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1.  Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells 
Cell Death & Disease  2014;5(5):e1231-.
Lymphangioleiomyomatosis (LAM) is a female-predominant interstitial lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 activation. The gender specificity of LAM suggests that estradiol contributes to disease development, yet the underlying pathogenic mechanisms are not completely understood. Using metabolomic profiling, we identified an estradiol-enhanced pentose phosphate pathway signature in Tsc2-deficient cells. Estradiol increased levels of cellular NADPH, decreased levels of reactive oxygen species, and enhanced cell survival under oxidative stress. Mechanistically, estradiol reactivated Akt in TSC2-deficient cells in vitro and in vivo, induced membrane translocation of glucose transporters (GLUT1 or GLUT4), and increased glucose uptake in an Akt-dependent manner. 18F-FDG-PET imaging demonstrated enhanced glucose uptake in xenograft tumors of Tsc2-deficient cells from estradiol-treated mice. Expression array study identified estradiol-enhanced transcript levels of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. Consistent with this, G6PD was abundant in xenograft tumors and lung metastatic lesions of Tsc2-deficient cells from estradiol-treated mice. Molecular depletion of G6PD attenuated estradiol-enhanced survival in vitro, and treatment with 6-aminonicotinamide, a competitive inhibitor of G6PD, reduced lung colonization of Tsc2-deficient cells. Collectively, these data indicate that estradiol promotes glucose metabolism in mTORC1 hyperactive cells through the pentose phosphate pathway via Akt reactivation and G6PD upregulation, thereby enhancing cell survival under oxidative stress. Interestingly, a strong correlation between estrogen exposure and G6PD was also found in breast cancer cells. Targeting the pentose phosphate pathway may have therapeutic benefit for LAM and possibly other hormonally dependent neoplasms.
doi:10.1038/cddis.2014.204
PMCID: PMC4047866  PMID: 24832603
tuberin; Akt; pentose phosphate pathway; glucose transporters; glucose uptake; 6-aminonicotinamide
2.  The histone deacetylase SIRT2 stabilizes Myc oncoproteins 
Cell Death and Differentiation  2012;20(3):503-514.
Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin–proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin–protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.
doi:10.1038/cdd.2012.147
PMCID: PMC3569991  PMID: 23175188
neuroblastoma; pancreatic cancer; N-Myc; histone deacetylase; SIRT2; NEDD4
3.  Peri-Procedural Morbidity and Mortality Associated with Stent-Assisted Coiling for Intracranial Aneurysms 
Interventional Neuroradiology  2013;19(1):43-48.
Summary
Despite experience and technological improvements, stent-assisted coiling for intracranial aneurysms still has inherent risks. We evaluated peri-procedural morbidity and mortality associated with stent-assisted coiling for intracranial aneurysms.
Patients with cerebral aneurysms that were broad-based (>4 mm) or had unfavorable dome/neck ratios (<1.5) were enrolled in this study between February and November 2011 at our center. Aneurysms were treated with the self-expanding neurovascular stents with adjunctive coil embolization.
Seventy-two consecutive patients (27 men and 45 women; 22-78 years of age; mean age, 52.8 years) underwent 13 procedures for 13 ruptured aneurysms and 64 procedures for 73 unruptured aneurysms. Nine [11.7%, 95%CI(4.5%-18.9%)] procedure-related complications occurred: one and eight with initial embolization of ruptured and unruptured aneurysms, respectively. Complications included six acute in-stent thromboses, one spontaneous stent migration, one post-procedural aneurysm rupture, and one perforator occlusion. Three complications had no neurologic consequences. Two caused transient neurologic morbidity, two persistent neurologic morbidity, and two death. Procedure-related neurologic morbidity and mortality rates, respectively, were as follows: overall, 5.2% (95%CI, 0.2%-10.2%) and 2.6% (95%CI, 0%-6.2%); ruptured aneurysms, 7.7% (95%CI, 0%-36%) and 0%(95%CI, 0%-25%); unruptured aneurysms, 4.7% (95%CI, 0%-9.9%) and 3.1% (95%CI, 0%-7.3%). Combined procedure-related morbidity and mortality rates for ruptured and unruptured aneurysms were 7.7% (95%CI, 1.7%-13.7%) and 7.8% (95%CI, 1.8%-13.8%), respectively.
Stent-assisted coiling is an attractive option for intracranial aneurysms. However, stent-assisted coiling for unruptured aneurysms is controversial for its comparable risk to natural history.
PMCID: PMC3601616  PMID: 23472722
broad-based aneurysm, intracranial aneurysms, stent-assisted coiling, stents
4.  Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells 
Yang, D | Li, L | Liu, H | Wu, L | Luo, Z | Li, H | Zheng, S | Gao, H | Chu, Y | Sun, Y | Liu, J | Jia, L
Cell Death and Differentiation  2012;20(2):235-247.
Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.
doi:10.1038/cdd.2012.113
PMCID: PMC3554346  PMID: 22935614
ROC1; Cullin-RING ligase; autophagy; senescence; Deptor
5.  Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC 
Cancer gene therapy  2012;19(6):393-401.
The development of RNA interference-based cancer gene therapies has been delayed due to the lack of effective tumor-targeting delivery systems. Attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) has a natural tropism for solid tumors. We report here the use of attenuated S. Typhimurium as a vector to deliver shRNA directly into tumor cells. Constitutively activated signal transducer and activator of transcription 3 (Stat3) is a key transcription factor involved in both hepatocellular carcinoma (HCC) growth and metastasis. In this study, attenuated S. Typhimurium was capable of delivering shRNA-expressing vectors to the targeted cancer cells and inducing RNA interference in vivo. More importantly, a single oral dose of attenuated S. Typhimurium carrying shRNA-expressing vectors targeting Stat3 induced remarkably delayed and reduced HCC (in 70% of mice). Cancer in these cured mice did not recur over 2 years following treatment. These data demonstrated that RNA interference combined with Salmonella as a delivery system may offer a novel clinical approach for cancer gene therapy.
doi:10.1038/cgt.2012.12
PMCID: PMC3891655  PMID: 22555509
HCC; immune response; RNA interference; Stat3
6.  Gli1 inhibition suppressed cell growth and cell cycle progression and induced apoptosis as well as autophagy depending on ERK1/2 activity in human chondrosarcoma cells 
Sun, Y | Guo, W | Ren, T | Liang, W | Zhou, W | Lu, Q | Jiao, G | Yan, T
Cell Death & Disease  2014;5(1):e979-.
The transcription factor glioma-associated oncogene 1 (Gli1) has been recognized as a very important nuclear executor at the distal end of the Hedgehog (Hh) signal pathway, which has crucial roles in regulating many developmental processes, such as pattern formation, differentiation, proliferation, and apoptosis. Overexpression of patched 1 protein and Gli1 or constitutively active Indian Hedgehog (IHh)-parathyroid hormone-related protein signal pathway may lead to musculoskeletal tumorigenesis. However, for chondrosarcoma few studies have paid close attention to the IHh-Gli1 signal transduction cascade and more work needs to be carried out to fully elucidate Gli1 protein functions. Here we show that the IHh signal pathway was activated in chondrosarcoma, and knocking down the expression of Gli1 attenuated the disturbed IHh signal pathway, which not only suppressed cell proliferation and promoted G2/M cell cycle arrest but also enhanced cell apoptosis by downregulating Bcl-2 and Bcl-xl expression. Furthermore, Gli1 downregulation, not cyclopamine, induced autophagy by regulating mTOR phosphorylation, and inhibition of autophagy prevented Gli1 small interfering RNA-mediated cell death. We also demonstrated that extracellular signal-regulated kinase 1/2 activity may mediate these antiproliferative events induced by Gli1 inhibition. These results indicate that Gli1 inhibition could ultimately provide a promising new approach for chondrosarcoma treatment.
doi:10.1038/cddis.2013.497
PMCID: PMC4040663  PMID: 24384722
Gli1; cell cycle; apoptosis; autophagy; ERK1/2; chondrosarcoma
7.  Ghrelin receptor regulates HFCS-induced adipose inflammation and insulin resistance 
Nutrition & Diabetes  2013;3(12):e99-.
Background and Objectives:
High fructose corn syrup (HFCS) is the most commonly used sweetener in the United States. Some studies show that HFCS consumption correlates with obesity and insulin resistance, while other studies are in disagreement. Owing to conflicting and insufficient scientific evidence, the safety of HFCS consumption remains controversial.
Subjects/Methods:
We investigated the metabolic consequences of mice fed a (a) regular diet, (b) ‘Western' high-fat diet or (c) regular diet supplemented with 8% HFCS in drinking water (to mimic soft drinks) for 10 months. Adipose tissue macrophages (ATMs) have emerged as a major pathogenic factor for obesity and insulin resistance. ATMs consist of proinflammatory F4/80+CD11c+ macrophages and anti-inflammatory F4/80+CD11c− macrophages. In this study, we assessed the effects of HFCS on ATMs in intra-abdominal fat.
Results:
We found that HFCS feeding in mice induced more severe adipose inflammation and insulin resistance than even the higher-calorie-containing ‘Western' high-fat diet, and these HFCS-induced deleterious effects were independent of calorie intake or body fat content. We showed that similar to ‘Western' high-fat diet, HFCS triggered a robust increase of both proinflammatory ATMs and anti-inflammatory ATMs in intra-abdominal fat. Remarkably, however, the anti-inflammatory ATMs were much less abundant in HFCS-fed mice than in high-fat-fed mice. Furthermore, we showed that deletion of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) ameliorates HFCS-induced adipose inflammation and insulin resistance. HFCS-fed GHS-R-null mice exhibit decreased proinflammatory ATMs in intra-abdominal fat, reduced adipose inflammation and attenuated liver steatosis.
Conclusion:
Our studies demonstrate that HFCS has detrimental effects on metabolism, suggesting that dietary guidelines on HFCS consumption for Americans may need to be revisited. GHS-R deletion mitigates the effects of HFCS on adipose inflammation and insulin resistance, suggesting that GHS-R antagonists may represent a novel therapy for insulin resistance.
doi:10.1038/nutd.2013.41
PMCID: PMC3877431  PMID: 24366371
ghrelin receptor; HFCS; macrophages; inflammation; insulin resistance; liver steatosis
8.  Comparative evaluation of lymphatic vessels in primary versus recurrent pterygium 
Ling, S | Li, Q | Lin, H | Li, W | Wang, T | Ye, H | Yang, J | Jia, X | Sun, Y
Eye  2012;26(11):1451-1458.
Purpose
To compare lymphangiogenesis in primary versus recurrent pterygium.
Methods
Tissues from 88 excised primary and 34 recurrent pterygia were evaluated, and tissues from 7 nasal epibulbar conjunctivae segments were used as controls. The lymph-vascular area (LVA), lymph-microvascular density (LMD), and lymph-vascular luminal diameter (LVL) were examined and compared between the primary and recurrent pterygia. In addition, the expression of VEGF-A and VEGF-C in the primary and recurrent pterygia were determined by ELISA and real-time PCR. The relationships between the mRNA level and LVA, LMD, and LVL were clarified.
Results
Although there was no significant difference in quantification of LVL between primary and recurrent pterygia, the quantification of LVA and LMD in recurrent pterygia dramatically increased in comparison with primary pterygia (both P-values <0.01). Compared with primary pterygia, the VEGF-A and VEGF-C mRNA levels were up-regulated significantly in recurrent pterygia (both P-values <0.05). There was a significant relationship between VEGF-C mRNA and LVA, LMD, and LVL, while VEGF-A mRNA was only closely correlated with LMD in recurrent pterygia.
Conclusions
Lymphangiogenesis develops in recurrent pterygium, for which transient up-regulation of VEGF-C might be responsible.
doi:10.1038/eye.2012.194
PMCID: PMC3496107  PMID: 22975656
lymphangiogenesis; primary pterygium; recurrent pterygium
9.  Infrared evidence of a Slater metal-insulator transition in NaOsO3 
Scientific Reports  2013;3:2990.
The magnetically driven metal-insulator transition (MIT) was predicted by Slater in the fifties. Here a long-range antiferromagnetic (AF) order can open up a gap at the Brillouin electronic band boundary regardless of the Coulomb repulsion magnitude. However, while many low-dimensional organic conductors display evidence for an AF driven MIT, in three-dimensional (3D) systems the Slater MIT still remains elusive. We employ terahertz and infrared spectroscopy to investigate the MIT in the NaOsO3 3D antiferromagnet. From the optical conductivity analysis we find evidence for a continuous opening of the energy gap, whose temperature dependence can be well described in terms of a second order phase transition. The comparison between the experimental Drude spectral weight and the one calculated through Local Density Approximation (LDA) shows that electronic correlations play a limited role in the MIT. All the experimental evidence demonstrates that NaOsO3 is the first known 3D Slater insulator.
doi:10.1038/srep02990
PMCID: PMC3801134  PMID: 24141899
10.  Evaluation of dose reduction and image quality in chest CT using adaptive statistical iterative reconstruction with the same group of patients 
The British Journal of Radiology  2012;85(1018):e906-e911.
Objectives
The objective of this study was to compare the image quality and radiation dose of chest CT images reconstructed with a blend of adaptive statistical iterative reconstruction (ASIR) and filtered back-projection (FBP) with images generated using conventional FBP.
Methods
Patients with chest CT re-examinations were alternately assigned to two scanners with different reconstruction techniques. The study groups included noise index (NI) 11 with 30% ASIR (A30), NI 13 with 40% ASIR (A40), NI 15 with 50% ASIR (A50) and NI 17 with 60% ASIR (A60), sequentially changed every 2 months. The control images were obtained using FBP and NI 11. All acquisitions were performed with automatic dose modulation. Paired t-test and non-parameter test were applied to compare the difference.
Results
The radiation doses were significantly lower in the examinations that used ASIR (p<0.001). The mean dose reduction rate was 27.7%, 45.2%, 57.1% and 71.8% for Groups A30, A40, A50 and A60, respectively. The image quality of Groups A30–A50 was not inferior to that of the control examinations. The image noise of Group A60 was greater and subjective image quality was inferior to that of the control.
Conclusions
ASIR enabled the use of a higher NI with automatic dose modulation. With 50% ASIR and a NI of 15, the effective radiation dose was reduced by 57%, without compromising image quality.
doi:10.1259/bjr/66327067
PMCID: PMC3474005  PMID: 22595496
11.  Which should be the routine cross-sectional reconstruction mode in spectral CT imaging: monochromatic or polychromatic? 
The British Journal of Radiology  2012;85(1018):e887-e890.
Objective
To provide evidence for the selection of an optimal cross-sectional reconstruction mode in spectral CT imaging of the abdomen, we compared the monochromatic images with polychromatic images.
Methods
Three phase-enhanced CT scans of the abdomen were recorded using the spectral imaging technique on 100 patients. Images were reconstructed using two modes: polychromatic and 70 keV monochromatic. The following variables were then compared: contrast-to-noise ratio (CNR) of the liver, spleen, gallbladder, kidney and pancreas, and the noise. Paired t-tests were used to compare differences between the two sets of images. Three experienced doctors graded the quality of the images with a five-point scale. The image quality scores were compared with a non-parametric rank sum test.
Results
Compared with polychromatic images, the 70 keV monochromatic mode images yielded significantly greater tissue-to-fat CNR and lower noise (p<0.001 for all comparisons). The image quality of the 70 keV monochromatic mode showed significantly better results than the polychromatic mode (p<0.001).
Conclusions
In abdominal spectral CT imaging, 70 keV monochromatic mode reconstruction images were better than those reconstructed using the polychromatic mode. The monochromatic mode may become the routine reconstruction mode for cross-sectional images.
doi:10.1259/bjr/27844842
PMCID: PMC3474011  PMID: 22723512
12.  Recombinant human arginase induced caspase-dependent apoptosis and autophagy in non-Hodgkin's lymphoma cells 
Zeng, X | Li, Y | Fan, J | Zhao, H | Xian, Z | Sun, Y | Wang, Z | Wang, S | Zhang, G | Ju, D
Cell Death & Disease  2013;4(10):e840-.
Arginase, an arginine-degrading enzyme, has gained increased attention recently as a new experimental therapeutics for a variety of malignant solid cancers. In this study, we found that recombinant human arginase (rhArg) could induce remarkable growth inhibition, cell cycle arrest, and caspase-dependent apoptosis in Raji and Daudi non-Hodgkin's lymphoma (NHL) cells through arginine deprivation. Interestingly, rhArg-treatment resulted in the appearance of autophagosomes and upregulation of microtubule-associated protein light chain 3 II, indicating that rhArg induced autophagy in lymphoma cells. Further study suggested that mammalian target of rapamycin/S6k signaling pathway may be involved in rhArg-induced autophagy in NHL cells. Moreover, blocking autophagy using pharmacological inhibitors (3-methyladenine and chloroquine) or genetic approaches (small interfering RNA targeting autophagy-related gene 5 and Beclin-1) enhanced the cell killing effect of rhArg. These results demonstrated that rhArg has a potent anti-lymphoma activity, which could be improved by in combination with autophagic inhibitors, suggesting that rhArg, either alone or in combination with autophagic inhibitors, could be a potential novel therapeutics for the treatment of NHL.
doi:10.1038/cddis.2013.359
PMCID: PMC3824669  PMID: 24113174
autophagy; apoptosis; recombinant human arginase; non-Hodgkin's lymphoma
13.  Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group 
Journal of Clinical Oncology  2012;30(27):3361-3367.
Purpose
Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II.
Patients and Methods
Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m2 per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response.
Results
Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036).
Conclusion
Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.
doi:10.1200/JCO.2011.41.2395
PMCID: PMC3438233  PMID: 22915658
14.  Large-angular separation of particles induced by cascaded deflection angles in optical sorting 
Applied physics letters  2008;93(26):263901-363903.
A composite microlens array (MLA) with two cascaded guiding axes has been fabricated to achieve a large lateral separation of an object with different refractive indices or sizes. The MLA projects a composite pattern formed by its focal spots into a microchamber for optical sorting in a microscopic system. This approach enables passive, high power, efficient, and continuous microfluidic sorting without requiring complicated optical assembly. Separation of particles with different refractive indices to a lateral angle of 40° is experimentally demonstrated with moderate laser power.
doi:10.1063/1.3040697
PMCID: PMC3757087  PMID: 23997243
15.  The Effect of Tissue Culture on Suture Holding Strength and Degradation in Canine Tendon 
The purpose of this study was to assess tendon metabolism and suture pull-out strength after simple tendon suture in a tissue culture model. One hundred and twelve flexor digitorum profundus tendons from 28 dogs were cultured for 7, 14, or 21 days with or without a static tensile load. In both groups increased levels of matrix metalloproteinase (MMP) mRNA was noted. Suture pull-out strength did not decrease during tissue culture. While the presence of a static load had no effect on the pull-out strength, it did affect MMP mRNA expression. This tissue culture model could be useful in studying the effect of factors on the tendon-suture interface.
doi:10.1177/1753193409104564
PMCID: PMC3694784  PMID: 19587082
tissue culture; matrix metalloproteinases; tendon repair; suture strength
16.  Magnetoelectric coupling in the paramagnetic state of a metal-organic framework 
Scientific Reports  2013;3:2024.
Although the magnetoelectric effects - the mutual control of electric polarization by magnetic fields and magnetism by electric fields, have been intensively studied in a large number of inorganic compounds and heterostructures, they have been rarely observed in organic materials. Here we demonstrate magnetoelectric coupling in a metal-organic framework [(CH3)2NH2]Mn(HCOO)3 which exhibits an order-disorder type of ferroelectricity below 185 K. The magnetic susceptibility starts to deviate from the Curie-Weiss law at the paraelectric-ferroelectric transition temperature, suggesting an enhancement of short-range magnetic correlation in the ferroelectric state. Electron spin resonance study further confirms that the magnetic state indeed changes following the ferroelectric phase transition. Inversely, the ferroelectric polarization can be improved by applying high magnetic fields. We interpret the magnetoelectric coupling in the paramagnetic state in the metal-organic framework as a consequence of the magnetoelastic effect that modifies both the superexchange interaction and the hydrogen bonding.
doi:10.1038/srep02024
PMCID: PMC3685827  PMID: 23778158
17.  Aberrant Activation of the Intrarenal Renin-Angiotensin System in the Developing Kidneys of Type 2 Diabetic Rats 
We have previously reported that intrarenal angiotensin II (Ang II) levels are increased long before diabetes becomes apparent in obese Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of type 2 diabetes. In this study, we examined the changes in intrarenal renin-angiotensin system (RAS) activity in the developing kidneys of OLETF rats. Ang II contents and mRNA levels of RAS components were measured in male OLETF and control Long-Evans Tokushima (LETO) rats at postnatal days (PND) 1, 5, and 15, and at 4–30 weeks of age. In both LETO and OLETF rats, kidney Ang II levels peaked at PND 1, then decreased during the pre- and post-weaning periods. However, Ang II levels and gene expression of RAS components, including angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), were not significantly different between LETO and OLETF rats. Intrarenal Ang II contents further decreased during puberty (from 7 to 11 weeks of age) in LETO rats, bur not in OLETF rats. At 11 weeks of age, kidney Ang II levels, urinary AGT excretion, and mRNA levels of AGT and renin were higher in OLETF rats than in LETO rats, while blood glucose levels were not significantly different between these groups of rats. These data indicate that continued intrarenal expression of Ang II during pubescence contributes to the increases in intrarenal Ang II levels in prediabetic OLETF rats, and is associated with increased intrarenal AGT and renin expression. Inappropriate activation of the intrarenal RAS in the prediabetic stage may facilitate the onset and development of diabetic nephropathy in later life.
doi:10.1055/s-0032-1331256
PMCID: PMC3655199  PMID: 23322513
angiotensin II; developing kidney; diabetes; angiotensinogen
18.  Analysis of 85Kr: a comparison at the 10-14 level using micro-liter samples 
Scientific Reports  2013;3:1596.
The isotopic abundance of 85Kr in the atmosphere, currently at the level of 10−11, has increased by orders of magnitude since the dawn of nuclear age. With a half-life of 10.76 years, 85Kr is of great interest as tracers for environmental samples such as air, groundwater and ice. Atom Trap Trace Analysis (ATTA) is an emerging method for the analysis of rare krypton isotopes at isotopic abundance levels as low as 10−14 using krypton gas samples of a few micro-liters. Both the reliability and reproducibility of the method are examined in the present study by an inter-comparison among different instruments. The 85Kr/Kr ratios of 12 samples, in the range of 10−13 to 10−10, are measured independently in three laboratories: a low-level counting laboratory in Bern, Switzerland, and two ATTA laboratories, one in Hefei, China, and another in Argonne, USA. The results are in agreement at the precision level of 5%.
doi:10.1038/srep01596
PMCID: PMC3615332  PMID: 23549244
19.  Semiautomatic Segmentation of Ventilated Airspaces in Healthy and Asthmatic Subjects Using Hyperpolarized 3He MRI 
A segmentation algorithm to isolate areas of ventilation from hyperpolarized helium-3 magnetic resonance imaging (HP 3He MRI) is described. The algorithm was tested with HP 3He MRI data from four healthy and six asthmatic subjects. Ventilated lung volume (VLV) measured using our semiautomated technique was compared to that obtained from manual outlining of ventilated lung regions and to standard spirometric measurements. VLVs from both approaches were highly correlated (R = 0.99; P < 0.0001) with a mean difference of 3.8 mL and 95% agreement indices of −30.8 mL and 38.4 mL. There was no significant difference between the VLVs obtained through the semiautomatic approach and the manual approach. A Dice coefficient which quantified the intersection of the two datasets was calculated and ranged from 0.95 to 0.97 with a mean of 0.96 ± 0.01 (mean ± SD). VLVs obtained through the semiautomatic algorithm were also highly correlated with measurements of forced expiratory volume in one second (FEV1) (R = 0.82; P = 0.0035) and forced vital capacity (FVC) (R = 0.95; P < 0.0001). The technique may open new pathways toward advancing more quantitative characterization of ventilation for routine clinical assessment for asthma severity as well as a number of other respiratory diseases.
doi:10.1155/2013/624683
PMCID: PMC3626384  PMID: 23606904
20.  Cell-surface galectin-3 confers resistance to TRAIL by impeding trafficking of death receptors in metastatic colon adenocarcinoma cells 
Cell Death and Differentiation  2011;19(3):523-533.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis and preferentially kills tumor cells by engaging specific glycosylated death receptors, resulting in the internalization of ligand/receptor complexes and recruitment of the initiator caspase-8 to an activation platform known as the death-inducing signaling complex (DISC). However, emergence of TRAIL-resistant sub-populations may contribute to therapeutic failure. To investigate resistance mechanisms, we isolated a stable TRAIL-resistant sub-population of the metastatic colon cancer cell line LS-LIM6, designated LIM6-TR. LIM6-TR cells are impaired in endocytosis of TRAIL/death receptors complexes and failed to recruit/activate caspase-8 to the DISC upon TRAIL stimulation. Differential activation of Wnt and JNK pathways is not responsible for acquisition of TRAIL resistance. LIM6-TR cells display a marked increase in cell-surface expression of galectin-3, an endogenous lectin, which co-localizes with and binds death receptors. Silencing of galectin-3 restores TRAIL sensitivity and promotes TRAIL-mediated endocytosis of TRAIL/death receptors complexes. Inhibitors of galectin-3 and glycosylation also re-sensitize LIM6-TR to TRAIL and restore internalization of ligand/receptors complexes. These studies identify a novel TRAIL-resistance mechanism in which galectin-3 impedes trafficking of death receptor by anchoring them in glycan nano-clusters, blocking the execution of the apoptosis signal.
doi:10.1038/cdd.2011.123
PMCID: PMC3246527  PMID: 21941373
galectin-3; TRAIL; apoptosis; colon cancer
21.  Temperature-Dependent Survival of Hepatitis A Virus during Storage of Contaminated Onions 
Applied and Environmental Microbiology  2012;78(14):4976-4983.
Pre- or postharvest contamination of green onions by hepatitis A virus (HAV) has been linked to large numbers of food-borne illnesses. Understanding HAV survival in onions would assist in projecting the risk of the disease associated with their consumption. This study defined HAV inactivation rates in contaminated green onions contained in air-permeable, moisture-retaining high-density polyethylene packages that were stored at 3, 10, 14, 20, 21, 22, and 23°C. A protocol was established to recover HAV from whole green onions, with 31% as the average recovery by infectivity assay. Viruses in eluates were primarily analyzed by a 6-well plaque assay on FRhK-4 cells. Eight storage trials, including two trials at 3°C, were conducted, with 3 to 7 onion samples per sampling and 4 to 7 samplings per trial. Linear regression correlation (r2 = 0.80 to 0.98) was observed between HAV survival and storage time for each of the 8 trials, held at specific temperatures. Increases in the storage temperature resulted in greater HAV inactivation rates, e.g., a reduction of 0.033 log PFU/day at 3.4 ± 0.3°C versus 0.185 log PFU/day at 23.4 ± 0.7°C. Thus, decimal reduction time (D) values of 30, 14, 11, and 5 days, respectively, were obtained for HAV in onions stored at 3, 10, 14, and 23°C. Further regression analysis determined that 1 degree Celsius increase would increase inactivation of HAV by 0.007 log PFU/day in onions (r2 = 0.97). The data suggest that natural degradation of HAV in contaminated fresh produce is minimal and that a preventive strategy is critical to produce safety. The results are useful in predicting the risks associated with HAV contamination in fresh produce.
doi:10.1128/AEM.00402-12
PMCID: PMC3416355  PMID: 22544253
22.  Endovascular Treatment of Paraclinoid Aneurysms 
Interventional Neuroradiology  2011;17(4):425-430.
Summary
The anatomical complexity of the paraclinoid region has made surgical treatment of intracranial ophthalmic segment aneurysms (OSAs) difficult. This study evaluated the safety and efficacy of endovascular treatment of paraclinoid aneurysms. We conducted a retrospective study of 28 patients with 30 aneurysms of the paraclinoid in whom treatment with endovascular techniques was attempted. Patient age, sex, presence of subarachnoid hemorrhage, aneurysm type, size of aneurismal sac and treatment modality were reviewed. Clinical evaluation and control angiography were performed between one and 43 months. Overall, complete occlusion was obtained in 26 aneurysms (86.6%), nearly complete (>90%) occlusion in two aneurysms (6.7%) and incomplete occlusion was observed in two aneurysms (6.7%). All endovascular techniques were successful. Procedure-related complications were observed in two patients (7.1%). Patients underwent follow-up for a mean of 14.8 months (range 1-43 months). Repeated coil treatment was performed in one patient. One patient died of massive brain infarction six days postoperatively and thus no follow-up data were available for this case. In 27 patients with follow-up studies, aneurysm closure was complete in 22 (81.5%) and incomplete in five (18.5%). Endovascular treatment is a safe and efficient alternative approach for paraclinoid aneurysms.
PMCID: PMC3296501  PMID: 22192545
aneurysm, embolization, internal carotid artery, paraclinoid
23.  Candidate Gene Association Study of Esophageal Squamous Cell Carcinoma in a High-Risk Region in Iran 
Cancer research  2009;69(20):7994-8000.
A region with a high risk for esophageal squamous cell carcinoma (ESCC) in northeast of Iran was identified more than three decades ago. Previous studies suggest that hereditary factors play a role in the high incidence of cancer in the region. Polymorphisms of several genes have been associated with susceptibility to esophageal cancer in various populations, but these have not been studied in Iran. We selected 22 functional variants (and 130 related tagSNPs) from 15 genes which previously have been suggested to be associated with an increased risk of ESCC. We genotyped a primary set of samples from 451 Turkmen (197 cases and 254 controls). Seven of 152 variants were associated with ESCC at the P = 0.05 level; these SNPs were then studied in a validation set of 1668 cases and controls (Turkmen and non-Turkmen) under dominant and recessive models. In the joint sample set, five variants, from five different genes, showed significant associations with ESCC at the P = 0.05 level. For one variant, in ADH1B, the association was strong and was present in both Turkmen and non-Turkmen. The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC under a recessive model (OR = 0.41, 95%, CI = 0.19 to 0.49; P = 4×10−4). For four additional variants, an association was present in the Turkmen subgroup, but the statistical significance of these was less compelling than for ADH1B. Two variants showed deleterious effects and two were protective. The G allele of the c.870A>G variant of CCND1 gene was associated with a 1.5-fold increased risk of ESCC under the recessive model (OR = 1.50, 95% CI = 1.14 to 2.16, P = 0.02) and the A allele of the rs1625895 variant of TP53 gene was associated with a 1.5-fold increased risk of ESCC under a dominant model (OR = 1.54, 95% CI = 1.21 to 4.07, P = 0.005). The C allele of the rs886205 variant of ALDH2 was associated with a decreased risk of ESCC under a recessive model (OR = 0.58, 95% CI = 0.34 to 0.87, P = 0.02) and the A allele of the rs7087131 variant of MGMT was associated with a decreased risk of ESCC under the recessive model (OR = 0.26, 95% CI = 0.05 to 0.49, P=0.01). These results confirm that genetic predisposition to ESCC plays a role in high incidence of this cancer among Turkmens who live in northeast of Iran.
doi:10.1158/0008-5472.CAN-09-1149
PMCID: PMC3505030  PMID: 19826048
Esophageal squamous cell carcinoma; Turkmen population; ADH1B; ALDH2; MGMT; TP53; CCND1

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