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage III non-small cell lung cancer: a preliminary report 
In recent years, the combination of cetuximab and chemoradiotherapy (CRT) has been used to treat stage III non-small cell lung cancer (NSCLC); however, limited data are available for Chinese patients. Herein, we report preliminary data from a phase I/II study testing the combination of cetuximab with inductive chemotherapy, followed by concurrent CRT (CCRT) in Chinese patients with stage III NSCLC.
Eligibility criteria were Zubrod performance status (PS) 0-1, forced expiratory volume in 1 second (FEV1) ≥1.2 L and adequate organ function. Enrolled patients received weekly cetuximab (initial dose of 400 mg/m2 on day 1 of week 1 and a maintenance dose of 250 mg/m2 on week 2 to the end of CCRT) with cisplatin/vinorelbine (NP) chemotherapy (every 3 weeks for 2 cycles from week 2, followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy (TRT) (60-66 Gy/2 Gy). The primary endpoints were toxicity and feasibility. All patients received positron emission tomography-computerized tomography (PET-CT) scans within the 2 weeks prior to enrollment. Univariate analyses were used to assess the correlation between SUV-T, SUV-N, SUV-TOTAL, gender, age, histology, tumor-node-metastasis (TNM) stage, PS and smoking status and survival. Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test.
Seventeen patients were enrolled and 16 completed the full regime. The overall response rate (ORR) was 58.8% and 82.3% after the induction and CCRT phases, respectively. With a median follow-up duration of 27.6 months, the median survival was 27.6 months [95% confidence interval (CI): 11.3-43.9 months] with 1- and 2-year survival rates of 88.2% (95% CI, 60.6-96.9%) and 58.8% (95% CI, 60.6-77.8%), respectively. Three patients remain progression-free to date, and the median progression-free survival (PFS) was 13.5 months (95% CI, 6.8-20.2 months). No treatment-related death occurred; however, 76% of the patients experienced grade 3+ adverse events (AEs), including nausea/vomiting, intestinal obstruction, and esophagitis (<6%), while other AEs were mostly of hematological nature (71%). The cut-off values for SUV-T and SUV-TOTAL were 11 and 20, respectively. Univariate analyses revealed SUV-TOTAL (P=0.027), SUV-T (P=0.025), and PS (P=0.006) as potential survival predictors, with a hazard ratio (HR) of 3.4, 3.7, and 9.9, respectively.
The combination of cetuximab with induction chemotherapy followed by CCRT appears feasible and promising. Local and locoregional maximal SUVs, defined by 18F-FDG PET-CT scanning, may represent a prognostic indicator for long-term survival for these patients, which warrants further study.
PMCID: PMC4409976  PMID: 25937779
Cetuximab; induction chemotherapy; concurrent chemoradiotherapy (CRT); positron emission tomography-computerized tomography (PET-CT); locally advanced non-small cell lung cancer (NSCLC)
9.  Angiopoietin and vascular endothelial growth factor expression in colorectal disease models 
AIM: To investigate angiopoietin (Ang) and vascular endothelial growth factor (VEGF) expression in rats with ulcerative colitis (UC) and colorectal cancer (CRC).
METHODS: Dysplasia and cancer were investigated in rats that received three cycles of 3.5% dextran sulfate sodium (DSS) in drinking water for 7 d followed by distilled water for 14 d after intraperitoneal pretreatment with 20 mg/kg 1,2-dimethylhydrazine (DMH) (CRC group). Colitis was investigated in rats that received three cycles of 3.5% DSS in drinking water for 7 d followed by distilled water for 14 d after intraperitoneal pretreatment with saline (UC group). Rats without DSS or DMH treatment served as controls. Expression of the tyrosine kinase with immunoglobulin-like and EGF-like domains (Tie)-2 and its ligands, Ang-1 and Ang-2, as well as VEGF were evaluated in the colorectum by Western blotting.
RESULTS: Compared with rats in the control group, rats in the CRC and UC groups developed the symptoms of acute colitis with diarrhea, rectal bleeding, wasting, and loss of body weight (P < 0.05). In addition, the mean length of colorectum of CRC and UC rats was significantly shorter than that of control rats (8.29 ± 0.21 and 8.31 ± 0.86, respectively, vs 12.34 ± 0.12 cm; P < 0.05). Furthermore, rats in the CRC group, but not in the UC or control groups, developed multiple tumors in the colorectal region. Western blot analysis revealed that rats in the CRC and UC groups had markedly increased protein levels of Ang-1, Ang-2, Tie-2, and VEGF in the colorectum compared to rats in the control group.
CONCLUSION: Increased expression of Ang-1, Ang-2, Tie-2, and VEGF in ulcerative colitis-derived colorectal cancer might lead to chronic colitis and pathologic angiogenesis in rats.
PMCID: PMC4351214  PMID: 25759532
Angiopoietin-1; Angiopoietin-2; Colorectal cancer; Tie-2; Ulcerative colitis; Vascular endothelial growth factor
10.  Type III Interferon Attenuates a Vesicular Stomatitis Virus-Based Vaccine Vector 
Journal of Virology  2014;88(18):10909-10917.
Vesicular stomatitis virus (VSV) has been extensively studied as a vaccine vector and oncolytic agent. Nevertheless, safety concerns have limited its widespread use in humans. The type III lambda interferon (IFN-λ) family of cytokines shares common signaling pathways with the IFN-α/β family and thus evokes similar antiviral activities. However, IFN-λ signals through a distinct receptor complex that is expressed in a cell type-specific manner, which restricts its activity to epithelial barriers, particularly those corresponding to the respiratory and gastrointestinal tracts. In this study, we determined how IFN-λ expression from recombinant VSV would influence vector replication, spread, and immunogenicity. We demonstrate that IFN-λ expression severely attenuates VSV in cell culture. In vivo, IFN-λ limits VSV replication in the mouse lung after intranasal administration and reduces virus spread to other organs. Despite this attenuation, however, the vector retains its capacity to induce protective CD8 T cell and antibody responses after a single immunization. These findings demonstrate a novel method of viral vector attenuation that could be used in both vaccine and oncolytic virus applications.
IMPORTANCE Viruses such as VSV that are used as vaccine vectors can induce protective T cell and antibody responses after a single dose. Additionally, IFN-λ is a potent antiviral agent that has certain advantages for clinical use compared to IFN-α/β, such as fewer patient side effects. Here, we demonstrate that IFN-λ attenuates VSV replication and spread following intranasal virus delivery but does not reduce the ability of VSV to induce potent protective immune responses. These findings demonstrate that the type III IFN family may have widespread applicability for improving the safety and efficacy of viral vaccine and oncolytic vectors.
PMCID: PMC4178858  PMID: 25008938
11.  Endoscopic variceal ligation compared with endoscopic injection sclerotherapy for treatment of esophageal variceal hemorrhage: A meta-analysis 
AIM: To compare the effect of endoscopic variceal ligation (EVL) with that of endoscopic injection sclerotherapy (EIS) in the treatment of patients with esophageal variceal bleeding.
METHODS: We performed a systematic literature search of multiple online electronic databases. Meta-analysis was conducted to evaluate risk ratio (RR) and 95% confidence interval (CI) of combined studies for the treatment of patients with esophageal variceal bleeding between EVL and EIS.
RESULTS: Fourteen studies comprising 1236 patients were included in the meta-analysis. The rebleeding rate in actively bleeding varices patients in the EVL group was significantly lower than that in the EIS group (RR = 0.68, 95%CI: 0.57-0.81). The variceal eradication rate in actively bleeding varices patients in the EVL group was significantly higher than that in the EIS group (RR = 1.06, 95%CI: 1.01-1.12). There was no significant difference about mortality rate between the EVL group and EIS group (RR = 0.95, 95%CI: 0.77-1.17). The rate of complications in actively bleeding varices patients in the EVL group was significantly lower than that in the EIS group (RR = 0.28, 95%CI: 0.13-0.58).
CONCLUSION: Our meta-analysis has found that EVL is better than EIS in terms of the lower rates of rebleeding, complications, and the higher rate of variceal eradication. Therefore, EVL is the first choice for esophageal variceal bleeding.
PMCID: PMC4342933  PMID: 25741164
Esophageal variceal bleeding; Endoscopic variceal ligation; Endoscopic injection sclerotherapy; Rebleeding; Variceal eradication; Meta-analysis
12.  Macrophages associated with tumors as potential targets and therapeutic intermediates 
Nanomedicine (London, England)  2014;9(5):695-707.
Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mφ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs.
PMCID: PMC4149280  PMID: 24827844
biodistribution of nanoparticles; cancer stem cell; eradication of cancer cells; macrophage; nanocarrier; phagocytosis; reprogramming of macrophages; ‘Trojan horses’; tumor-associated macrophage; tumor-supporting function
13.  Effects of low-flow sevoflurane anesthesia on renal function in low birth weight infants 
BMC Anesthesiology  2015;15:6.
Low-flow sevoflurane anesthesia has been shown to influence renal function in rats, but not in adult humans. Presently, no study has assessed the effects of sevoflurane on renal function in low birth weight infants. Our aim was to study the renal function in low birth weight infants undergoing surgery with low-flow sevoflurane anesthesia.
Forty infants graded as American Society of Anesthesiologists (ASA) grade I or II undergoing abdominal surgery were selected. After the induction of anesthesia, they received sevoflurane semi-closed inhalation anesthesia with an oxygen flow rate of 1 L/minute. According to patient vital signs, in-tidal sevoflurane concentration was maintained at 2.5%–4.0%. Peripheral vein blood samples and urine specimens were obtained before surgery (T0), at the end of surgery (T1), and 24 (T2), 48 (T3), and 72 hours (T4) after surgery. Serum creatinine (Cr), blood urea nitrogen (BUN), urinary retinol binding protein (RBP), and β-N-acetyl-glucosaminidase (NAG) levels were determined at these time points. Also, a temperature probe was inserted into the center of a soda lime canister and temperature readings were obtained.
There were no significant differences in Cr and BUN before and after surgery (P > 0.05). However, RBP and NAG levels increased after surgery (P < 0.05), but returned to preoperative levels 72 hours (T4) after surgery. The highest soda lime temperature was 37.3 ± 3.1°C.
Low-flow sevoflurane semi-closed inhalation anesthesia has no significant effect on the renal function of low birth weight infants.
PMCID: PMC4429475  PMID: 25971310
Low-flow; Inhalation anesthetics; Low birth weight infants; Renal function
14.  Resonance metallic ureteric stent in a case of ketamine bladder induced bilateral ureteric obstruction with one year follow up 
Upper urinary tract occlusion is well recognized in patients with chronic ketamine abuse. The mechanism is generally unknown, but the ulcerative cystitis contracture may be responsible for obstruction. We present the first reported use of the Resonance metallic ureteric stent in the management ureteric obstruction caused by ketamine-induced uropathy.
Presentation of case
A 31-year-old lady with one-year history of recreational ketamine abuse presented with symptoms related to drug-induced ulcerative cystitis over twelve-months. She presented with acute renal failure with bilateral pyonephrosis and sepsis, and was initially treated with bilateral nephrostomy insertions and antegrade stenting. The J stents recovered the renal function, but the patient suffered from recurrent urinary tract infections (UTI’s) with the prosthesis in-situ. The patient successfully underwent bilateral insertion of 12 cm 6.0 French Cook Resonance metallic ureteric stents. One year following the placement of the metallic stents, the patient maintained optimal renal function with no episode of UTI.
Ketamine induced uropathy is a well documented complication of chronic drug-induced ulcerative cystitis. The mechanical strength and inert property of metallic ureteric stents make it an ideal device to manage this problematic benign cause of ureteric obstruction.
This is the first reported case of therapeutic bilateral metallic ureteric stents in the management of patients with ketamine induced uropathy with one year follow up.
PMCID: PMC4353962  PMID: 25625490
Ketamine induced uropathy; Management; Resonance stent
15.  Dimensional schizotypy and social cognition: an fMRI imaging study 
Impairment in empathy has been demonstrated in patients with schizophrenia and individuals with psychosis proneness. In the present study, we examined the neural correlates underlying theory of mind (ToM) and empathy and the relationships between these two social cognitive abilities with schizotypy. Fifty-six first-year college students (31 males, 25 females) between 17 and 21 years of age (M = 19.3, SD = 0.9) from a medical university in China participated. All participants undertook a comic strips functional imaging task that specifically examined both empathy and ToM. In addition, they completed two self-report scales: the Chapman Psychosis Proneness scale and the Interpersonal Responsivity Index (IRI). Results showed that both empathy and ToM conditions of the task were associated with brain activity in the middle temporal gyrus, the temporo-parietal junction (TPJ), the precuneus and the posterior cingulate gyrus. In addition, we found positive correlations between negative schizotypy and brain activity in regions involved in social cognition, namely, the middle temporal gyrus, the TPJ, as well as the medial prefrontal gyrus. These findings highlight that different dimensions of schizotypy may show different associations with brain regions involved in social cognitive abilities. More importantly, the positive correlation between brain activity and anhedonia suggests the presence of compensatory mechanisms in high-risk populations.
PMCID: PMC4444828  PMID: 26074796
schizotypy; theory of mind; empathy; fMRI; anhedonia
16.  Acute kidney injury associated with minimal change disease in systemic lupus erythematosus: a case report 
In systemic lupus erythematosus, acute kidney injury is usually associated with severe lupus nephritis and rarely associated with other glomerular diseases.
Case presentation
We recently encountered a patient with acute kidney injury that was associated with minimal change disease in systemic lupus erythematosus. A 26-year-old Chinese woman who had a history of systemic lupus erythematosus presented with nephrotic syndrome and acute kidney injury. She fulfilled four of the American College of Rheumatology criteria for the classification of systemic lupus erythematosus. However, a renal biopsy revealed that there were no glomerular abnormalities or deposition of immune complex. Her generalized edema disappeared, and her high serum creatinine level decreased to normal after prednisolone therapy.
Though the relationship between lupus and minimal change disease is still not defined, the possibility of systemic lupus erythematosus combined with minimal change disease must be differentiated in patients with lupus and severe proteinuria.
PMCID: PMC4301750  PMID: 25495593
Acute kidney injury; Minimal change disease; Systemic lupus erythematosus
17.  Incidence, Risk Factors and Consequences of Emergence Agitation in Adult Patients after Elective Craniotomy for Brain Tumor: A Prospective Cohort Study 
PLoS ONE  2014;9(12):e114239.
Emergence agitation is a frequent complication that can have serious consequences during recovery from general anesthesia. However, agitation has been poorly investigated in patients after craniotomy. In this prospective cohort study, adult patients were enrolled after elective craniotomy for brain tumor. The sedation-agitation scale was evaluated during the first 12 hours after surgery. Agitation developed in 35 of 123 patients (29%). Of the agitated patients, 28 (80%) were graded as very and dangerously agitated. By multivariate stepwise logistic regression analysis, independent predictors for agitation included male sex, history of long-term use of anti-depressant drugs or benzodiazepines, frontal approach of the operation, method and duration of anesthesia and presence of endotracheal intubation. Total intravenous anesthesia and balanced anesthesia with short duration were protective factors. Emergence agitation was associated with self-extubation (8.6% vs 0%, P = 0.005). Sedatives were administered more in agitated patients than non-agitated patients (85.7% vs 6.8%, P<0.001). In conclusion, emergence agitation was a frequent complication in patients after elective craniotomy for brain tumors. The clarification of risk factors could help to identify the high-risk patients, and then to facilitate the prevention and treatment of agitation. For patients undergoing craniotomy, greater attention should be paid to those receiving a frontal approach for craniotomy and those anesthetized under balanced anesthesia with long duration. More researches are warranted to elucidate whether total intravenous anesthesia could reduce the incidence of agitation after craniotomy.
Trial Registration NCT00590499.
PMCID: PMC4262354  PMID: 25493435
18.  Deviation analysis of C2 translaminar screw placement assisted by a novel rapid prototyping drill template: a cadaveric study 
European Spine Journal  2013;22(12):2770-2776.
The goal of this study is to evaluate the accuracy of patient-specific CT-based rapid prototype drill templates for C2 translaminar screw insertion.
Volumetric CT scanning was performed in 32 cadaveric cervical spines. Using computer software, the authors constructed drill templates that fit onto the posterior surface of the C2 vertebrae with drill guides to match the slope of the patient’s lamina. Thirty-two physical templates were created from the computer models using a rapid prototyping machine. The drill templates were used to guide drilling of the lamina and post-operative CT images were obtained. The entry point and direction of the planned and inserted screws were measured and compared.
Sixty-four C2 translaminar screws were placed without violating the cortical bone of a single lamina. The bilateral average transverse angle of intended and actual screw for C2TLS was 56.60 ± 2.22°, 56.38 ± 2.51°, 56.65 ± 2.24°, 56.39 ± 2.45°. The bilateral mean coronal angle of the planned and actual screw for C2TLS was 0°, 0°, −0.07 ± 0.32°, 0.12 ± 0.57°. The average displacement of the entry point of the superior and inferior C2TLS in the x, y, z axis was 0.27 ± 0.85, 0.49 ± 1.46, −0.28 ± 0.69, 0.43 ± 0.88, 0.38 ± 1.51, 0.23 ± 0.64 mm.
The small deviations seen are likely due to human error in the form of small variations in the surgical technique and use of software to design the prototype. This technology improves the safety profile of this fixation technique and should be further studied in clinical applications.
PMCID: PMC3843787  PMID: 24005997
Rapid prototyping; Post–pre registration; Personalized drill template; Computer-assisted; C2 translaminar screws
19.  Mucosal Healing Did Not Predict Sustained Clinical Remission in Patients with IBD after Discontinuation of One-Year Infliximab Therapy 
PLoS ONE  2014;9(10):e110797.
To assess the endoscopic activity and Clinical activity after a one-year period of infliximab therapy and to evaluate the association between mucosal healing and need for retreatment after stopping infliximab in patients with Inflammatory bowel disease (IBD).
The data from 109 patients with Crohn’s disease (CD) and 107 patients with Ulcerative colitis (UC) received one-year infliximab were assessed. The primary endpoint of the study was the proportion of clinical remission, mucosal healing and full remission in IBD after the one-year period of maintenance infliximab therapy. The secondary endpoint was the frequency of relapses in the next year.
A total of 84.4% (92/109) CD patients and 81.3% (87/107) UC patients achieved clinical remission, 71.56% (78/109) of CD patients and 69.16% (74/107) of UC patients achieved mucosal healing, 56.88% (62/109) of CD patients and 54.21% (58/107) of UC patients achieved full remission at the end of the year of infliximab therapy. Infliximab therapy was restarted in the 10.19% (22/216) patients (13 CD, 9 UC) who achieved mucosal healing, and 13.89% (30/216) patients (18 CD, 12 UC) who achieved clinical remission and 6.48% (14/216) patients (8 CD, 6 UC) who achieved full remission had to be retreated within the next year. Neither clinical remission nor mucosal healing was associated with the time to restarting Infliximab therapy in IBD.
Mucosal healing did not predict sustained clinical remission in patients with IBD in whom the infliximab therapies had been stopped. And stopping or continuing infliximab therapy may be determined by assessing the IBD patient’s general condition and the clinical activity.
PMCID: PMC4203839  PMID: 25330148
20.  In Vivo Antibacterial Activity of MRX-I, a New Oxazolidinone 
MRX-I is a potent oxazolidinone antibiotic against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), penicillin-intermediate S. pneumoniae (PISP), and vancomycin-resistant enterococci (VRE). In this study, the in vivo efficacy of orally administered MRX-I was evaluated using linezolid as a comparator. MRX-I showed the same or better efficacy than linezolid in both systemic and local infection models against the tested strains.
PMCID: PMC4023790  PMID: 24395231
21.  Effect of Ovariectomy on Stimulating Intracortical Remodeling in Rats 
BioMed Research International  2014;2014:421431.
Objective. Technically primates and dogs represent ideal models to investigate diseases characterized by abnormal intracortical remodeling. High expenses and ethical issues, however, restrict the use of those animals in research. Rodent models have been used as alternatives instead, but their value is limited, if none, because these animals lack intracortical bone remodeling. This study aimed at investigating the effect of ovariectomy onto the stimulation of intracortical remodeling in rat mandibles. Materials and Methods. Sixteen 12-week-old Spraque-Dawly (SD) female rats were randomly assigned into two groups, receiving either ovariectomy or sham operation. All the rats were sacrificed 18 weeks postoperatively. The entire mandibles were harvested for microcomputed tomography (micro-CT) and histomorphometric assessments. Results. Micro-CT examination showed significantly decreased bone mineral density (0.95 ± 0.01 versus 1.01 ± 0.02 g/cm3, P < 0.001) and bone volume (65.78 ± 5.45 versus 87.41 ± 4.12%, P < 0.001) in ovariectomy group. Histomorphometric assessment detected a sixfold increased intracortical bone remodeling as well as an increased bone modeling in mandibles of ovariectomized rats. Conclusion. For the first time, to the authors' knowledge, it was detected that ovariectomy stimulates intracortical remodeling in rat mandibles. This animal model might be of use to study various bone diseases associated with an abnormal intracortical remodeling process.
PMCID: PMC4189761  PMID: 25309912
22.  Suppression of inflammatory response by flurbiprofen following focal cerebral ischemia involves the NF-κB signaling pathway 
Some studies of animal models of middle cerebral artery occlusion indicate that inflammation plays a key role in the pathogenesis of cerebral ischemia and secondary damage. Flurbiprofen has been suggested to alleviate cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanisms underlying the protective action are still incompletely understood. In this study we want to investigate the protective effect of flurbiprofen after transient middle cerebral artery occlusion (MCAO) in rats and the role of the NF-κB signaling pathway on this neuroprotective effect. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. Flurbiprofen was administrated via tail-vein injection at the onset of reperfusion. HE staining and Immunohistochemistry were carried out to detect the morphological changes in ischemic penumbra cortex. The expression of inflammatory cytokines genes (IL-1β, IL-6 and TNF-α) and the levels of p-NF-κB (p65) in ischemic penumbra cortex were measured by RT-PCR and western blot. Administration of flurbiprofen at the doses of 5 mg/kg and 10 mg/kg significantly attenuated cerebral ischemia/reperfusion injury, as shown by a reduction in the morphological changes and inhibition of pro-inflammatory cytokine expression in ischemic penumbra cortex. Moreover, our findings further demonstrated that the inhibition of NF-κB activity was involved in the neuroprotective effect of flurbiprofen on inflammatory responses. Flurbiprofen protects against cerebral injury by reducing expression of inflammatory cytokines genes and this effect may be partly due to the inhibition of NF-κB signaling pathway.
PMCID: PMC4211836  PMID: 25356186
Flurbiprofen; focal cerebral ischemia; inflammation; nuclear factor-κB
23.  Effect and safety of dual anti-human epidermal growth factor receptor 2 therapy compared to monotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer: a systematic review 
BMC Cancer  2014;14:625.
Dual anti-human epidermal growth factor receptor 2 (HER2) therapies have been shown to improve outcomes of HER2-positive breast cancer patients. We undertook a systematic review to compare treatment outcomes for patients who received single or combined anti-HER2 therapies.
We identified randomized control trials that compared dual anti-HER2 therapy and anti-HER2 monotherapy in patients with HER2-positive breast cancer. Outcomes included pathologic complete response (pCR), overall survival (OS), progression-free survival (PFS), and adverse events. Included in the analysis were seven trials that recruited 2,609 patients.
In the neoadjuvant setting, the pooled pCR rate in the dual anti-HER2 therapy and monotherapy groups in combination with chemotherapy was 54.8% and 36%, respectively. This difference was statistically significant (relative risk, 1.56; 95% confidence interval (CI), 1.23–1.97; p < 0.001). In the metastatic setting, dual anti-HER2 therapy demonstrated significant benefits in both PFS (hazard ratio (HR), 0.71; 95% CI, 0.62–0.81; p < 0.001) and OS (HR, 0.68; 95% CI, 0.57–0.82; p < 0.001). Subgroup analyses indicated that the addition of chemotherapy to dual anti-HER2 therapy could greatly improve pCR in the neoadjuvant settings. However, in the metastatic setting, similar PFS and OS were found in patients receiving dual anti-HER2 therapy with or without chemotherapy. Dual anti-HER2 therapy was associated with more frequent adverse events than monotherapy, but no statistical differences were observed in cardiac toxicity.
This systematic review provides a summary of all the data currently available, and confirms the benefits and risks of dual anti-HER2 therapy for HER2-positive breast cancer.
PMCID: PMC4161893  PMID: 25164542
anti-HER2 therapy; HER2-positive breast cancer; Systematic review
24.  Deep resequencing reveals allelic variation in Sesamum indicum 
BMC Plant Biology  2014;14:225.
Characterization of genome-wide patterns of allelic variation and linkage disequilibrium can be used to detect reliable phenotype–genotype associations and signatures of molecular selection. However, the use of Sesamum indicum germplasm for breeding is limited by the lack of polymorphism data.
Here we describe the massively parallel resequencing of 29 sesame strains from 12 countries at a depth of ≥ 13-fold coverage for each of the samples tested. We detected an average of 127,347 SNPs, 17,961 small InDels, and 9,266 structural variants per sample. The population SNP rate, population diversity (π) and Watterson’s estimator of segregating sites (θw) were estimated at 8.6 × 10-3, 2.5 × 10-3 and 3.0 × 10-3 bp-1, respectively. Of these SNPs, 23.2% were located within coding regions. Polymorphism patterns were nonrandom among gene families, with genes mediating interactions with the biotic or abiotic environment exhibiting high levels of polymorphism. The linkage disequilibrium (LD) decay distance was estimated at 150 kb, with no distinct structure observed in the population. Phylogenetic relationships between each of the 29 sesame strains were consistent with the hypothesis of sesame originating on the Indian subcontinent. In addition, we proposed novel roles for adenylate isopentenyltransferase (ITP) genes in determining the number of flowers per leaf axil of sesame by mediating zeatin biosynthesis.
This study represents the first report of genome-wide patterns of genetic variation in sesame. The high LD distance and abundant polymorphisms described here increase our understanding of the forces shaping population-wide sequence variation in sesame and will be a valuable resource for future gene–phenotype and genome-wide association studies (GWAS).
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0225-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4148021  PMID: 25138716
Sesamum indicum; Resequencing; Variation; Linkage disequilibrium
25.  Blocking TRPV1 in Nucleus Accumbens Inhibits Persistent Morphine Conditioned Place Preference Expression in Rats 
PLoS ONE  2014;9(8):e104546.
The function of TRPV1 (transient receptor potential vanilloid subfamily, member 1) in the central nervous system is gradually elucidated. It has been recently proved to be expressed in nucleus accumbens (NAc), a region playing an essential role in mediating opioid craving and taking behaviors. Based on the general role of TRPV1 antagonist in blocking neural over-excitability by both pre- and post-synaptic mechanisms, TRPV1 antagonist capsazepine (CPZ) was tested for its ability to prohibit persistent opioid craving in rats. In the present study, we assessed the expression of TRPV1 in nucleus accumbens and investigated the effect of CPZ in bilateral nucleus accumbens on persistent morphine conditioned place preference (mCPP) in rats. We also evaluated the side-effect of CPZ on activity by comparing cross-beam times between groups. We found that morphine conditioned place preference increased the TRPV1 expression and CPZ attenuated morphine conditioned place preference in a dose-dependent and target–specific manner after both short- and long-term spontaneous withdrawal, reflected by the reduction of the increased time in morphine-paired side. CPZ (10 nM) could induce prolonged and stable inhibition of morphine conditioned place preference expression. More importantly, CPZ did not cause dysfunction of activity in the subjects tested, which indicates the inhibitory effect was not obtained at the sacrifice of regular movement. Collectively, these results indicated that injection of TRPV1 antagonist in nucleus accumbens is capable of attenuating persistent morphine conditioned place preference without affecting normal activity. Thus, TRPV1 antagonist is one of the promising therapeutic drugs for the treatment of opioid addiction.
PMCID: PMC4131889  PMID: 25118895

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