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1.  Regional increases of cortical thickness in untreated, first-episode major depressive disorder 
Translational Psychiatry  2014;4(4):e378-.
The large majority of structural MRI studies of major depressive disorder (MDD) investigated volumetric changes in chronic medicated patients in whom course of illness and treatment effects may impact anatomic measurements. Further, in few studies, separate measurements of cortical thickness and surface area have been performed that reflect different neurobiological processes regulated by different genetic mechanisms. In the present study, we investigated both cortical thickness and surface area in first-episode, treatment-naïve, mid-life MDD to elucidate the core pathophysiology of this disease and its early impact on the brain. We observed increased cortical thickness in the right hemisphere, including medial orbitofrontal gyrus, pars opercularis, rostral middle frontal gyrus and supramarginal gyrus. Increased thickness of rostral middle frontal gyrus was negatively related with depression severity on the Hamilton Depression Rating Scale. Furthermore, MDD patients showed significantly increased associations in cortical thickness measurements among areas where increased cortical thickness was observed. Analysis of pial area revealed a trend toward increased surface area in the left parahippocampal gyrus in MDD. To permit comparison of our data with those of previous gray matter volume studies, voxel-based morphometry was performed. That analysis revealed significantly increased gray matter volume in left paracentral lobule, left superior frontal gyrus, bilateral cuneus and thalamus which form limbic-cortico–striato–pallido–thalamic loops. These changes in first-episode, treatment-naïve, mid-life MDD patients may reflect an active illness-related cortical change close to illness onset, and thus potentially provide important new insight into the early neurobiology of the disorder.
doi:10.1038/tp.2014.18
PMCID: PMC4012282  PMID: 24713859
3.  Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases 
Using a comprehensive set of discovery and optimization tools, antibodies were produced with the ability to neutralize SARS coronavirus (SARS-CoV) infection in Vero E6 cells and in animal models. These anti-SARS antibodies were discovered using a novel DNA display method, which can identify new antibodies within days. Once neutralizing antibodies were identified, a comprehensive and effective means of converting the mouse sequences to human frameworks was accomplished using HuFR™ (human framework reassembly) technology. The best variant (61G4) from this screen showed a 3.5–4-fold improvement in neutralization of SARS-CoV infection in vitro. Finally, using a complete site-saturation mutagenesis methodology focused on the CDR (complementarity determining regions), a single point mutation (51E7) was identified that improved the 80% plaque reduction neutralization of the virus by greater than 8-fold. These discovery and evolution strategies can be applied to any emerging pathogen or toxin where a causative agent is known.
doi:10.1093/protein/gzn027
PMCID: PMC2461042  PMID: 18480090
antibody discovery; humanized; optimized; SARS-CoV
4.  FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium 
Agarwal, D | Pineda, S | Michailidou, K | Herranz, J | Pita, G | Moreno, L T | Alonso, M R | Dennis, J | Wang, Q | Bolla, M K | Meyer, K B | Menéndez-Rodríguez, P | Hardisson, D | Mendiola, M | González-Neira, A | Lindblom, A | Margolin, S | Swerdlow, A | Ashworth, A | Orr, N | Jones, M | Matsuo, K | Ito, H | Iwata, H | Kondo, N | Hartman, M | Hui, M | Lim, W Y | T-C Iau, P | Sawyer, E | Tomlinson, I | Kerin, M | Miller, N | Kang, D | Choi, J-Y | Park, S K | Noh, D-Y | Hopper, J L | Schmidt, D F | Makalic, E | Southey, M C | Teo, S H | Yip, C H | Sivanandan, K | Tay, W-T | Brauch, H | Brüning, T | Hamann, U | Dunning, A M | Shah, M | Andrulis, I L | Knight, J A | Glendon, G | Tchatchou, S | Schmidt, M K | Broeks, A | Rosenberg, E H | van't Veer, L J | Fasching, P A | Renner, S P | Ekici, A B | Beckmann, M W | Shen, C-Y | Hsiung, C-N | Yu, J-C | Hou, M-F | Blot, W | Cai, Q | Wu, A H | Tseng, C-C | Van Den Berg, D | Stram, D O | Cox, A | Brock, I W | Reed, M W R | Muir, K | Lophatananon, A | Stewart-Brown, S | Siriwanarangsan, P | Zheng, W | Deming-Halverson, S | Shrubsole, M J | Long, J | Shu, X-O | Lu, W | Gao, Y-T | Zhang, B | Radice, P | Peterlongo, P | Manoukian, S | Mariette, F | Sangrajrang, S | McKay, J | Couch, F J | Toland, A E | Yannoukakos, D | Fletcher, O | Johnson, N | Silva, I dos Santos | Peto, J | Marme, F | Burwinkel, B | Guénel, P | Truong, T | Sanchez, M | Mulot, C | Bojesen, S E | Nordestgaard, B G | Flyer, H | Brenner, H | Dieffenbach, A K | Arndt, V | Stegmaier, C | Mannermaa, A | Kataja, V | Kosma, V-M | Hartikainen, J M | Lambrechts, D | Yesilyurt, B T | Floris, G | Leunen, K | Chang-Claude, J | Rudolph, A | Seibold, P | Flesch-Janys, D | Wang, X | Olson, J E | Vachon, C | Purrington, K | Giles, G G | Severi, G | Baglietto, L | Haiman, C A | Henderson, B E | Schumacher, F | Le Marchand, L | Simard, J | Dumont, M | Goldberg, M S | Labrèche, F | Winqvist, R | Pylkäs, K | Jukkola-Vuorinen, A | Grip, M | Devilee, P | Tollenaar, R A E M | Seynaeve, C | García-Closas, M | Chanock, S J | Lissowska, J | Figueroa, J D | Czene, K | Eriksson, M | Humphreys, K | Darabi, H | Hooning, M J | Kriege, M | Collée, J M | Tilanus-Linthorst, M | Li, J | Jakubowska, A | Lubinski, J | Jaworska-Bieniek, K | Durda, K | Nevanlinna, H | Muranen, T A | Aittomäki, K | Blomqvist, C | Bogdanova, N | Dörk, T | Hall, P | Chenevix-Trench, G | Easton, D F | Pharoah, P D P | Arias-Perez, J I | Zamora, P | Benítez, J | Milne, R L
British Journal of Cancer  2014;110(4):1088-1100.
Background:
Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.
Methods:
Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.
Results:
Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.
Conclusion:
Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
doi:10.1038/bjc.2013.769
PMCID: PMC3929867  PMID: 24548884
breast cancer; SNP; FGF receptors; susceptibility; disease subtypes
5.  The expression and function of midkine in the vertebrate retina 
British Journal of Pharmacology  2014;171(4):913-923.
The functional role of midkine during development, following injury and in disease has been studied in a variety of tissues. In this review, we summarize what is known about midkine in the vertebrate retina, focusing largely on recent studies utilizing the zebrafish (Danio rerio) as an animal model. Zebrafish are a valuable animal model for studying the retina, due to its very rapid development and amazing ability for functional neuronal regeneration following neuronal cell death. The zebrafish genome harbours two midkine paralogues, midkine-a (mdka) and midkine-b (mdkb), which, during development, are expressed in nested patterns among different cell types. mdka is expressed in the retinal progenitors and mdkb is expressed in newly post-mitotic cells. Interestingly, studies of loss-and gain-of-function in zebrafish larvae indicate that midkine-a regulates cell cycle kinetics. Moreover, both mdka and mdkb are expressed in different cell types in the normal adult zebrafish retina, but after light-induced death of photoreceptors, both are up-regulated and expressed in proliferating Müller glia and photoreceptor progenitors, suggesting an important and (perhaps) coincident role for these cytokines during stem cell-based neuronal regeneration. Based on its known role in other tissues and the expression and function of the midkine paralogues in the zebrafish retina, we propose that midkine has an important functional role both during development and regeneration in the retina. Further studies are needed to understand this role and the mechanisms that underlie it.
Linked Articles
This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4
doi:10.1111/bph.12495
PMCID: PMC3925030  PMID: 24460673
development; regeneration; zebrafish; mdka; mdkb; Müller glia; light-lesion; neurogenesis; id2a
6.  Distribution and clinical significance of tumour-associated macrophages in pancreatic ductal adenocarcinoma: a retrospective analysis in China 
Current Oncology  2015;22(1):e11-e19.
Background
We aimed to characterize the localization and prognostic significance of tumour-associated macrophages (tams) in pancreatic ductal adenocarcinoma (pdac).
Methods
Tumour specimens from 70 patients with pdac and inflammatory specimens from 13 patients with chronic pancreatitis were collected and analyzed for tam and M2 macrophage counts by immunohistochemistry. Correlations between tam distributions and clinicopathologic features were determined.
Results
Immunohistochemical analysis showed that tam and M2 macrophage counts were higher in tissues from pdac than from chronic pancreatitis. The tams and M2 macrophages both infiltrated more into peritumour. Both macrophage types were positively associated with lymph node metastasis (p = 0.041 for tams in peritumour, p = 0.013 for M2 macrophages in introtumour, p = 0.006 for M2 macrophage in peritumour). In addition, abdominal pain was significantly more frequent in pdac patients with a greater tams count. The survival rate was much lower in patients having high infiltration by M2 macrophages than in those having low infiltration.
Conclusions
The tam count might be associated with neural invasion in pdac, and M2 macrophages might play an important role in lymph node metastasis. Higher counts of either macrophage type were associated with increased risk of lymph node metastasis, and the M2 macrophage count could potentially be a marker for evaluating prognosis.
doi:10.3747/co.22.2150
PMCID: PMC4324348
Pancreatic cancer; tumour-associated macrophages; lymph node metastasis; neural invasion
7.  An anti-leishmanial thiadiazine agent induces multiple myeloma cell apoptosis by suppressing the nuclear factor kappaB signalling pathway 
Chen, G | Han, K | Xu, X | Du, X | Zhang, Z | Tang, J | Shi, M | Wang, M | Li, J | Cao, B | Mao, X
British Journal of Cancer  2013;110(1):63-70.
Background:
Nuclear factor κB (NFκB) has a critical role in the pathophysiology of multiple myeloma. Targeting NFκB is an important strategy for anti-myeloma drug discovery.
Methods:
Luciferase assay was used to evaluate the effects of DETT on NFκB activity. Annexin V–PI double staining and immunoblotting were used to evaluate DETT-induced cell apoptosis and suppression of NFκB signalling. Anti-myeloma activity was studied in nude mice.
Results:
DETT downregulated IKKα, β, p65, and p50 expression and inhibited phosphorylation of p65 (Ser536) and IκBα. Simultaneously, DETT increased IκBα, an inhibitor of the p65/p50 heterodimer, even in the presence of stimulants lipopolysaccharide, tumour necrosis factor-α, or interleukin-6. DETT inhibited NFκB transcription activity and downregulated NFκB-targeted genes, including Bcl-2, Bcl-XL, and XIAP as measured by their protein expression. Deregulation of NFκB signalling by DETT resulted in MM cell apoptosis characterised by cleavage of caspase-3, caspase-8, and PARP. Notably, this apoptosis was partly blocked by the activation of NFκB signalling in the presence of TNFα and IL-6. Moreover, DETT delayed myeloma tumour growth in nude mice without overt toxicity.
Conclusion:
DETT displays a promising potential for MM therapy as an inhibitor of the NFκB signalling pathway.
doi:10.1038/bjc.2013.711
PMCID: PMC3887303  PMID: 24231956
3,5-diethyl-1,3,5-thiadiazinane-2-thione (DETT); NFκB; multiple myeloma; apoptosis
8.  Novel Gene Variants Predict Serum Levels of the Cytokines IL-18 and IL-1ra in Older Adults 
Cytokine  2013;65(1):10-16.
Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P = 1.9×10−32) and in the IL1 gene family region of chromosome 2 for IL-1ra (rs6743376, P = 2.3×10−26). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P = 2.7×10−19). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.
doi:10.1016/j.cyto.2013.10.002
PMCID: PMC4060632  PMID: 24182552
chronic inflammation; genome-wide association studies; older adults
9.  Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation 
Liu, T | Zhang, B | Jin, X | Wang, W | Lee, J | Li, J | Yuan, H | Cheng, X
Eye  2013;28(1):26-33.
Purpose
To describe the characteristic ophthalmic phenotypes of a large Chinese family with familial amyloid polyneuropathy due to a missense mutation in transthyretin (TTR) (c.307 C>G).
Methods
Twenty-seven individuals (12 affected, 15 unaffected) from a five-generation Chinese family underwent general medical examination and comprehensive ophthalmic examination, including best correct visual acuity, intraocular pressure measurements, Schirmer test, slitlamp examination, fundoscopy, and ocular ultrasonography. Histological examination of vitreous biopsies using Congo red staining and immunohistochemistry was performed. Cardiovascular magnetic resonance (CMR), electrocardiogram, and echocardiogram were used to evaluate cardiac amyloidosis. Electromyography was used to evaluate nerve function. All four exons of TTR were amplified by PCR, sequenced using a Bigdye terminator v3.1 cycle sequencing kit and analyzed on an ABI 3700XL Genetic Analyzer.
Results
All 12 affected individuals in the family had ocular manifestations, including severe vitreous opacities, secondary glaucoma, xerophthalmia, dyscoria, and attenuated retinal arteries. Congo red staining demonstrated amyloid deposits in the vitreous, and immunohistochemical staining confirmed the deposition of TTR proteins in the vitreous. Twelve individuals had polyneuropathy, and electromyography detected functional damage in peripheral nerves. One individual was diagnosed with cardiac amyloidosis by CMR. Direct sequencing revealed the heterozygous missense mutation in TTR (c.307 C>G p.Gly83Arg) in all 12 affected individuals. The mutation co-segregated with the disease phenotype and was absent in 100 normal controls.
Conclusions
Vitreous opacity is very common in patients with the TTR Gly83Arg mutation; other clinical characteristics associated with the mutation include polyneuropathy and cardiac amyloidosis.
doi:10.1038/eye.2013.217
PMCID: PMC3890754  PMID: 24113303
familial amyloid polyneuropathy; transthyretin; mutation; Gly83Arg; vitreous; Chinese
10.  CeO2 nanocubes-graphene oxide as durable and highly active catalyst support for proton exchange membrane fuel cell 
Scientific Reports  2014;4:7415.
Rapid degradation of cell performance still remains a significant challenge for proton exchange membrane fuel cell (PEMFC). In this work, we develop novel CeO2 nanocubes-graphene oxide nanocomposites as durable and highly active catalyst support for proton exchange membrane fuel cell. We show that the use of CeO2 as the radical scavenger in the catalysts remarkably improves the durability of the catalyst. The catalytic activity retention of Pt-graphene oxide-8 wt.% CeO2 nanocomposites reaches as high as 69% after 5000 CV-cycles at a high voltage range of 0.8–1.23 V, in contrast to 19% for that of the Pt-graphene oxide composites. The excellent durability of the Pt-CeO2 nanocubes-graphene oxide catalyst is attributed to the free radical scavenging activity of CeO2, which significantly slows down the chemical degradation of Nafion binder in catalytic layers, and then alleviates the decay of Pt catalysts, resulting in the excellent cycle life of Pt-CeO2-graphene oxide nanocomposite catalysts. Additionally, the performance of single cell assembled with Nafion 211 membrane and Pt-CeO2-graphene oxide catalysts with different CeO2 contents in the cathode as well as the Pt-C catalysts in the anode are also recorded and discussed in this study.
doi:10.1038/srep07415
PMCID: PMC4261163  PMID: 25491655
11.  Infected hematopoietic stem cells and with integrated HBV DNA generate defective T cells in chronic HBV infection patients 
Shi, Y | Lan, Y | Cao, F | Teng, Y | Li, L | Wang, F | Li, J | Zhou, J | Li, Y
Journal of Viral Hepatitis  2014;21(7):e39-e47.
A weak T-cell response plays a key role in the persistence of hepatitis B virus (HBV) infection. We aimed to confirm that T-cell defects in patients with chronic HBV infection are associated with HBV DNA infection of bone marrow (BM) hematopoietic stem cells (HSCs). Using reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH), we observed the transcription of HBsAg coding genes and confirmed the integration of HBV DNA in CD34+ BM HSCs from chronic HBV infection patients. T cells were generated by coculturing the HSCs with delta-like ligand 1-expressing OP9 (OP9-DL1) cells. The phenotypes of the T cells were then evaluated by flow cytometric (FACS) analysis on days 14 and 25. The results demonstrated that fewer CD3+TCRaβ+ CD3+CD4+ and CD4+CD8+ T cells were generated from the HSCs of the patients than from the healthy controls, (P < 0.01) but the frequency of CD3+D8+ T cells was not significantly different between the two group (P > 0.05). In contrast, CD4+CD25+ T cells were more in the patient group than in healthy controls (P < 0.01) on both days 14 and 25. There were fewer CD3+CD4+/CD3+CD8+ cells in the patient group than in the healthy control group on day 25 (P < 0.05). Less proliferation and lower levels of IL-2 and IFN- γ were also observed in the patient group compared with the control group (P < 0.05).These data suggest that HBV DNA infected and integrated into the BM HSCs from patients with chronic HBV infection and that these BM HSCs generated defective T cells.
doi:10.1111/jvh.12236
PMCID: PMC4237112  PMID: 24620791
HBV DNA; HSCs; integration; replication; T-cell defects
12.  Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity 
Cancer research  2013;73(22):10.1158/0008-5472.CAN-13-1346.
The taccalonolides are highly acetylated steroids that stabilize cellular microtubules and overcome multiple mechanisms of taxane resistance. Recently, two potent taccalonolides, AF and AJ, were identified that bind tubulin directly and enhance microtubule polymerization. Extensive studies were conducted to characterize these new taccalonolides. AF and AJ caused aberrant mitotic spindles and bundling of interphase microtubules that differed from the effects of either paclitaxel or laulimalide. AJ also distinctly affected microtubule polymerization in that it enhanced the rate and extent of polymerization in the absence of any noticeable effect on microtubule nucleation. Additionally, the resulting microtubules were found to be profoundly cold stable. These data, along with studies showing synergistic antiproliferative effects between AJ and either paclitaxel or laulimalide, suggest a distinct binding site. Direct binding studies demonstrated that AJ could not be displaced from microtubules by paclitaxel, laulimalide or denaturing conditions, suggesting irreversible binding of AJ to microtubules. Mass spectrometry confirmed a covalent interaction of AJ with a peptide of β-tubulin containing the cyclostreptin binding sites. Importantly, AJ imparts strong inter-protofilament stability in a manner different from other microtubule stabilizers that covalently bind tubulin, consistent with the distinct effects of the taccalonolides as compared to other stabilizers. AF was found to be a potent and effective antitumor agent that caused tumor regression in the MDA-MB-231 breast cancer xenograft model. The antitumor efficacy of some taccalonolides, which stabilize microtubules in a manner different from other microtubule stabilizers, provides the impetus to explore the therapeutic potential of this site.
doi:10.1158/0008-5472.CAN-13-1346
PMCID: PMC3839246  PMID: 24048820
taccalonolide; microtubule; paclitaxel; microtubule stabilizer; tubulin
13.  Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients 
British Journal of Cancer  2013;109(10):2629-2635.
Background:
Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined.
Methods:
Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with those of peripheral blood Treg.
Results:
The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3+CD25hi Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3+ Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3+CD4+ Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg.
Conclusion:
These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ.
doi:10.1038/bjc.2013.645
PMCID: PMC3833228  PMID: 24169351
regulatory T cells; checkpoint receptors; tumour-infiltrating lymphocytes; head and neck cancer
14.  Optical properties of quantum-dot-doped liquid scintillators 
Semiconductor nanoparticles (quantum dots) were studied in the context of liquid scintillator development for upcoming neutrino experiments. The unique optical and chemical properties of quantum dots are particularly promising for the use in neutrinoless double-beta decay experiments. Liquid scintillators for large scale neutrino detectors have to meet specific requirements which are reviewed, highlighting the peculiarities of quantum-dot-doping. In this paper, we report results on laboratory-scale measurements of the attenuation length and the fluorescence properties of three commercial quantum dot samples. The results include absorbance and emission stability measurements, improvement in transparency due to filtering of the quantum dot samples, precipitation tests to isolate the quantum dots from solution and energy transfer studies with quantum dots and the fluorophore PPO.
doi:10.1088/1748-0221/8/10/P10015
PMCID: PMC4225632  PMID: 25392711
Scintillators, scintillation and light emission processes (solid, gas and liquid scintillators); Large detector systems for particle and astroparticle physics; Neutrino detectors
15.  mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells 
Leukemia  2013;27(10):2040-2046.
Hematopoietic stem/progenitor cells (HSPCs) function to give rise to mature blood cells. Effective DNA damage response (DDR) and maintenance of genomic stability are crucial for normal functioning of HSPCs. Mammalian target of rapamycin (mTOR) integrates signals from nutrients and growth factors to control protein synthesis, cell growth, survival and metabolism, and has been shown to regulate DDR in yeast and human cancer cells through the p53/p21 signaling cascade. Here, we show that gene targeting of mTOR in HSPCs causes a defective DDR due to a variety of DNA damage agents, mimicking that caused by deficient FANCD2, a key component of the Fanconi anemia (FA) DDR machinery. Mechanistically, mTOR −/− HSPCs express drastically reduced FANCD2. Consistent with these genetic findings, inactivation of mTOR in human lymphoblast cells by pp242 or Torin 1, mTOR kinase inhibitors, suppresses FANCD2 expression and causes a defective DDR that can be rescued by reconstitution of exogenous FANCD2. Further mechanistic studies show that mTOR deficiency or inactivation increases phosphorylation and nuclear translocation of nuclear factor (NF)-κB, which results in an enhanced NF-kB binding to FANCD2 promoter to suppress FANCD2 expression. Thus, mTOR regulates DDR and genomic stability in hematopoietic cells through a noncanonical pathway involving NF-κB-mediated FANCD2 expression.
doi:10.1038/leu.2013.93
PMCID: PMC4225699  PMID: 23538752
mTOR; FANCD2; NF-κB; DNA damage response; hematopoietic cells
16.  Role of hepcidin in murine brain iron metabolism 
Brain iron homeostasis is maintained by a balance of both iron uptake and release, and accumulating evidence has revealed that brain iron concentrations increase with aging. Hepcidin, an iron regulatory hormone produced by hepatocytes in response to inflammatory stimuli, iron, and hypoxia, has been shown to be the long-sought hormone responsible for the regulation of body iron balance and recycling in mammals. In this study, we report that hepcidin is widely expressed in the murine brain. In cerebral cortex, hippocampus and striatum, hepcidin mRNA levels increased with aging. Injection of hepcidin into the lateral cerebral ventricle resulted in decreased Fpn1 protein levels in cerebral cortex, hippocampus, and striatum. Additionally, treatment of primary cultured neurons with hepcidin caused decreased neuronal iron release and Fpn1 protein levels. Together, our data provide further evidence that hepcidin may be involved in the regulation of brain iron metabolism.
doi:10.1007/s00018-009-0167-3
PMCID: PMC4225129  PMID: 19898775
Hepcidin; Ferroportin1; Brain iron metabolism; Aging; Murine
17.  Uptake and Accumulation of Four PPCP/EDCs in Two Leafy Vegetables 
Many pharmaceutical and personal care products (PPCPs) and endocrine-disrupting chemicals (EDCs) are present in reclaimed water, leading to concerns of human health risks from the consumption of food crops irrigated with reclaimed water. This study evaluated the potential for plant uptake and accumulation of four commonly occurring PPCP/EDCs, i.e., bisphenol A (BPA), diclofenac sodium (DCL), naproxen (NPX), and 4-nonylphenol (NP), by lettuce (Lactuca sativa) and collards (Brassica oleracea) in hydroponic culture, using 14C-labeled compounds. In both plant species, plant accumulation followed the order of BPA > NP > DCL > NPX and accumulation in roots was much greater than in leaves and stems. Concentrations of 14C-PPCP/EDCs in plant tissues ranged from 0.22±0.03 to 927± 213 ng/g, but nearly all 14C-residue was non-extractable. PPCP/EDCs, particularly BPA and NP, were also extensively transformed in the nutrient solution. Dietary uptake of these PPCP/EDCs by humans was predicted to be negligible.
doi:10.1016/j.envpol.2013.06.038
PMCID: PMC3910503  PMID: 23911624
Reclaimed water; pharmaceuticals; endocrine disrupting chemicals; plant uptake; non-extractable residue
18.  The N-terminal region of p27 inhibits HIF-1α protein translation in ribosomal protein S6-dependent manner by regulating PHLPP-Ras-ERK-p90RSK axis 
Zhang, D | Liu, J | Mi, X | Liang, Y | Li, J | Huang, C
Cell Death & Disease  2014;5(11):e1535-.
P27 was identified as a tumor suppressor nearly two decades, being implicated in cell-cycle control, differentiation, senescence, apoptosis and motility. Our present study, for the first time to the best of our knowledge, revealed a potential role of p27 in inhibiting S6-mediated hypoxia-inducible factor-1α (HIF-1α) protein translation, which contributed to the protection from environmental carcinogen (sodium arsenite)-induced cell transformation. Our findings showed that depletion of p27 expression by knockout and knockdown approaches efficiently enhanced S6 phosphorylation in arsenite response via overactivating Ras/Raf/MEK/ERK pathway, which consequently resulted in the stimulation of p90RSK (90 kDa ribosomal S6 kinase), a direct kinase for S6 phosphorylation. Although PI3K/AKT pathway was also involved in S6 activation, blocking AKT and p70S6K activation did not attenuate arsenite-induced S6 activation in p27−/− cells, suggesting p27 specifically targeted Ras/ERK pathway rather than PI3K/AKT pathway for inhibition of S6 activation in response to arsenite exposure. Further functional studies found that p27 had a negative role in cell transformation induced by chronic low-dose arsentie exposure. Mechanistic investigations showed that HIF-1α translation was upregulated in p27-deficient cells in an S6 phosphorylation-dependent manner and functioned as a driving force in arsenite-induced cell transformation. Knockdown of HIF-1α efficiently reversed arsenite-induced cell transformation in p27-depleted cells. Taken together, our findings provided strong evidence showing that by targeting Ras/ERK pathway, p27 provided a negative control over HIF-1α protein synthesis in an S6-dependent manner, and abrogated arsenite-induced cell transformation via downregulation of HIF-1α translation.
doi:10.1038/cddis.2014.496
PMCID: PMC4260754  PMID: 25412313
19.  Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia 
Investigational new drugs  2011;30(3):1107-1115.
Summary
Eg5 (kinesin spindle protein) is a microtubule motor protein, essential for centrosome separation during mitosis. This Phase I/II, open-label, multicenter, two-part study investigated AZD4877, a potent Eg5 inhibitor, in patients with acute myeloid leukemia. Primary objectives were to determine the maximum tolerated dose (MTD) (part A), assess efficacy (part B) and determine the pharmacokinetic profile (parts A and B). Secondary objectives included assessment of safety and tolerability. AZD4877 was administered at a range of doses (2, 4, 7, 10, 13, 16 and 18 mg/day) as a 1-hour intravenous infusion on three consecutive days of a continuous 2-week schedule. The MTD in part A was defined as 16 mg/day based on dose-limiting stomatitis at 16 and 18 mg/day, hyperbilirubinemia at 16 mg/day and palmar–plantar erythrodysesthesia syndrome at 18 mg/day. Systemic exposure to AZD4877 generally increased with increasing dose whereas half-life was not dose dependent. No evaluable patients experienced a complete remission (CR) or CR with incomplete blood count recovery (CRi), demonstrating no evidence of AZD4877 efficacy in this population. Evidence of monoasters in all but the 4 mg/day dose group provided proof of mechanism for AZD4877. This study was terminated due to lack of efficacy.
doi:10.1007/s10637-011-9660-2
PMCID: PMC4205950  PMID: 21494838
AML; Eg5 inhibitor; Phase I/II; Safety; MTD; Pharmacokinetics
20.  Propofol pretreatment attenuates lipopolysaccharide-induced acute lung injury in rats by activating the phosphoinositide-3-kinase/Akt pathway 
The aim of this study was to investigate the effect of propofol pretreatment on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway in this procedure. Survival was determined 48 h after LPS injection. At 1 h after LPS challenge, the lung wet- to dry-weight ratio was examined, and concentrations of protein, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method or ELISA. Lung injury was assayed via lung histological examination. PI3K and p-Akt expression levels in the lung tissue were determined by Western blotting. Propofol pretreatment prolonged survival, decreased the concentrations of protein, TNF-α, and IL-6 in BALF, attenuated ALI, and increased PI3K and p-Akt expression in the lung tissue of LPS-challenged rats, whereas treatment with wortmannin, a PI3K/Akt pathway specific inhibitor, blunted this effect. Our study indicates that propofol pretreatment attenuated LPS-induced ALI, partly by activation of the PI3K/Akt pathway.
doi:10.1590/1414-431X20143949
PMCID: PMC4244672  PMID: 25387673
Acute lung injury; Propofol; Lipopolysaccharide; PI3K/Akt pathway
21.  Multiplanar 3D ultrasound imaging to assess the anatomy of the upper airway and measure the subglottic and tracheal diameters in adults 
The British Journal of Radiology  2013;86(1030):20130253.
Objective:
To evaluate the feasibility of using three-dimensional (3D) ultrasound to assess the anatomy of the airway.
Methods:
11 young volunteers were recruited for 3D ultrasound and MRI of the airway. 3D ultrasound data were obtained from the level of the true vocal cords, cricoid cartilage and upper trachea. Multiplanar 3D ultrasound images were rendered and compared visually with corresponding MRI and cadaver anatomical sections. The anteroposterior (AP) and transverse diameter of the subglottic space and transverse diameter of the upper trachea were also measured in the 3D ultrasound and MR images and compared.
Results:
The airway anatomy was clearly delineated in the multiplanar 3D ultrasound images. It was also possible to identify the cricothyroid junction, and a simple method to measure the AP diameter of the subglottic space using this landmark is described. We were also able to accurately measure the transverse diameter of the upper trachea, but the transverse diameter of the subglottic space was overestimated using ultrasound. There was a strong correlation for the AP diameter measurement (r=0.94, p<0.05) and moderate correlation for the transverse diameter measurement (r=0.82, p=0.002) of the subglottic space, and a strong correlation for the transverse diameter measurement (r=0.91, p<0.05) of the upper trachea, in the ultrasound and MR images.
Conclusion:
The anatomy of the adult airway can be assessed using 3D ultrasound. It can also be used to accurately measure the AP diameter of the subglottic space and the transverse diameter of the upper trachea.
Advances in knowledge:
This is the first report to describe the use of 3D ultrasound to evaluate the anatomy of the upper airway and accurately measure the AP diameter of the subglottic space and the transverse diameter of the upper trachea.
doi:10.1259/bjr.20130253
PMCID: PMC3798330  PMID: 23966375
22.  Displacement of the lumpectomy cavity defined by surgical clips and seroma based on 4D-CT scan for external-beam partial breast irradiation after breast-conserving surgery: a comparative study 
Ding, Y | Li, J | Wang, W | Wang, S | Fan, T | Xu, M | Shao, Q | Ma, Z
The British Journal of Radiology  2013;86(1030):20130416.
Objective:
To compare the displacements of the lumpectomy cavity delineated by the surgical clips and the seroma based on four-dimensional CT (4D-CT) for external-beam partial breast irradiation (EB-PBI) after breast-conserving surgery (BCS).
Methods:
14 breast cancer patients after BCS were recruited for EB-PBI and undertook 4D-CT simulation. On the 10 sets of the 4D-CT images, all the surgical clips in the cavity were delineated. The gross tumour volume (GTV) formed by the clips, the seroma, and both the clips and the seroma were defined as GTVc, GTVs and GTVc+s, respectively. The displacements of the centre of mass (COM) of the clips, GTVc, GTVs, GTVc+s and the selected clips in the three-dimensional (3D) directions were recorded and compared.
Results:
In the left–right, anterior–posterior and superior–inferior directions, the displacements were 2.20, 1.80 and 2.70 mm for the clip COM; 0.90, 1.05 and 1.20 mm for GTVc; 0.80, 1.05 and 0.80 mm for GTVs; and 0.90, 1.20 and 1.40 mm for GTVc+s, respectively. In the 3D directions, the displacements of the clip COM were greater than the GTVc, GTVs, GTVc+s, and the displacements of the clip COM, GTVc+s, GTVc and GTVs were significantly greater than the displacements of the selected clips (p<0.05).
Conclusion:
The displacements of the clip COM were greater than that of the GTVc, GTVs, GTVc+s and the four selected clips. The optimal internal target volume should be defined based on the boundary displacements.
Advances in knowledge:
When the GTV was delineated using the clips and/or the seroma, there was displacement difference between the lumpectomy cavity centre and the boundary for the EB-PBI. The optimal internal target volume should be defined based on the boundary displacements of the lumpectomy cavity.
doi:10.1259/bjr.20130416
PMCID: PMC3798338  PMID: 23995875
23.  MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy 
Li, X | Du, N | Zhang, Q | Li, J | Chen, X | Liu, X | Hu, Y | Qin, W | Shen, N | Xu, C | Fang, Z | Wei, Y | Wang, R | Du, Z | Zhang, Y | Lu, Y
Cell Death & Disease  2014;5(10):e1479-.
Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which can result in cardiac hypertrophy and subsequent heart failure, associated with pyroptosis, the pro-inflammatory programmed cell death. MicroRNAs (miRNAs), small endogenous non-coding RNAs, have been shown to be involved in diabetic cardiomyopathy. However, whether miRNAs regulate pyroptosis in diabetic cardiomyopathy remains unknown. Our study revealed that mir-30d expression was substantially increased in streptozotocin (STZ)-induced diabetic rats and in high-glucose-treated cardiomyocytes as well. Upregulation of mir-30d promoted cardiomyocyte pyroptosis in diabetic cardiomyopathy; conversely, knockdown of mir-30d attenuated it. In an effort to understand the signaling mechanisms underlying the pro-pyroptotic property of mir-30d, we found that forced expression of mir-30d upregulated caspase-1 and pro-inflammatory cytokines IL-1β and IL-18. Moreover, mir-30d directly repressed foxo3a expression and its downstream protein, apoptosis repressor with caspase recruitment domain (ARC). Furthermore, silencing ARC by siRNA mimicked the action of mir-30d: upregulating caspase-1 and inducing pyroptosis. These findings promoted us to propose a new signaling pathway leading to cardiomyocyte pyroptosis under hyperglycemic conditions: mir-30d↑→foxo3a↓→ ARC↓→caspase-1↑→IL-1β, IL-18↑→pyroptosis↑. Therefore, mir-30d may be a promising therapeutic target for the management of diabetic cardiomyopathy.
doi:10.1038/cddis.2014.430
PMCID: PMC4237254  PMID: 25341033
24.  Therapeutic Hypothermia as a Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Brain Injury and Traumatic Brain Injury 
Current molecular medicine  2012;12(10):1282-1296.
Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated. Hypoxic-ischemic brain injury and traumatic brain injury both trigger a series of biochemical and molecular events that cause additional brain insult. Induction of therapeutic hypothermia seems to ameliorate the molecular cascade that culminates in neuronal damage. Hypothermia attenuates the toxicity produced by the initial injury that would normally produce reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis. Experiments have been performed on various depths and levels of hypothermia to explore neuroprotection. This review summarizes what is currently known about the beneficial effects of therapeutic hypothermia in experimental models of neonatal hypoxic-ischemic brain injury and traumatic brain injury, and explores the molecular mechanisms that could become the targets of novel therapies. In addition, this review summarizes the clinical implications of therapeutic hypothermia in newborn hypoxic-ischemic encephalopathy and adult traumatic brain injury.
PMCID: PMC4173077  PMID: 22834830
Apoptosis; hypothermia; hypoxic-ischemic encephalopathy; neonatal hypoxic-ischemic brain injury; neuroprotection; traumatic brain injury
25.  Genetic variants in the SOX6 gene are associated with bone mineral density in both Caucasian and Chinese populations 
Summary
Given the biological function of SOX6 and recent genome-wide association finding, we performed a fine-mapping association analyses to investigate the relationship between SOX6 and BMD both in Caucasian and Chinese populations. We identified many single-nucleotide polymorphisms (SNPs) within or near the SOX6 gene to be significantly associated with hip bone mineral density (BMD).
Introduction
SOX6 gene is an essential transcription factor in chondrogenesis and cartilage formation. Recent genome-wide association studies (GWAS) detected a SNP (rs7117858) located at the downstream of SOX6 significantly associated with hip BMD.
Methods
Given the biological function of SOX6 and the GWAS finding, we considered SOX6 as a new candidate for BMD and osteoporosis. Therefore, in this study, we performed a fine-mapping association analyses to investigate the relationship between SNPs within and near the SOX6 gene and BMD at both hip and spine. A total of 301 SNPs were tested in two independent US Caucasian populations (2,286 and 1,000 unrelated subjects, respectively) and a Chinese population (1,627 unrelated Han subjects).
Results
We confirmed that the previously reported rs7117858-A was associated with reduced hip BMD, with combined P value of 2.45×10−4. Besides this SNP, we identified another 19 SNPs within or near the SOX6 gene to be significantly associated with hip BMD after false discovery rate adjustment. The most significant SNP was rs1347677 located at the intron 3 (P=3.15×10−7). Seven additional SNPs in high linkage disequilibrium with rs1347677 were also significantly associated with hip BMD. SNPs in SOX6 showed significant skeletal site specificity since no SNP was detected to be associated with spine BMD.
Conclusion
Our study identified many SNPs in the SOX6 gene associated with hip BMD even across different ethnicities, which further highlighted the importance of the SOX6 gene influencing BMD variation and provided more information to the understanding of the genetic architecture of osteoporosis.
doi:10.1007/s00198-011-1626-x
PMCID: PMC4171834  PMID: 21625884
Association; BMD; Osteoporosis; SOX6

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