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1.  Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease 
Molecular Psychiatry  2014;20(2):252-262.
Amylin, a pancreatic peptide, and amyloid-beta peptides (Aβ), a major component of Alzheimer's disease (AD) brain, share similar β-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aβ in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aβ1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aβ in the serum, the magnitude of which is proportionate to the amount of Aβ in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aβ than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aβ1-42 as well as Aβ1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood–brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aβ from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aβ in blood. As naturally occurring amylin may play a role in regulating Aβ in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD.
PMCID: PMC4161670  PMID: 24614496
2.  A polymorphism in the DNA repair domain of APEX1 is associated with the radiation-induced pneumonitis risk among lung cancer patients after radiotherapy 
Li, H | Liu, G | Xia, L | Zhou, Q | Xiong, J | Xian, J | Du, M | Zhang, L | Liao, L | Su, X | Li, Z | Luo, Q | Cheng, Y | Zhang, T | Wang, D | Yang, Z-Z
The British Journal of Radiology  2014;87(1040):20140093.
To examine the association of tag single nucleotide polymorphisms (tagSNPs) (rs1130409, rs1760944, rs2307486 and rs3136817) in APEX1 with the risk of severe radiation-induced pneumonitis (RP) after radiotherapy among Han Chinese patients with lung cancer.
A total of 168 patients with lung cancer who were receiving radiotherapy were prospectively recruited. RP was evaluated according to the Radiation Therapy Oncology Group. A case–control study was performed. The case group included patients with RP grade of ≥3, while the control group comprised patients with RP grades <3. Four tagSNPs of APEX1 were genotyped in 126 patients with complete follow-up by multi-SNaPshot® (Genesky Biotechnologies Inc., Shanghai, China) genotyping assays. Results were assessed by a logistic regression model for RP risk and Mantal–Cox log-rank test for the cumulative RP probability by the genotypes.
rs1130409 was associated with severe RP. GT genotype of rs1130409 was significantly higher in patients with RP than in those of the control group [68.8% vs 41.8%; p = 0.025; resulting odds ratio (OR), 5.98]. Patients with lung cancer bearing the G allele had a 5.83-fold higher risk of RP than those with the wild TT genotype [OR = 5.83; 95% confidence interval (CI), 1.27–26.90; p = 0.024], and this was further confirmed by the binary regression adjusted by some confounding factors, including Karnofsky performance scale, concurrent chemotherapy–radiotherapy and lung volume receiving >30 Gy (OR = 6.96; 95% CI, 1.36–35.77; p = 0.02). rs1130409 was also associated with the time to occurrence of severe RP (p = 0.04). Three-dimensional model APEX1 protein showed that rs1130409 is located in the random coil structure corresponding to the DNA repair function region.
Advances in knowledge:
rs1130409 of APEX1 can be a predictor of RP grades ≥3 among patients with lung cancer.
PMCID: PMC4112388  PMID: 24884729
3.  Feasibility study on energy prediction of microwave ablation upon uterine adenomyosis and leiomyomas by MRI 
The British Journal of Radiology  2014;87(1040):20130770.
To evaluate the feasibility of energy prediction of percutaneous microwave ablation (PMWA) upon uterine leiomyomas and adenomyosis by MRI.
63 patients (49 patients with 49 uterine leiomyomas and 14 patients with adenomyosis) who underwent ultrasound-guided PMWA treatment were studied during the period from June 2011 to December 2012. Before PMWA, contrast-enhanced MRI (ceMRI) was performed for all of the patients. Based on the signal intensity (SI) of T2 weighted MRI, uterine leiomyomas were classified as hypointense, isointense and hyperintense. During ablation, the output energy of the microwave was set at 50 W, and T11a microwave antennas were used. ceMRI was performed within 7 days after PMWA treatment. Non-perfused volume and energy required per unit volume were analysed statistically.
When unit volume of lesions was ablated, uterine adenomyosis needed more energy than did uterine leiomyomas, and hyperintense uterine leiomyomas needed more energy than did hypointense pattern.
MRI SI of uterine leiomyomas and uterine adenomyosis can be used to predict PMWA energy.
Advances in knowledge:
The conclusions indicate that MRI SI can be used to perform pre-treatment planning, which will make the treatment more precise.
PMCID: PMC4112404  PMID: 24947033
4.  Similar blood-borne DNA methylation alterations in cancer and inflammatory diseases determined by subpopulation shifts in peripheral leukocytes 
Li, H | Zheng, T | Chen, B | Hong, G | Zhang, W | Shi, T | Li, S | Ao, L | Wang, C | Guo, Z
British Journal of Cancer  2014;111(3):525-531.
Although many DNA methylation (DNAm) alterations observed in peripheral whole blood/leukocytes and serum have been considered as potential diagnostic markers for cancer, their origin and their specificity for cancer (e.g., vs inflammatory diseases) remain unclear.
From publicly available datasets, we identified changes in the methylation of blood-borne DNA for multiple cancers and inflammatory diseases. We compared the identified changes with DNAm difference between myeloid and lymphoid cells extracted from two datasets.
At least 94.7% of the differentially methylated DNA loci (DM loci) observed in peripheral whole blood/leukocytes and serum of cancer patients overlapped with DM loci that distinguish between myeloid and lymphoid cells and >99.9% of the overlapped DM loci had consistent alteration states (hyper- or hypomethylation) in cancer samples compared to normal controls with those in myeloid cells compared to lymphoid cells (binomial test, P-value <2.2 × 10−16). Similar results were observed for DM loci in peripheral whole blood/leukocytes in patients with rheumatoid arthritis or inflammatory bowel diseases. The direct comparison between DM loci observed in the peripheral whole blood/leukocytes of patients with inflammatory diseases and DM loci observed in the peripheral whole blood of patients with cancer showed that DM loci detected from cancer and inflammatory diseases also had significantly consistent alteration states (binomial test, P-value <2.2 × 10−16).
DNAm changes observed in the peripheral whole blood/leukocytes and serum of cancer patients and in the peripheral whole blood/leukocytes of inflammatory disease patients are predominantly determined by the increase of myeloid cells and the decrease of lymphoid cells under the disease conditions, in the sense that their alteration states in disease samples compared to normal controls mainly reflect the DNAm difference between myeloid and lymphoid cells. These analyses highlight the importance of comparing cancer and inflammatory disease directly for the identification of cancer-specific diagnostic biomarkers.
PMCID: PMC4119994  PMID: 24960404
DNA methylation biomarker; myeloid cell; lymphoid cell; inflammatory disease
5.  Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial 
BMC Medicine  2015;13:162.
The use of adult stem cells is limited by the quality and quantity of host stem cells. It has been demonstrated that Wharton’s jelly–derived mesenchymal stem cells (WJMSCs), a primitive stromal population, could integrate into ischemic cardiac tissues and significantly improve heart function. In this randomized, controlled trial, our aim was to assess the safety and efficacy of intracoronary WJMSCs in patients with ST-elevation acute myocardial infarction (AMI).
In a multicenter trial, 116 patients with acute ST-elevation MI were randomly assigned to receive an intracoronary infusion of WJMSCs or placebo into the infarct artery at five to seven days after successful reperfusion therapy. The primary endpoint of safety: the incidence of adverse events (AEs) within 18 months, was monitored and quantified. The endpoint of efficacy: the absolute changes in myocardial viability and perfusion of the infarcted region from baseline to four months, global left ventricular ejection fraction (LVEF) from baseline to 18 months were measured using F-18-fluorodeoxyglucose positron emission computed tomography (F-18-FDG-PET) and 99mTc-sestamibi single-photon emission computed tomography (99mTc-SPECT), and two-dimensional echocardiography, respectively.
During 18 months follow-up, AEs rates and laboratory tests including tumor, immune, and hematologic indexes were not different between the two groups. The absolute increase in the myocardial viability (PET) and perfusion within the infarcted territory (SPECT) was significantly greater in the WJMSC group [6.9 ± 0.6 % (95 %CI, 5.7 to 8.2)] and [7.1 ± 0.8 % (95 %CI, 5.4 to 8.8) than in the placebo group [3.3 ± 0.7 % (95 %CI, 1.8 to 4.7), P <0.0001] and 3.9 ± 0.6(95 %CI, 2.8 to 5.0), P = 0.002] at four months. The absolute increase in the LVEF at 18 months in the WJMSC group was significantly greater than that in the placebo group [7.8 ± 0.9 (6.0 to approximately 9.7) vs. 2.8 ± 1.2 (0.4 to approximately 5.1), P = 0.001]. Concomitantly, the absolute decreases in LV end-systolic volumes and end-diastolic volumes at 18 months in the WJMSC group were significantly greater than those in the placebo group (P = 0.0004, P = 0.004, respectively).
Intracoronary infusion of WJMSCs is safe and effective in patients with AMI, providing clinically relevant therapy within a favorable time window. This study encourages additional clinical trials to determine whether WJMSCs may serve as a novel alternative to BMSCs for cardiac stem cell-based therapy.
Trial registration
Clinical Trials NCT01291329 (02/05/2011).
PMCID: PMC4499169  PMID: 26162993
Myocardial infarction; Mesenchymal stem cells; Wharton’s jelly of umbilical cord
Little is known about genes affecting childhood body weight.
To examine alleles of the mitochondrial uncoupling protein-2 (UCP2) gene for association with obesity, since UCP2 may influence energy expenditure.
We related UCP2 genotype to body composition, and to resting energy expenditure, in 105 children aged 6–10y. Overweight children and non-overweight children of overweight parents were genotyped for a 45 bp deletion/insertion (del/ins) in 3’ UTR of exon 8 and for an exon 4 C to T transition.
89 children were genotyped for the exon 8 allele: 50 children had del/del, 33 del/ins, and 6 ins/ins. Body mass index (BMI) was greater for del/ins (24.1 ± 5.9 kg/m2) than for del/del (20.4 ± 4.8 kg/m2, p<0.001). BMI of ins/ins (23.7 ± 7.8 kg/m2) was not different from del/ins. This effect was independent of race and gender (ANOVAs, p< 0.05). Body composition was also different according to UCP2 genotype. All body circumferences and skin fold thicknesses examined were significantly greater in del/ins than in del/del. DXA body fat mass (p<0.005) was also greater in del/ins than del/del. For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the three exon 4 genotypes. Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype.
The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight.
PMCID: PMC4495659  PMID: 10837279
Body Mass Index; Weight; Obesity; Polymorphism; Genetics
7.  Robust Logistic and Probit Methods for Binary and Multinomial Regression 
In this paper we introduce new robust estimators for the logistic and probit regressions for binary, multinomial, nominal and ordinal data and apply these models to estimate the parameters when outliers or inluential observations are present. Maximum likelihood estimates don't behave well when outliers or inluential observations are present. One remedy is to remove inluential observations from the data and then apply the maximum likelihood technique on the deleted data. Another approach is to employ a robust technique that can handle outliers and inluential observations without removing any observations from the data sets. The robustness of the method is tested using real and simulated data sets.
PMCID: PMC4464778  PMID: 26078914
8.  Mediterranean Diet and Depressive Symptoms Among Older Adults Over Time 
To examine whether adherence to a Mediterranean-based dietary pattern is predictive of depressive symptoms among older adults.
Generalized estimating equation models were used to test the association between a Mediterranean-based dietary pattern and depressive symptoms over time. Models were adjusted for age, sex, race, education, income, widowhood, antidepressant use, total calorie intake, body mass index, smoking, alcohol consumption, number of self-reported medical conditions, cognitive function, and physical disability.
Chicago, Illinois.
Community-dwelling participants (n=3502) of the Chicago Health and Aging Project aged 65+ years (59% African American) who had no evidence of depression at the baseline.
Adherence to a Mediterranean-based dietary pattern was assessed by the MedDietScore. Dietary evaluation was performed with a food frequency questionnaire at baseline and related to incident depression as measured by the presence of four or more depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale.
Over an average follow-up of 7.2 years, greater adherence to a Mediterranean-based diet was associated with a reduced number of newly occurring depressive symptoms (parameter estimate = -0.002, standard error = 0.001; p = 0.04). The annual rate of developing depressive symptoms was 98.6% lower among persons in the highest tertile of a Mediterranean-based dietary pattern compared with persons in the lowest tertile group.
Our results support the hypothesis that adherence to a diet comprised of vegetables, fruits, whole grains, fish, and legumes may protect against the development of depressive symptoms in older age.
PMCID: PMC4454450  PMID: 23636545
Diet; mediterranean dietary pattern; depressive symptoms; older adults
9.  Dual yolk-shell structure of carbon and silica-coated silicon for high-performance lithium-ion batteries 
Scientific Reports  2015;5:10908.
Silicon batteries have attracted much attention in recent years due to their high theoretical capacity, although a rapid capacity fade is normally observed, attributed mainly to volume expansion during lithiation. Here, we report for the first time successful synthesis of Si/void/SiO2/void/C nanostructures. The synthesis strategy only involves selective etching of SiO2 in Si/SiO2/C structures with hydrofluoric acid solution. Compared with reported results, such novel structures include a hard SiO2-coated layer, a conductive carbon-coated layer, and two internal void spaces. In the structures, the carbon can enhance conductivity, the SiO2 layer has mechanically strong qualities, and the two internal void spaces can confine and accommodate volume expansion of silicon during lithiation. Therefore, these specially designed dual yolk-shell structures exhibit a stable and high capacity of 956 mA h g−1 after 430 cycles with capacity retention of 83%, while the capacity of Si/C core-shell structures rapidly decreases in the first ten cycles under the same experimental conditions. The novel dual yolk-shell structures developed for Si can also be extended to other battery materials that undergo large volume changes.
PMCID: PMC4454089  PMID: 26039972
10.  Mitochondria-focused gene expression profile reveals common pathways and CPT1B dysregulation in both rodent stress model and human subjects with PTSD 
Translational Psychiatry  2015;5(6):e580-.
Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (P<0.007) and in the blood (P<0.01) of stressed rats compared with non-stressed controls. In human subjects with (n=28) or without PTSD (n=31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P=0.0027, false discovery rate (FDR)=0.043) and PPAR (P=0.006, FDR=0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.
PMCID: PMC4490278  PMID: 26080315
11.  Development of biodegradable Zn-1X binary alloys with nutrient alloying elements Mg, Ca and Sr 
Scientific Reports  2015;5:10719.
Biodegradable metals have attracted considerable attentions in recent years. Besides the early launched biodegradable Mg and Fe metals, Zn, an essential element with osteogenic potential of human body, is regarded and studied as a new kind of potential biodegradable metal quite recently. Unfortunately, pure Zn is soft, brittle and has low mechanical strength in the practice, which needs further improvement in order to meet the clinical requirements. On the other hand, the widely used industrial Zn-based alloys usually contain biotoxic elements (for instance, ZA series contain toxic Al elements up to 40 wt.%), which subsequently bring up biosafety concerns. In the present work, novel Zn-1X binary alloys, with the addition of nutrition elements Mg, Ca and Sr were designed (cast, rolled and extruded Zn-1Mg, Zn-1Ca and Zn-1Sr). Their microstructure and mechanical property, degradation and in vitro and in vivo biocompatibility were studied systematically. The results demonstrated that the Zn-1X (Mg, Ca and Sr) alloys have profoundly modified the mechanical properties and biocompatibility of pure Zn. Zn-1X (Mg, Ca and Sr) alloys showed great potential for use in a new generation of biodegradable implants, opening up a new avenue in the area of biodegradable metals.
PMCID: PMC4448657  PMID: 26023878
12.  Multipoint targeting of the PI3K/mTOR pathway in mesothelioma 
British Journal of Cancer  2014;110(10):2479-2488.
Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis.
Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations.
We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation.
These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.
PMCID: PMC4021537  PMID: 24762959
mesothelioma; tyrosine kinases; PI3K/AKT/mTOR; PI3K/AKT/MDM2
13.  X ray storage performance of KCl:Eu2+ with high cumulated dose 
The effects of high cumulative radiation dose on the luminescence properties of KCl:Eu2+ are investigated. Pellet samples of KCl:Eu2+ were given doses of up to 200 kGy at the Louisiana State University Synchrotron facility. After synchrotron irradiation, samples were optically bleached and given a clinical dose of 2 Gy from a 6 MV medical linear accelerator. Optical properties were evaluated using photostimulated luminescence (PSL), photoluminescence (PL), and temperature-dependent PSL measurements. For a cumulated dose of up to 5–10 kGy, the PSL emission intensity increased by 15% compared to the PSL signal with no radiation history. For doses higher than 10 kGy, the PSL emission intensity retained at least 70% of the original intensity. Spatial correlation of the charge storage centers increased for doses up to 5 kGy and then decreased for higher cumulative doses. Emission band at 975 nm was attributed to transitions of Eu1+. PL spectra showed an intense peak centered at 420 nm for all cumulative doses. The results of this work show that KCl:Eu2+ storage phosphors are excellent reusable materials for radiation therapy dosimetry.
PMCID: PMC4000036  PMID: 24778460
X-ray storage phosphors; KCl:Eu2+; Photostimulated luminescence; Radiation hardness; Spatial correlation
14.  Temperature dependence of the photostimulated luminescence in KCl:Eu2+ 
The goal of this work is to understand the physical mechanism behind the signal stabilization process in KCl:Eu2+, a storage phosphor material that has generated renewed interest due to its potential in radiation therapy dosimetry application. The temperature dependency of the photostimulated luminescence (PSL) spectra and intensity vs. time post x ray irradiation was measured. Commercial BaFBr:Eu2+ materials were included in this study for comparison. Unlike BaFBr:Eu2+, broadening of the F(Cl−) stimulation band and red-shift of the peak were observed for KCl:Eu2+ with increasing temperature. For irradiations at temperatures lower than 200 K, PSL intensity of KCl:Eu2+ showed recuperation behavior in the first 2 hrs post-irradiation and stayed almost constant with time thereafter. Moreover, spatially-correlated storage centers increased from 24% for irradiation at 50 K to 31% at 195 K and almost 100% at room temperature. The data suggest that certain types of charge storage-centers were mobile and contribute to the fast fading in PSL.
PMCID: PMC4000040  PMID: 24778461
storage phosphor; photostimulated luminescence; temporal stability
15.  Phase II study of concurrent selective lymph node late course accelerated hyper-fractionated radiotherapy and pemetrexed and cisplatin for locally advanced oesophageal squamous cell carcinoma 
Fu, C | Li, B | Guo, L | Li, H | Huang, W | Gong, H | Sun, M | Wang, Z | Zhou, T | Liu, C
The British Journal of Radiology  2014;87(1037):20130656.
To determine the clinical efficacy and toxicity of pemetrexed combined with low-dose cisplatin (CDDP) concurrent with late-course accelerated hyperfractionated (LCAF) intensity-modulated radiation therapy (IMRT) in patients with inoperable locally advanced oesophageal squamous cell carcinoma (ESCC).
Patients with locally advanced ESCC (less than or equal to 75 years of age, clinical stages IIB–IVA and Karnofsky performance status ≥70) were enrolled into the study. A target group size of 22 was projected based on the estimation that 2-year overall survival (OS) would increase from 20% to 40%. Patients were treated with pemetrexed, low-dose CDDP and LCAF IMRT concurrently. The main objective of the study was for a 2-year OS, and the secondary objectives were progression-free survival (PFS), objective response, locoregional failure rate, and acute and late toxicities.
25 patients were recruited from October 2008 to July 2011. The median OS was 21 months, with 2- and 5-year OS rates of 44% and 44%, respectively. The median PFS was 18.2 months. The objective response rate was 96% (24/25), with 11 complete responses and 13 partial responses. The locoregional failure rate was 16%. Grades 4 and 5 acute toxicity rates were 8% and 4%, respectively, while no Grade 3 or greater late toxicity was observed.
The findings of this Phase II study indicated that the therapeutic regimen appears to achieve an excellent response rate and favourable survival for locally advanced ESCC. However, the severe acute side effects should be considered cautiously in further studies.
Advances in knowledge:
To our knowledge, this is the first study that introduced pemetrexed and low-dose CDDP combined with LCAF IMRT to treat locally advanced ESCC. The 5-year OS rate was as high as 44%, which was more favourable than other studies.
PMCID: PMC4075529  PMID: 24666012
16.  Prevalence of hereditary angioedema in untested first-degree blood relatives of known subjects with hereditary angioedema 
Allergy and Asthma Proceedings  2015;36(3):206-212.
Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurring attacks of nonpruritic, nonpitting edema caused by an inherited deficiency or dysfunction of C1 esterase inhibitor (C1 INH). Symptoms can present years before an accurate diagnosis is made. The objective of this study, the Angioedema Clinical Epidemiology Testing Initiative for the Study of Hereditary Angioedema, was to determine the prevalence and clinical manifestations of HAE in untested first-degree blood relatives of known patients with HAE. Patients with a confirmed diagnosis of HAE recruited first-degree relatives who had not been evaluated for HAE. Enrolled subjects underwent complement testing (C4, C1 INH antigen, and functional C1 INH). If the lab tests were abnormal, the enrolled subjects returned to the site for a follow-up visit and questionnaire. Overall, 31 patients with HAE and 46 first-degree relatives enrolled in the study. Of 46 enrolled relatives, 30 (65%) had lab test results that ruled out a diagnosis of HAE, two (4%) were categorized as “HAE not ruled out,” and 14 (30%) were newly diagnosed with HAE. Of 14 newly diagnosed subjects, nine (64%) reported having experienced symptoms that may have been related to HAE, such as swelling in the throat, face, or extremities or abdominal pain. When reported, median age of symptom onset in these 14 subjects was nine years whereas newly diagnosed asymptomatic subjects had a median chronological age of six years. These 14 subjects reported a historic mean standard deviation rate of 2.51 (5.59) swelling episodes per month with a mean standard deviation duration of 1.6 (0.74) days. This study's findings reinforce the importance of testing family members of patients with HAE to detect this hereditary condition.
PMCID: PMC4405600  PMID: 25803135
First-degree relatives; C1 inhibitor antigen; C1 esterase deficiency; functional C1 inhibitor; questionnaire; epidemiology; diagnosis; hereditary angioedema
17.  Local-to-remote cortical connectivity in early- and adulthood-onset schizophrenia 
Translational Psychiatry  2015;5(5):e566-.
Schizophrenia is increasingly thought of as a brain network or connectome disorder and is associated with neurodevelopmental processes. Previous studies have suggested the important role of anatomical distance in developing a connectome with optimized performance regarding both the cost and efficiency of information processing. Distance-related disturbances during development have not been investigated in schizophrenia. To test the distance-related miswiring profiles of connectomes in schizophrenia, we acquired resting-state images from 20 adulthood-onset (AOS) and 26 early-onset schizophrenia (EOS) patients, as well as age-matched healthy controls. All patients were drug naive and had experienced their first psychotic episode. A novel threshold-free surface-based analytic framework was developed to examine local-to-remote functional connectivity profiles in both AOS and EOS patients. We observed consistent increases of local connectivity across both EOS and AOS patients in the right superior frontal gyrus, where the connectivity strength was correlated with a positive syndrome score in AOS patients. In contrast, EOS but not AOS patients exhibited reduced local connectivity within the right postcentral gyrus and the left middle occipital cortex. These regions' remote connectivity with their interhemispheric areas and brain network hubs was altered. Diagnosis–age interactions were detectable for both local and remote connectivity profiles. The functional covariance between local and remote homotopic connectivity was present in typically developing controls, but was absent in EOS patients. These findings suggest that a distance-dependent miswiring pattern may be one of the key neurodevelopmental features of the abnormal connectome organization in schizophrenia.
PMCID: PMC4471290  PMID: 25966366
18.  Two-dimensional high spatial-resolution dosimeter using europium doped potassium chloride: a feasibility study 
Physics in medicine and biology  2014;59(8):1899-1909.
Recent research has shown that KCl:Eu2+ has great potential for use in megavoltage radiation therapy dosimetry because this material exhibits excellent storage performance and is reusable due to strong radiation hardness. This work reports the authors’ attempts to fabricate 2D KCl:Eu2+ storage phosphor films (SPFs) using both a physical vapor deposition (PVD) method and a tape casting method. X ray diffraction analysis showed that a 10 µm thick PVD sample was composed of highly crystalline KCl. No additional phases were observed, suggesting that the europium activator had completed been incorporated into the KCl matrix. Photostimulated luminescence and photoluminescence spectra suggested that F (Cl-) centers were the electron storage centers post×ray irradiation and that Eu2+ cations acted as luminescence centers in the photostimulation process. The 150-µm thick casted KCl:Eu2+ SPF showed sub-millimeter spatial resolution. Monte Carlo simulations further demonstrated that the admixture of 20% KCl:Eu2+ and 80% low Z polymer binder exhibited almost no energy dependence in a 6 MV beam. KCl:Eu2+ pellet samples showed a large dynamic range from 0.01 cGy to 60 Gy dose-to-water, and saturated at approximately 500 Gy as a result of KCl’s intrinsic high radiation hardness. Taken together, this work provides strong evidence that KCl:Eu2+ based SPF with associated readout apparatus could result in a novel electronic film system that has all the desirable features associated with classic radiographic film and, importantly, water equivalence and the capability of permanent identification of each detector.
PMCID: PMC4019811  PMID: 24651448
radiation therapy dosimetry; dosimeter; storage phosphor
20.  Atomic interaction mechanism for designing the interface of W/Zr-based bulk metallic glass composites 
Scientific Reports  2015;5:8967.
The interaction between active element Zr and W damages the W fibers and the interface and decreases the mechanical properties, especially the tensile strength of the W fibers reinforced Zr-based bulk metallic glass composites (BMGCs). From the viewpoint of atomic interaction, the W-Zr interaction can be restrained by adding minor elements that have stronger interaction with W into the alloy. The calculation about atomic interaction energy indicates that Ta and Nb preferred to segregate on the W substrate surface. Sessile drop experiment proves the prediction and corresponding in-situ coating appears at the interface. Besides, the atomic interaction mechanism was proven to be effective in many other systems by the sessile drop technique. Considering the interfacial morphology, Nb was added into the alloy to fabricate W/Zr-based BMGCs. As expected, the Nb addition effectively suppressed the W-Zr reaction and damage to W fibers. Both the compressive and tensile properties are improved obviously.
PMCID: PMC4355671  PMID: 25758910
21.  Silibinin improves palmitate-induced insulin resistance in C2C12 myotubes by attenuating IRS-1/PI3K/Akt pathway inhibition 
The present study investigated the effect of silibinin, the principal potential anti-inflammatory flavonoid contained in silymarin, a mixture of flavonolignans extracted from Silybum marianum seeds, on palmitate-induced insulin resistance in C2C12 myotubes and its potential molecular mechanisms. Silibinin prevented the decrease of insulin-stimulated 2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) uptake and the downregulation of glutamate transporter type 4 (GLUT4) translocation in C2C12 myotubes induced by palmitate. Meanwhile, silibinin suppressed the palmitate-induced decrease of insulin-stimulated Akt Ser473 phosphorylation, which was reversed by wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K). We also found that palmitate downregulated insulin-stimulated Tyr632 phosphorylation of insulin receptor substrate 1 (IRS-1) and up-regulated IRS-1 Ser307 phosphorylation. These effects were rebalanced by silibinin. Considering several serine/threonine kinases reported to phosphorylate IRS-1 at Ser307, treatment with silibinin downregulated the phosphorylation of both c-Jun N-terminal kinase (JNK) and nuclear factor-κB kinase β (IKKβ), which was increased by palmitate in C2C12 myotubes mediating inflammatory status, whereas the phosphorylation of PKC-θ was not significantly modulated by silibinin. Collectively, the results indicated that silibinin prevented inhibition of the IRS-1/PI3K/Akt pathway, thus ameliorating palmitate-induced insulin resistance in C2C12 myotubes.
PMCID: PMC4445668  PMID: 25760026
Silibinin; Insulin resistance; Palmitate; C2C12
22.  Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer 
Wang, N | Zhan, T | Ke, T | Huang, X | Ke, D | Wang, Q | Li, H
British Journal of Cancer  2014;110(4):1034-1044.
The purpose of this study was to confirm that RRM2 as a novel target of HPVE7 involved in cervical cancer angiogenesis.
Gene expression was analysed by RT-qPCR, western blot and immunohistochemistry in cervical cancer tissue and cell lines. Luciferase reporter assay was used to determine the activities of various RRM2 promoters. Secreted VEGF was measured by ELISA. RRM2-mediated capillary tube formation induced by HPVE7 in cervical cancer cells were evaluated using human umbilical vein endothelial cells in vitro. ROS induced by RRM2 in cercal cancer cells was confirmed by flow cytometry. The growth of cervical cancer cell overexpression RRM2 was examined by nude mouse xenograft.
RRM2 as a novel downstream target for HPVE7 was upregulated by it at the transcriptional level through the E7-pRb interaction and binding of E2F to the RRM2 promoter region. Immunohistochemical analysis showed that the level of RRM2 positively correlated with the HPVE7 level in human cervical cancer. Functionally, overexpression of RRM2 enhanced the expression of HIF-1α and VEGF via activation of the ERK1/2 signalling pathway in cervical cancer cells, and significantly associated with increased microvessel densities in cervical cancer tissues. In vitro, HPVE7 stimulated RRM2-dependent capillary tube formation by HUVECs, and RRM2-enhanced angiogenesis was VEGF dependent. RRM2-activated ERK1/2 pathway was mediated through production of ROS. In the xenograft mouse model, overexpression of RRM2 in cervical cancer cells enhanced tumour growth as well as microvessel densities.
HPVE7 induces upregulation of RRM2, which then promotes cervical carcinogenesis via ROS-ERK1/2-HIF-1α-VEGF-induced angiogenesis. Thus, the inhibition of RRM2 activity may be a novel therapeutic strategy for human cervical cancer.
PMCID: PMC3929894  PMID: 24423925
RRM2; HPVE7; ROS; angiogenesis; ERK1/2
24.  Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo 
British Journal of Pharmacology  2014;171(3):663-675.
Background and Purpose
Osteoclasts play a pivotal role in diseases such as osteoporosis, rheumatoid arthritis and tumour bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. Here, we examined changes in osteoclastogenesis and LPS-induced osteolysis in response to andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata.
Experimental Approach
Effects of AP on osteoclast differentiation and bone resorption were measured in vitro. Western blots and RT-PCR techniques were used to examine the underlying molecular mechanisms. The bone protective activity of AP in vivo was assessed in a mouse model of osteolysis.
Key Results
AP concentration-dependently suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro and reduced the expression of osteoclast-specific markers, including tartrate-resistant acid phosphatase, calcitonin receptors and cathepsin K. Further molecular analysis revealed that AP impaired RANKL-induced NF-κB signalling by inhibiting the phosphorylation of TGF-β-activated kinase 1, suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the nuclear translocation of the NF-κB p65 subunit. AP also inhibited the ERK/MAPK signalling pathway without affecting p38 or JNK signalling.
Conclusions and Implications
AP suppressed RANKL-induced osteoclastogenesis through attenuating NF-κB and ERK/MAPK signalling pathways in vitro, thus preventing bone loss in vivo. These data indicated that AP is a promising natural compound for the treatment of osteoclast-related bone diseases.
PMCID: PMC3969079  PMID: 24125472
andrographolide; osteoclast; osteolysis; NF-κB; ERK
25.  An injectable acoustic transmitter for juvenile salmon 
Scientific Reports  2015;5:8111.
Salmon recovery and the potential detrimental effects of dams on fish have been attracting national attention due to the environmental and economic implications. In recent years acoustic telemetry has been the primary method for studying salmon passage. However, the size of the existing transmitters limits the minimum size of fish that can be studied, introducing a bias to the study results. We developed the first acoustic fish transmitter that can be implanted by injection instead of surgery. The new injectable transmitter lasts four times longer and weighs 30% less than other transmitters. Because the new transmitter costs significantly less to use and may substantially reduce adverse effects of implantation and tag burden, it will allow for study of migration behavior and survival of species and sizes of fish that have never been studied before. The new technology will lead to critical information needed for salmon recovery and the development of fish-friendly hydroelectric systems.
PMCID: PMC4309970  PMID: 25630763

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