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1.  PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway 
Zhou, J | Wu, J | Li, B | Liu, D | Yu, J | Yan, X | Zheng, S | Wang, J | Zhang, L | Zhang, L | He, F | Li, Q | Chen, A | Zhang, Y | Zhao, X | Guan, Y | Zhao, X | Yan, J | Ni, J | Nobrega, MA | Löwenberg, B | Delwel, R | Valk, PJM | Kumar, A | Xie, L | Tenen, DG | Huang, G | Wang, Q-f
Leukemia  2013;28(7):1436-1448.
Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hematopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.
PMCID: PMC4410691  PMID: 24445817
PU.1; MEIS1; MLL leukemia; transcription regulation
3.  Simultaneous saccharification and fermentation of steam exploded duckweed: Improvement of the ethanol yield by increasing yeast titre 
Bioresource Technology  2015;194:263-269.
•Steam explosion of duckweed enhances SSF at low (2% w/v) substrate concentrations.•High substrate concentrations (20% w/v) result in much lower ethanol yields.•Ethanol yields can be considerably increased with higher yeast inoculum.•Or by preconditioning yeasts in steam explosion liquor containing inhibitors.•The extra/preconditioned yeast metabolise fermentation inhibitors.
This study investigated the conversion of Lemna minor biomass to bioethanol. The biomass was pre-treated by steam explosion (SE, 210 °C, 10 min) and then subjected to simultaneous saccharification and fermentation (SSF) using Cellic® CTec 2 (20 U or 0.87 FPU g−1 substrate) cellulase plus β-glucosidase (2 U g−1 substrate) and a yeast inoculum of 10% (v/v or 8.0 × 107 cells mL−1). At a substrate concentration of 1% (w/v) an ethanol yield of 80% (w/w, theoretical) was achieved. However at a substrate concentration of 20% (w/v), the ethanol yield was lowered to 18.8% (w/w, theoretical). Yields were considerably improved by increasing the yeast titre in the inoculum or preconditioning the yeast on steam exploded liquor. These approaches enhanced the ethanol yield up to 70% (w/w, theoretical) at a substrate concentration of 20% (w/v) by metabolising fermentation inhibitors.
PMCID: PMC4534771  PMID: 26210138
BG, Novozyme® 188; CE, Celluclast® 1.5; CTec 2, Cellic® CTec 2; CWMs, cell wall materials; FDM, freeze dry and freeze mill; SE, steam explosion; SSF, simultaneous saccharification and fermentation; YM, yeast and mould broth; Duckweed; Bioethanol production; Steam explosion; Cellulase; Simultaneous saccharification and fermentation
4.  HLA and KIR genotyping correlates with relapse after T-cell-replete haploidentical transplantation in chronic myeloid leukaemia patients 
British Journal of Cancer  2014;111(6):1080-1088.
Conflicting results have been reported regarding the predicative roles of alloreactive natural killer (NK) cells on the outcomes of transplantation in leukaemia patients.
We prospectively analysed the human leukocyte antigen (HLA) typing of donor–recipient pairs and the KIR typing of the donors in 97 CML patients to address the predictive roles of NK cells in relapse undergoing T-cell-replete haploidentical transplantation.
Patients with class I ligands for the donor-inhibitory KIR gene exhibited decreased molecular and haematologic relapse rates (P=0.003 and P=0.015, respectively). There was a significantly reduced risk of molecular and haematologic relapse in patients with HLA-C1C2 or C2C2 who accepted donors with KIR2DS1 or in patients with HLA-Bw4 who accepted donors with KIR3DS1 (‘recipient with relevant KIR ligand for donor-activating KIR', n=25), compared with the remaining transplants (n=72, P=0.009 and P=0.009, respectively). In addition, the presence of class I ligand in the recipients of donor-activating KIR contributed to a decreased relapse rate in patients lacking class I ligand in the recipient of donor-inhibitory KIR (P=0.04 and P=0.03, respectively).
This study suggests that the presence of class I ligands for the donor-activating or donor-inhibitory KIR gene in the recipient might confer some protection against leukaemic relapse in T-cell-replete haploidentical transplantation.
PMCID: PMC4453853  PMID: 25077441
KIR; haploidentical; HSCT; CML
5.  Multi-dimensional Reduction and Transfer Function Design using Parallel Coordinates 
Multi-dimensional transfer functions are widely used to provide appropriate data classification for direct volume rendering. Nevertheless, the design of a multi-dimensional transfer function is a complicated task. In this paper, we propose to use parallel coordinates, a powerful tool to visualize high-dimensional geometry and analyze multivariate data, for multi-dimensional transfer function design. This approach has two major advantages: (1) Combining the information of spatial space (voxel position) and parameter space; (2) Selecting appropriate high-dimensional parameters to obtain sophisticated data classification. Although parallel coordinates offers simple interface for the user to design the high-dimensional transfer function, some extra work such as sorting the coordinates is inevitable. Therefore, we use a local linear embedding technique for dimension reduction to reduce the burdensome calculations in the high dimensional parameter space and to represent the transfer function concisely. With the aid of parallel coordinates, we propose some novel high-dimensional transfer function widgets for better visualization results. We demonstrate the capability of our parallel coordinates based transfer function (PCbTF) design method for direct volume rendering using CT and MRI datasets.
PMCID: PMC4536824  PMID: 26278929
6.  Field evidence for earlier leaf-out dates in alpine grassland on the eastern Tibetan Plateau from 1990 to 2006 
Biology Letters  2014;10(8):20140291.
Worldwide, many plant species are experiencing an earlier onset of spring phenophases due to climate warming. Rapid recent temperature increases on the Tibetan Plateau (TP) have triggered changes in the spring phenology of the local vegetation. However, remote sensing studies of the land surface phenology have reached conflicting interpretations about green-up patterns observed on the TP since the mid-1990s. We investigated this issue using field phenological observations from 1990 to 2006, for 11 dominant plants on the TP at the levels of species, families (Gramineae—grasses and Cyperaceae—sedges) and vegetation communities (alpine meadow and alpine steppe). We found a significant trend of earlier leaf-out dates for one species (Koeleria cristata). The leaf-out dates of both Gramineae and Cyperaceae had advanced (the latter significantly, starting an average of 9 days later per year than the former), but the correlation between them was significant. The leaf-out dates of both vegetation communities also advanced, but the pattern was only significant in the alpine meadow. This study provides the first field evidence of advancement in spring leaf phenology on the TP and suggests that the phenology of the alpine steppe can differ from that of the alpine meadow. These findings will be useful for understanding ecosystem responses to climate change and for grassland management on the TP.
PMCID: PMC4155906  PMID: 25099960
leaf-out date; alpine meadow; alpine steppe; climate change; plant phenology; Tibetan Plateau
7.  Nuclear CSPP1 expression defined subtypes of basal-like breast cancer 
British Journal of Cancer  2014;111(2):326-338.
The multi-exon CSPP1 gene, encoding for centrosome and microtubule-associated proteins involved in ciliogenesis and cell division, is a candidate oncogene in luminal breast cancer but expression of CSPP1 proteins remained unexplored.
CSPP1 gene and protein expression was examined in normal mammary tissue, human breast cancer cell lines, and primary breast cancer biopsies from two patient cohorts. Cell type and epitope-dependent subcellular-specific CSPP1 staining pattern in normal mammary gland epithelium and cancer biopsies were correlated to molecular and clinical parameters.
A novel, nuclear localised CSPP1 isoform was exclusively detected in luminal epithelial cells, whereas cytoplasmic CSPP-L was generally expressed in normal mammary epithelium. Luminal cell-related nuclear CSPP1 expression was preserved in type-matched cell lines and carcinomas, and correlated to gene copy number and mRNA expression. In contrast, basal-like carcinomas displayed generally lower CSPP1 mRNA expression. Yet, a subgroup of basal-like breast carcinomas depicted nuclear CSPP1 expression, displayed luminal traits, and differed from nuclear CSPP1 devoid counterparts in expression of eight genes. Eight-gene signature defined groups of basal-like tumours from an independent cohort showed significant differences in survival.
Differential expression of a nuclear CSPP1 isoform identified biologically and clinically distinct subgroups of basal-like breast carcinoma.
PMCID: PMC4102947  PMID: 24901235
breast cancer; molecular subtypes; basal-like breast cancer; luminal-like breast cancer; CSPP1
8.  Optical projection tomography permits efficient assessment of infarct volume in the murine heart postmyocardial infarction 
Optical projection tomography permits rapid high-resolution imaging of intact murine heart in vitro and identification of tissue heterogeneity within individual optical slices of postmyocardial infarction hearts. Infarct volume derived from >400 slices correlates with in vivo magnetic resonance imaging and avoids the need for histological staining of multiple physical sections.
The extent of infarct injury is a key determinant of structural and functional remodeling following myocardial infarction (MI). Infarct volume in experimental models of MI can be determined accurately by in vivo magnetic resonance imaging (MRI), but this is costly and not widely available. Experimental studies therefore commonly assess injury by histological analysis of sections sampled from the infarcted heart, an approach that is labor intensive, can be subjective, and does not fully assess the extent of injury. The present study aimed to assess the suitability of optical projection tomography (OPT) for identification of injured myocardium and for accurate and efficient assessment of infarct volume. Intact, perfusion-fixed, optically cleared hearts, collected from mice 7 days after induction of MI by coronary artery occlusion, were scanned by a tomograph for autofluorescence emission after UV excitation, generating >400 transaxial sections for reconstruction. Differential autofluorescence permitted discrimination between viable and injured myocardium and highlighted the heterogeneity within the infarct zone. Two-dimensional infarct areas derived from OPT imaging and Masson's trichrome staining of slices from the same heart were highly correlated (r2 = 0.99, P < 0.0001). Infarct volume derived from reconstructed OPT sections correlated with volume derived from in vivo late gadolinium enhancement MRI (r2 = 0.7608, P < 0.005). Tissue processing for OPT did not compromise subsequent immunohistochemical detection of endothelial cell and inflammatory cell markers. OPT is thus a nondestructive, efficient, and accurate approach for routine in vitro assessment of murine myocardial infarct volume.
PMCID: PMC4537945  PMID: 26071543
mouse myocardial infarction; late gadolinium enhancement magnetic resonance imaging; troponin I; Masson's trichrome; ejection fraction
9.  Asymmetric insular function predicts positional blood pressure in non-demented elderly 
40% of non-demented octogenarians have Braak stages consistent with insular involvement, and may be at risk for “age–related” autonomic dysfunction. We examined the association between insular resting Cerebral Blood Flow (rCBF) and cardiovascular functions in 29 non-demented elderly subjects who were highly screened to exclude comorbid cardiovascular disease. Mean insular rCBF was significantly higher on the right (R) than left (L). However, 35.4% of subjects had L dominant rCBF = a "HIGH” risk group. R insular rCBF was significantly lower in the HIGH risk group. This subset had significantly increased positional drops in systolic blood pressure. While these data cannot address AD as the specific cause, this possibility is being investigated in other cohorts.
PMCID: PMC4459127  PMID: 19622688
autonomic function; asymmetry; aging; Alzheimer’s disease; insula; orthostasis
10.  Myomatous hepatic angiomyolipoma: imaging findings in 14 cases with radiological–pathological correlation and review of the literature 
The British Journal of Radiology  2014;87(1038):20130712.
To display and analyse the imaging features of myomatous hepatic angiomyolipomas (MHAMLs).
The imaging features (CT = 9; MRI = 10; ultrasound = 10; contrast-enhanced ultrasound = 4) of 14 patients with pathologically proven MHAMLs were reviewed retrospectively.
MHAMLs were surgically resected in the 14 patients (10 females and 4 males; age, 27–64 years; mean, 45 years), all of whom had negative hepatitis markers and were positive for the immunohistochemical stain homatropine methylbromide-45. The tumours were solitary and well defined, and ranged in size from 1.9 to 9.1 cm (mean, 5.7 cm). On dynamic contrast-enhanced CT, MRI and ultrasound scans, all tumours showed fast strong enhancement in the arterial phase and moderate washout in the portal venous and delayed phases, and the greater portions of the tumours were slightly lower than the surrounding hepatic parenchyma. In some cases, a small area of prolonged or increasing enhancement in the tumour was recognized in the delayed phase. Early draining vessels to the portal vein or hepatic vein could be seen in some cases. However, no capsular signs could be confidently identified in the delayed phase. Haemorrhagic cavities were recognized in two cases, and nodular low-intensity areas in the tumours on T2 weighted imaging that showed slow and faint enhancement on dynamic scans were seen in two cases. However, no necrosis was identified.
Dynamic enhanced imaging studies revealed some specific features of MHAMLs that distinguish them from other hypervascular hepatic tumours, especially when combined with clinical features. Familiarity with imaging and clinical features of MHAMLs could avoid unnecessary surgical resection of these generally benign tumours.
Advances in knowledge:
This article systematically describes the imaging features of MHAMLs.
PMCID: PMC4075552  PMID: 24670055
11.  Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Aβ ligation to β1-integrin conformers 
Cell Death and Differentiation  2015;22(6):921-934.
The accumulation of amyloid-β protein (Aβ) is an early event associated with synaptic and mitochondrial damage in Alzheimer's disease (AD). Recent studies have implicated the filamentous actin (F-actin) severing protein, Cofilin, in synaptic remodeling, mitochondrial dysfunction, and AD pathogenesis. However, whether Cofilin is an essential component of the AD pathogenic process and how Aβ impinges its signals to Cofilin from the neuronal surface are unknown. In this study, we found that Aβ42 oligomers (Aβ42O, amyloid-β protein 1–42 oligomers) bind with high affinity to low or intermediate activation conformers of β1-integrin, resulting in the loss of surface β1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of β1-integrin prevented Aβ42O-induced Cofilin activation, and allosteric modulation or activation of β1-integrin significantly reduced Aβ42O binding to neurons while blocking Aβ42O-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, depletion of F-actin/focal Vinculin, and apoptosis. Cofilin, in turn, was required for Aβ42O-induced loss of cell surface β1-integrin, disruption of F-actin/focal Talin–Vinculin, and depletion of F-actin-associated postsynaptic proteins. SSH1 reduction, which mitigated Cofilin activation, prevented Aβ42O-induced mitochondrial Cofilin translocation and apoptosis, while AD brain mitochondria contained significantly increased activated/oxidized Cofilin. In mechanistic support in vivo, AD mouse model (APP (amyloid precursor protein)/PS1) brains contained increased SSH1/Cofilin and decreased SSH1/14-3-3 complexes, indicative of SSH1–Cofilin activation via release of SSH1 from 14-3-3. Finally, genetic reduction in Cofilin rescued APP/Aβ-induced synaptic protein loss and gliosis in vivo as well as deficits in long-term potentiation (LTP) and contextual memory in APP/PS1 mice. These novel findings therefore implicate the essential involvement of the β1-integrin–SSH1–Cofilin pathway in mitochondrial and synaptic dysfunction in AD.
PMCID: PMC4423195  PMID: 25698445
12.  Mesenchymal stromal cells derived from acute myeloid leukemia bone marrow exhibit aberrant cytogenetics and cytokine elaboration 
Blood Cancer Journal  2015;5(4):e302-.
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) play a fundamental role in the BM microenvironment (BME) and abnormalities of these cells may contribute to acute myeloid leukemia (AML) pathogenesis. The aim of the study was to characterize the cytokine and gene expression profile, immunophenotype and cytogenetics of BM-MSCs from AML patients compared to normal BM-MSCs from healthy donors. AML BM-MSCs showed decreased monocyte chemoattractant protein-1 levels compared to normal BM-MSCs. AML BM-MSCs expressed similar β1 integrin, CD44, CD73, CD90 and E-cadherin compared to normal BM-MSCs. Cytogenetic analysis revealed chromosomal aberrations in AML BM-MSCs, some overlapping with and others distinct from their corresponding AML blasts. No significant difference in gene expression was detected between AML BM-MSCs compared to normal BM-MSCs; however, comparing the differences between AML and MSCs from AML patients with the differences between normal hematopoietic cells and normal MSCs by Ingenuity pathway analysis showed key distinctions of the AML setting: (1) upstream gene regulation by transforming growth factor beta 1, tumor necrosis factor, tissue transglutaminase 2, CCAAT/enhancer binding protein alpha and SWItch/Sucrose NonFermentable related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; (2) integrin and interleukin 8 signaling as overrepresented canonical pathways; and (3) upregulation of transcription factors FBJ murine osteosarcoma viral oncogene homolog and v-myb avian myeloblastosis viral oncogene homolog. Thus, phenotypic abnormalities of AML BM-MSCs highlight a dysfunctional BME that may impact AML survival and proliferation.
PMCID: PMC4450324  PMID: 25860293
13.  Enhanced Magnetic Anisotropies of Single Transition-Metal Adatoms on a Defective MoS2 Monolayer 
Scientific Reports  2015;5:9361.
Single magnetic atoms absorbed on an atomically thin layer represent the ultimate limit of bit miniaturization for data storage. To approach the limit, a critical step is to find an appropriate material system with high chemical stability and large magnetic anisotropic energy. Here, on the basis of first-principles calculations and the spin-orbit coupling theory, it is elucidated that the transition-metal Mn and Fe atoms absorbed on disulfur vacancies of MoS2 monolayers are very promising candidates. It is analysed that these absorption systems are of not only high chemical stabilities but also much enhanced magnetic anisotropies and particularly the easy magnetization axis is changed from the in-plane one for Mn to the out-of-plane one for Fe by a symmetry-lowering Jahn-Teller distortion. The results point out a promising direction to achieve the ultimate goal of single adatomic magnets with utilizing the defective atomically thin layers.
PMCID: PMC4369737  PMID: 25797135
14.  Downregulation of miR-518a-3p activates the NIK-dependent NF-κB pathway in colorectal cancer 
The aim of the present study was to investigate the biological role and underlying mechanisms of action of miR-518a-3p in the progression and invasion of colorectal cancer (CRC). Reverse transcription-quantitative PCR (RT-qPCR) was used to examine the mRNA expression levels of miR-518a-3p in 5 CRC cell lines (SW480, SW620, HCT116, HT29 and LoVo) in a normal colonic cell line, NCM460, as well as in tumor tissues with or without metastases. The biological effects of miR-518a-3p were assessed in the CRC cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis, and RT-qPCR and western blot analyses were employed to evaluate the expression of miR-518a-3p targets. The regulation of NF-κB-inducing kinase (NIK) by miR-518a-3p was confirmed using luciferase activity assays. Our results revealed that miR-518a-3p was significantly downregulated in the CRC cell lines compared with the normal colonic cell line (P<0.05), as well as in the CRC tissues with distant metastases compared with the tissues without metastases. The downregulation of miR-518a-3p was associated with tumor size, distant metastasis and TNM stage in the patients with CRC. Moreover, the ectopic expression of miR-518a-3p and the inhibition of NIK by RNA interference markedly reduced cell proliferation and enhanced the apoptosis of CRC cells. Further experiments revealed that NIK, a regulator of NF-κB, was a downstream target of miR-518a-3p. The presents findings indicate that miR-518a-3p plays an important role in the progression of CRC by targeting NIK.
PMCID: PMC4380201  PMID: 25812680
miR-518a-3p; colorectal cancer; nuclear factor-κB-inducing kinase; nuclear factor-κB activation
15.  MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27Kip1 
British Journal of Cancer  2014;110(5):1260-1268.
The phosphoinositide 3-kinase (PI3K)/Akt signalling pathway appears to be a key regulator in cervical carcinogenesis. However, the downstream regulatory mechanism of PI3K/Akt signalling remains largely unknown.
The expression of miR-196a in cervical cancer cell lines and cervical cancer tissues was examined using real-time PCR. The effects of miR-196a on PI3K/Akt signalling and cellular proliferation were evaluated by bromodeoxyuridine labelling, 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide, colony formation assays and luciferase assays.
The expression level of miR-196a was markedly increased in cervical cancer tissues and cell lines compared with normal cervical tissue and normal cervical squamous cells. Upregulation of miR-196a was correlated with advanced tumour stage and poor overall and recurrence-free survival in cervical cancer patients. Upregulation of miR-196a enhanced G1/S-phase transition and the proliferative ability of cervical cancer cells, whereas suppression of miR-196a had the opposite effect. Using bioinformatics and biological approaches, we showed that FOXO1 and p27Kip1, two key effectors of PI3K/Akt signalling, were direct targets of miR-196a.
Our findings suggest that miR-196a has an important role in promoting human cervical cancer cell proliferation and may represent a novel therapeutic target of microRNA-mediated suppression of cell proliferation in cervical cancer.
PMCID: PMC3950858  PMID: 24423924
miRNA; miR-196a; cervical cancer; proliferation; FOXO1; p27Kip1
16.  A comprehensive, multispecialty approach to an acute exacerbation of chronic central pain in a tetraplegic 
Spinal cord  2014;52(0 1):S17-S18.
Study design
We present a case report describing the multidisciplinary treatment of a tetraplegic spinal cord injury (SCI) patient who developed an acute exacerbation of chronic central pain.
To bring further awareness to the importance of using a comprehensive, multidisciplinary approach in treating acute exacerbation of chronic central pain in SCI patients.
University of California Irvine Medical Center, Orange, CA, USA.
Case report
We present a 34-year-old man with a past medical history of C5 American Spinal Injury Association B tetraplegia secondary to a surfing accident 8 years prior, central pain syndrome, spasticity, autonomic dysreflexia and anxiety who arrived at the emergency room with a 1-month history of worsening acute on chronic pain refractory to opioid escalation. The multispecialty treatment plan included treatment of the patient’s urinary tract infection by the primary medicine service, management of the patient’s depression by the psychiatric service, treatment of bowel obstruction by general surgery and adjustment of pain medications by pain management. The patient was found to have stable neurological findings, neuroimaging unchanged from prior imaging and a urinary tract infection. Hospitalization was complicated by severe colonic dilation that required disimpaction by general surgery.
The treatment of this patient’s acutely worsened central pain highlights the importance of applying a multidisciplinary approach to SCI patients with an acute exacerbation of chronic central pain. In this case, the multispecialty treatment plan included treatment of the patient’s urinary tract infection by the primary medicine service, management of the patient’s depression by the psychiatric service, treatment of bowel obstruction by general surgery, and adjustment of pain medications by pain management.
PMCID: PMC4347803  PMID: 24513720
spinal cord injury; central pain; multidisciplinary; acute on chronic; case report; tetraplegia
17.  Evaluation of 99mTc-peptide-ZHER2:342 Affibody® molecule for in vivo molecular imaging 
The British Journal of Radiology  2013;87(1033):20130484.
The aim of this study was to develop an improved method for labelling ZHER2:342 with Technetium-99m (99mTc) using Gly-(d) Ala-Gly-Gly as a chelator and to evaluate the feasibility of its use for visualization of HER2 expression in vivo.
The Affibody® molecule ZHER2:342 was synthesized by Fmoc/tBu solid phase synthesis. The chelator, Gly-(d) Ala-Gly-Gly, was introduced by manual synthesis as the N-terminal extensions of ZHER2:342. ZHER2:342 was labelled with 99mTc. The labelling efficiency, radiochemical purity and in vitro stability of the labelled molecular probe were analysed by reversed-phase high performance liquid chromatography. Biodistribution and molecular imaging using 99mTc-peptide-ZHER2:342 were performed.
The molecular probe was successfully synthesized and labelled with 99mTc with the labelling efficiency of 98.10 ± 1.73% (n = 5). The radiolabelled molecular probe remained highly stable in vitro. The molecular imaging showed high uptake in HER2-expressing SKOV-3 xenografts, whereas the MDA-MB-231 xenografts with low HER2 expression were not clearly imaged at any time after the injection of 99mTc-peptide-ZHER2:342. The predominant clearance pathway for 99mTc-peptide-ZHER2:342 was through the kidneys.
99mTc-peptide-ZHER2:342 using Gly-(d) Ala-Gly-Gly as a chelator is a promising tracer agent with favourable biodistribution and imaging properties that may be developed as a radiopharmaceutical for the detection of HER2-positive malignant tumours.
Advances in knowledge:
The 99mTc-peptide-ZHER2:342 molecular probe is a promising tracer agent, and the results in this study provide a foundation for future development of protocols for earlier visual detection of cancer in the clinical setting.
PMCID: PMC3898972  PMID: 24273251
18.  Liraglutide inhibits autophagy and apoptosis induced by high glucose through GLP-1R in renal tubular epithelial cells 
ZHAO, X | LIU, G | SHEN, H | GAO, B | LI, X | FU, J | ZHOU, J | JI, Q
Tubular atrophy and dysfunction is a critical process underlying diabetic nephropathy (DN). Understanding the mechanisms underlying renal tubular epithelial cell survival is important for the prevention of kidney failure associated with glucotoxicity. Autophagy is a cellular pathway involved in protein and organelle degradation. It is associated with many types of cellular homeostasis and human diseases. To date, little is known of the association between high concentrations of glucose and autophagy in renal tubular cells. In the present study, we investigated high glucose-induced toxicity in renal tubular epithelial cells by means of several complementary assays, including cell viability, cell death assays and changes in ultrastructure in an immortalized human kidney cell line, HK-2 cells. The extent of apoptosis was significantly increased in the HK-2 cells following treatment with high levels of glucose. In addition, in in vivo experiments using diabetic rats, high glucose exerted harmful effects on the tissue structure of the kidneys in the diabetic rats. Chronic exposure of the HK-2 cells and tubular epithelial cells of nephritic rats to high levels of glucose induced autophagy. Liraglutide inhibited these effects; however, treatment witht a glucagon-like peptide-1 receptor (GLP-1R) antagonist enhanced these effects. Our results also indicated that the exposure of the renal tubular epithelial cells to high glucose concentrations in vitro led to the downregulation of GLP-1R expression. Liraglutide reversed this effect, while the GLP-1R antagonist promoted it, promoting autophagy, suggesting that liraglutide exerts a renoprotective effect in the presence of high glucose, at least in part, by inhibiting autophagy and increasing GLP-1R expression in the HK-2 cells and kidneys of diabetic rats.
PMCID: PMC4314412  PMID: 25573030
high glucose; autophagy; autophagy-related gene; glucagon-like peptide-1 receptor; liraglutide
19.  SRF expedites metastasis and modulates the epithelial to mesenchymal transition by regulating miR-199a-5p expression in human gastric cancer 
Zhao, X | He, L | Li, T | Lu, Y | Miao, Y | Liang, S | Guo, H | Bai, M | Xie, H | Luo, G | Zhou, L | Shen, G | Guo, C | Bai, F | Sun, S | Wu, K | Nie, Y | Fan, D
Cell Death and Differentiation  2014;21(12):1900-1913.
Dysregulation of transcription factors (TFs) is associated with tumor progression, but little is known about TF expression patterns in the context of gastric cancer (GC) metastasis. Using array-based profile analysis, we found that 22 TFs showed differential activities between GC cell lines with low- and high-metastatic potential. Of this group of TFs, serum response factor (SRF) was significantly upregulated in metastatic GC cells. SRF expression was frequently elevated in a panel of metastatic GC cells and tissues, and high-level expression of SRF was significantly associated with a more aggressive phenotype and poor prognosis in patients with GC. In GC cell lines, overexpression of SRF potently promoted cell migration and invasion in vitro as well as the formation of intrahepatic and pulmonary metastases in vivo, whereas loss of SRF inhibited GC cell invasion and metastasis. We also performed a microRNA microarray to screen for transcriptional targets of SRF and found that SRF transactivates miR-199a-5p and miR-199a-3p by directly binding to their promoters. We further determined that overexpression of miR-199a-5p, but not miR-199a-3p, increased GC cell invasion and metastasis. In contrast, inhibition of miR-199a-5p impaired the metastatic potential of GC cells in vitro and in vivo, and E-cadherin was identified as a direct and functional target of miR-199a-5p in GC cells. Specifically, our results showed that SRF promotes GC metastasis and the epithelial to mesenchymal transition (EMT) though miR-199a-5p-mediated downregulation of E-cadherin. The present study thus provides insight into the specific biological behavior of SRF in GC metastasis. As increased activity of the SRF/miR-199a-5p/E-cadherin pathway appears to promote GC cell EMT and metastasis, these regulators may therefore be developed as therapeutic targets or biomarkers for GC progression.
PMCID: PMC4227147  PMID: 25080937
20.  MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways 
Wu, N | Lin, X | Zhao, X | Zheng, L | Xiao, L | Liu, J | Ge, L | Cao, S
British Journal of Cancer  2013;109(11):2853-2863.
We have recently identified miR-125b upregulation in glioblastoma (GMB). The aim of this study is to determine the correlation between miR-125b expression and malignant grades of glioma and the genes targeted by miR-125b.
Real-time PCR was employed to measure the expression level of miR-125b. Cell viability was evaluated by cell growth and colony formation in soft-agar assays. Cell apoptosis was determined by Hoechst 33342 staining and AnnexinV-FITC assay. The Luciferase assay was used to confirm the actual binding sites of p38MAPK mRNA. Western blot was used to detect the gene expression level.
The expression level of miR-125b is positively correlated with the malignant grade of glioma. Ectopic expression of miR-125b promotes the proliferation of GMB cells. Knockdown of endogenous miR-125b inhibits cell proliferation and promotes cell apoptosis. Further studies reveal that p53 is regulated by miR-125b. However, downregulation of the endogenous miR-125b also results in p53-independent apoptotic pathway leading to apoptosis in p53 mutated U251 cells and p53 knockdown U87 cells. Moreover, p38MAPK is also regulated by miR-125b and downregulation of miR-125b activates the p38MAPK-induced mitochondria apoptotic pathway.
High-level expression of miR-125b is associated with poor outcomes of GMB. MiR-125b may have an oncogenic role in GMB cells by promoting cell proliferation and inhibiting apoptosis.
PMCID: PMC3844918  PMID: 24169356
microRNA; miR-125b; glioblastoma; cell apoptosis; p53; p38MAPK
21.  Localized micro- and nano-scale remodelling in the diabetic aorta 
Acta Biomaterialia  2014;10(11):4843-4851.
Graphical abstract
Diabetes is strongly associated with cardiovascular disease, but the mechanisms, structural and biomechanical consequences of aberrant blood vessel remodelling remain poorly defined. Using an experimental (streptozotocin, STZ) rat model of diabetes, we hypothesized that diabetes enhances extracellular protease activity in the aorta and induces morphological, compositional and localized micromechanical tissue remodelling. We found that the medial aortic layer underwent significant thickening in diabetic animals but without significant changes in collagen or elastin (abundance). Scanning acoustic microscopy demonstrated that such tissue remodelling was associated with a significant decrease in acoustic wave speed (an indicator of reduced material stiffness) in the inter-lamellar spaces of the vessel wall. This index of decreased stiffness was also linked to increased extracellular protease activity (assessed by semi-quantitative in situ gelatin zymography). Such a proteolytically active environment may affect the macromolecular structure of long-lived extracellular matrix molecules. To test this hypothesis, we also characterized the effects of diabetes on the ultrastructure of an important elastic fibre component: the fibrillin microfibril. Using size exclusion chromatography and atomic force microscopy, we isolated and imaged microfibrils from both healthy and diabetic aortas. Microfibrils derived from diabetic tissues were fragmented, morphologically disrupted and weakened (as assessed following molecular combing). These structural and functional abnormalities were not replicated by in vitro glycation. Our data suggest that proteolysis may be a key driver of localized mechanical change in the inter-lamellar space of diabetic rat aortas and that structural proteins (such as fibrillin microfbrils) may be biomarkers of diabetes induced damage.
PMCID: PMC4199142  PMID: 25014552
Arterial stiffening; Fibrillin microfibrils; Type 1 diabetes; Extracellular matrix; Mechanical properties
22.  Effects of the Cowpea chlorotic mottle bromovirus β-hexamer structure on virion assembly 
Virology  2003;306(2):280-288.
The X-ray crystal structure of Cowpea chlorotic mottle bromovirus (CCMV) revealed a unique tubular structure formed by the interaction of the N-termini from six coat protein subunits at each three-fold axis of the assembled virion. This structure, termed the β-hexamer, consists of six short β-strands. The β-hexamer was postulated to play a critical role in the assembly and stability of the virion by stabilizing hexameric capsomers (Speir et al., 1995). Mutational analyses of the β-hexamer structure, utilizing both in vitro and in vivo assembly assays, demonstrate that this structure is not required for virion formation devoid of nucleic acids in vitro or for RNA-containing virions in vivo. However, the β-hexamer structure does contribute to virion stability in vitro and modulates disease expression in vivo. These results support a model for CCMV assembly through pentamer intermediates.
PMCID: PMC4191912  PMID: 12642101
Virus structure; Virus assembly; Virus stability; Symptom expression
23.  A new method for determining gastric acid output using a wireless ph sensing capsule 
Alimentary pharmacology & therapeutics  2013;37(12):1198-1209.
Gastroesophageal reflux disease (GERD) and gastric acid hypersecretion respond well to suppression of gastric acid secretion. However, clinical management and research in diseases of acid secretion have been hindered by the lack of a non-invasive, accurate and reproducible tool to measure gastric acid output (GAO). Thus, symptoms or, in refractory cases, invasive testing may guide acid suppression therapy.
To present and validate a novel, non-invasive method of GAO analysis in healthy subjects using a wireless pH sensor, SmartPill® (SP) (SmartPill® Corporation, Buffalo, NY).
Twenty healthy subjects underwent conventional GAO studies with a nasogastric tube. Variables impacting liquid meal-stimulated GAO analysis were assessed by modeling and in vitro verification. Buffering capacity of Ensure Plus® was empirically determined. SP GAO was calculated using the rate of acidification of the Ensure Plus® meal. Gastric emptying scintigraphy and GAO studies with radiolabeled Ensure Plus® and SP assessed emptying time, acidification rate and mixing. Twelve subjects had a second SP GAO study to assess reproducibility.
Meal stimulated SP GAO analysis was dependent on acid secretion rate and meal buffering capacity but not on gastric emptying time. On repeated studies, SP GAO strongly correlated with conventional BAO (r=0.51, P=0.02), MAO (r=0.72, P=0.0004) and PAO; (r=0.60, P=0.006). The SP sampled the stomach well during meal acidification.
SP GAO analysis is a non-invasive, accurate and reproducible method for the quantitative measurement of GAO in healthy subjects. SP GAO analysis could facilitate research and clinical management of GERD and other disorders of gastric acid secretion.
PMCID: PMC3703786  PMID: 23639004
acid output; wireless capsule; SmartPill®; gastroesophageal reflux disease
24.  Extranodal Marginal Zone Lymphoma Presenting within the Meckel Diverticulum as Diverticulitis: A Case Report 
Case Reports in Pathology  2014;2014:374814.
Meckel diverticulum is the most common congenital defect of the gastrointestinal tract. It can be asymptomatic or mimic appendicitis and may be complicated by bleeding, diverticulitis, obstruction, and, rarely, neoplasia. We report the first case of extranodal marginal zone lymphoma occupying a Meckel diverticulum. A 44-year-old man with history of colonic diverticulitis presented to the emergency department for evaluation of acute abdominal pain. Radiography showed enteric obstruction, prompting diagnostic laparoscopy. Above the level of mid-ileum an intact Meckel diverticulum was identified. Microscopy showed extensive infiltration of sheets of small lymphocytes with abundant cytoplasm (monocytoid B-cells) prominently in submucosa and focally transmural involving serosal adipose tissue with multiple reactive germinal centers. The immunostains showed positivity for CD20, BCL-2, and CD43 (weak) and negativity for CD3, CD5, BCL-1, CD10, and BCL-6 in monocytoid B-cells. Fluorescence in situ hybridization studies revealed API2-MALT1 fusion signals consistent with t(11;18)(q21;q21), which confirmed the diagnosis of extranodal marginal zone lymphoma, also known as mucosa associated lymphoid tissue lymphoma.
PMCID: PMC4020529  PMID: 24868477
25.  Effects of single-dose atorvastatin on interleukin-6, interferon gamma, and myocardial no-reflow in a rabbit model of acute myocardial infarction and reperfusion 
The mechanisms of statins relieving the no-reflow phenomenon and the effects of single-dose statins on it are not well known. This study sought to investigate the effects of inflammation on the no-reflow phenomenon in a rabbit model of acute myocardial infarction and reperfusion (AMI/R) and to evaluate the effects of single-dose atorvastatin on inflammation and myocardial no-reflow. Twenty-four New Zealand white male rabbits (5-6 months old) were randomized to three groups of eight: a sham-operated group, an AMI/R group, and an atorvastatin-treated group (10 mg/kg). Animals in the latter two groups were subjected to 4 h of coronary occlusion followed by 2 h of reperfusion. Serum levels of interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. The expression of interferon gamma (IFN-γ) in normal and infarcted (reflow and no-reflow) myocardial tissue was determined by immunohistochemical methods. The area of no-reflow and necrosis was evaluated pathologically. Levels of serum IL-6 were significantly lower in the atorvastatin group than in the AMI/R group (P<0.01). Expression of IFN-γ in infarcted reflow and no-reflow myocardial tissue was also significantly lower in the atorvastatin group than in the AMI/R group. The mean area of no-reflow [47.01% of ligation area (LA)] was significantly smaller in the atorvastatin group than in the AMI/R group (85.67% of LA; P<0.01). The necrosis area was also significantly smaller in the atorvastatin group (85.94% of LA) than in the AMI/R group (96.56% of LA; P<0.01). In a secondary analysis, rabbits in the atorvastatin and AMI/R groups were divided into two groups based on necrosis area (90% of LA): a small group (<90% of LA) and a large group (>90% of LA). There was no significant difference in the area of no-reflow between the small (61.40% of LA) and large groups (69.87% of LA; P>0.05). Single-dose atorvastatin protected against inflammation and myocardial no-reflow and reduced infarct size during AMI/R in rabbits. No-reflow was not dependent on the reduction of infarct size.
PMCID: PMC3982946  PMID: 24554037
Myocardial infarction; No-reflow phenomenon; Inflammation; Atorvastatin

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