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Biomedical subjects

L Li

Publications and source records attributed to L Li.

At least 19 recordsLinked to original sources
PubMed2012

MRI roadmap-guided transendocardial delivery of exon-skipping recombinant adeno-associated virus restores dystrophin expression in a canine model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) cardiomyopathy patients currently have no therapeutic options. We evaluated catheter-based transendocardial delivery of a recombinant adeno-associated virus (rAAV) expressing a small nuclear U7 RNA (U7smOPT) complementary to specific cis-acting splicing signals. Eliminating specific exons restores the open reading frame resulting in translation of truncated dystrophin protein. To test this approach in a clinically relevant DMD model, golden retriever muscular dystrophy (GRMD) dogs received serotype 6 rAAV-U7smOPT via the intracoronary or transendocardial route. Transendocardial injections were administered with an injection-tipped catheter and fluoroscopic guidance using X-ray fused with magnetic resonance imaging (XFM) roadmaps. Three months after treatment, tissues were analyzed for DNA, RNA, dystrophin protein, and histology. Whereas intracoronary delivery did not result in effective transduction, transendocardial injections, XFM guidance, enabled 30&#xb1;10 non-overlapping injections per animal. Vector DNA was detectable in all samples tested and ranged from <1 to >3000 vector genome copies per cell. RNA analysis, western blot analysis, and immunohistology demonstrated extensive expression of skipped RNA and dystrophin protein in the treated myocardium. Left ventricular function remained unchanged over a 3-month follow-up. These results demonstrated that effective transendocardial delivery of rAAV-U7smOPT was achieved using XFM. This approach restores an open reading frame for dystrophin in affected dogs and has potential clinical utility.

Animals↗
PubMed2007

A conditionally replicative, Wnt/beta-catenin pathway-based adenovirus therapy for anaplastic thyroid cancer.

Thyroid cancer affects between 10,000 and 15,000 people per year in the US. Typically, this disease can be controlled with surgical resection and radioiodide treatment. However, resistance to these conventional therapies is observed in some patients, who develop intractable anaplastic thyroid cancer (ATC), for which no effective therapies exist. Recently, a sizable fraction of undifferentiated or poorly differentiated thyroid cancers were shown to contain mutations in beta-catenin, an oncogenic protein involved in the etiology of cancers of many tissues. We developed a conditionally replicative adenovirus (named 'HILMI') which, by virtue of TCF response elements drives E1A and E1B expression, replicates specifically in cells with an active Wnt/beta-catenin pathway. We show that several thyroid cancer cell lines, derived from undifferentiated or anaplastic tissues and possessing an active Wnt/beta-catenin pathway, are susceptible to cell killing by HILMI. Furthermore, viral replication in ATC cells as xenograft tumors in nude mice was observed, and prolonged survival of mice with ATC tumors was observed following administration of the HILMI therapeutic vector. The results warrant further development of this therapeutic approach for ATC patients.

Adenoviridae↗
PubMed2007

Altered immune function of monocytes in different stages of patients with acute on chronic liver failure.

The aim of this study was to investigate the characteristics of the immune function of monocytes in different stages of the patients with acute on chronic liver failure (ACLF). Human leucocyte antigen (HLA)-DR and Toll-like receptor 4 (TLR-4) expression on monocytes in early and late stages of acute on chronic liver failure were detected by flow cytometry. The secretion function of monocytes was measured by cytometric bead array. Compared with healthy controls, the levels of HLA-DR expression on monocytes in patients with chronic hepatitis B, liver cirrhosis and acute on chronic liver failure were gradually decreased, especially in the late stage of acute on chronic liver failure (P < 0.001). TLR-4 expression on monocytes in patients with liver cirrhosis and acute on chronic liver failure were higher than the healthy controls. The concentrations of interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha and IL-12p70 in early-stage ACLF were significantly higher compared with healthy controls and lower in late-stage ACLF (P < 0.01, 0.05). However, a significantly lower amount of IL-10 was found on monocytes in early-stage ACLF than that of late-stage ACLF and healthy controls (P < 0.01). Monocyte HLA-DR expression in patients who died was significantly lower compared with patients who survived in the early and late stages of ACLF (P < 0.01). The dynamic detection of HLA-DR expression or cytokines secreted from monocytes could contribute to the estimation of the status of the immune function of patients with acute on chronic liver failure.

Adult↗
PubMed2006

Distribution and expression of recombinant plasmid encoding chicken interleukin-2.

A plasmid DNA that encodes chicken interleukin-2 (pCI-ChIL-2-EGFP) was investigated for its distribution and expression after intramuscular (i.m.) injection in chickens. After the i.m. injection, serum distribution was detectable from 2 h post inoculation (p.i.), peaked at 8 h p.i., and disappeared at 7 days p.i. The plasmid DNA was also observed in several organs including heart, liver, lung, spleen, bursa and inoculated muscle at different time points, but at 19 days p.i. the plasmid DNA was not found in any organ except inoculated muscle. Fluorescence of enhanced green fluorescent protein (EGFP) was found in cytoplasm and nucleus of cultured Vero cells, chicken embryo fibroblasts and peripheral blood lymphocytes, which were transfected in vitro with the plasmid DNA or in vivo with Lipofectamine. The expression profile of the fusion gene (ChIL-2-EGFP) in vivo was measured by RT-PCR, ELISA and fluorescence microscopy. The EGFP expression was detected from 8 h p.i. to 14 days p.i. and peaked at 5 days p.i., when the number of EGFP-expression myocytes was about 5% in the injected site. These results demonstrate that intramuscular administration of plasmid DNA leads to widespread distribution and long-term expression in vivo.

Animals↗
PubMed2006

'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737.

ABT-737 is a subnanomolar inhibitor of the antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w. Although ABT-737 triggers extensive cell death in many small-cell lung carcinoma (SCLC) cell lines, some of the SCLC cell lines and the majority of the cancer cell lines derived from other solid tumors were found to be resistant to ABT-737. To better understand the mechanism of resistance to ABT-737, we screened a short interfering RNA library consisting of short interfering RNA against 4000 'druggable' targets in an SCLC-derived cell line, NCI-H196. By comparing the knockdowns with phenotypes, all of the three top 'hits' from the screen were found to result from off-target gene silencing. Interestingly, the three off-target siRNAs were found to knock down an antiapoptotic Bcl-2 family protein Mcl-1 owing to the complementation between their seed regions with the 3' untranslated region (3' UTR) of Mcl-1. Furthermore, reducing the level of Mcl-1 using siRNAs or the small-molecule compounds Bay43-9006 and Seliciclib was sufficient to overcome the resistance to ABT-737 in the resistant SCLC cell line and cancer cell lines derived from other solid tumors. These results provide further evidence that Mcl-1 is the major factor that causes resistance to ABT-737 in cancer cells derived from diverse solid tumors, and the combination of Mcl-1 downregulating agents with ABT-737 could be potent therapeutic regimens for patient with ABT-737-resistant SCLC and many other types of solid tumors.

3' Untranslated Regions↗
PubMed2006

Measurements and simulation of forest leaf area index and net primary productivity in Northern China.

Large scale process-based modeling is a useful approach to estimate distributions of global net primary productivity (NPP). In this paper, in order to validate an existing NPP model with observed data at site level, field experiments were conducted at three sites in northern China. One site is located in Qilian Mountain in Gansu Province, and the other two sites are in Changbaishan Natural Reserve and Dunhua County in Jilin Province. Detailed field experiments are discussed and field data are used to validate the simulated NPP. Remotely sensed images including Landsat Enhanced Thematic Mapper plus (ETM+, 30 m spatial resolution in visible and near infrared bands) and Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER, 15m spatial resolution in visible and near infrared bands) are used to derive maps of land cover, leaf area index, and biomass. Based on these maps, field measured data, soil texture and daily meteorological data, NPP of these sites are simulated for year 2001 with the boreal ecosystem productivity simulator (BEPS). The NPP in these sites ranges from 80 to 800 gCm(-2)a(-1). The observed NPP agrees well with the modeled NPP. This study suggests that BEPS can be used to estimate NPP in northern China if remotely sensed images of high spatial resolution are available.

Biomass↗
PubMed2006

Midbrain pathways for prepulse inhibition and startle activation in rat.

The midbrain is essential for prepulse inhibition (PPI) of the startle reflex, but the exact neural circuits for PPI are not yet determined. Electrical stimulation of the superior colliculus (SC) or pedunculopontine tegmentum was used to characterize the neurons and pathways that mediate PPI and the activation of startle that also occurs at higher currents in the same sites. Startle was inhibited by prepulses in most, but not all SC sites, with the lowest intensity sites in intermediate layers of SC. PPI latencies in SC sites were 4-6 ms longer than in inferior colliculus, intercollicular nucleus or pedunculopontine sites. Contrary to previous serial models, there must be two parallel midbrain pathways for PPI, a faster auditory pathway from inferior colliculus to pedunculopontine tegmentum, and a slower multimodal SC output for PPI. Double-pulse stimulation of SC sites shows that PPI results from direct stimulation of neurons with moderate refractory periods (0.4-1.0 ms), similar to SC neurons that mediate contraversive turning responses. By contrast, startle activation occurring at higher currents in all SC sites (even sites where PPI could not be elicited) results from stimulation of very short refractory period neurons (0.3-0.5 ms) and very long refractory period neurons (1.0-2.0 ms), with startle inhibition often found from 0.5-1.0 ms. Startle activation appears to result from stimulation of short refractory period neurons in deep SC layers that mediate fear-potentiated startle, plus long refractory period substrates in more dorsal SC sites.

Animals↗
PubMed2006

IgE isotype switch and IgE production are enhanced in IL-21-deficient but not IFN-gamma-deficient mice in a Th2-biased response.

IgE plays a critical role in the pathogenesis of allergy and asthma. Therefore, suppression of IgE production would provide therapeutic benefits to patients suffering from these diseases. We have reported that the production of IgE is regulated differently in the spleen vs. the draining lymph nodes (LN). IgE isotype switch and IgE producing B cell expansion occur in the draining LN after antigen (Ag) immunization, but do not happen in the spleen. In addition, a population of pre-existing IgE+ cells is observed in the spleen of normal or sham immunized mice, but is not present in the draining LN. To further understand the regulation of IgE production in different lymphoid organs, and the potential inhibitory factors of IgE isotype switch in the spleen, the involvement of IL-21 and IFN-gamma in regulating IgE production was investigated by using the IL-21 and the IFN-gamma deficient mice. We found that in the absence of IL-21 IgE isotype switch and IgE+ cell clonal expansion were dramatically enhanced in the spleen and IgE isotype switch was partially increased in the draining LN. In addition, IgE production of the pre-existing CD19-CD5+B220(low) IgE+ cells in the spleen was also increased in the absence of IL-21 under physiological conditions. In contrast, using the IFN-gamma deficient mice, we did not observe a negative impact of IFN-gamma on either IgE isotype switch or IgE production. Our data suggest that IL-21 appears to be a critical cytokine to keep low IgE levels under physiological and pathological conditions.

Animals↗
PubMed2006

Phase locking and in-phase supermode selection in monolithic multicore fiber lasers.

We report a compact multicore fiber laser that utilizes an all-fiber approach for phase locking and in-phase supermode selection. By splicing passive coreless fibers of controlled lengths to both ends of an active 19-core fiber, we demonstrate that the fundamental in-phase supermode can be selectively excited with a completely monolithic fiber device, instead of conventional free-space and bulk optics, to achieve phase-locked operation for a multiemitter laser device.

Journal Article↗
PubMed2006

The role of Ret receptor tyrosine kinase in dopaminergic neuron development.

Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent trophic factors identified for promoting survival and function of dopaminergic (DA) neurons in the midbrain. Ret, a member of the receptor tyrosine kinase (RTK) superfamily transduces GDNF signaling. The role of Ret in the development of DA neurons is not clear however. Here we demonstrate the involvement of Ret in the DA neuron development both in vitro and in vivo. The dopamine transporter (DAT) gene was clearly induced in rat embryonic neural precursors that had been transfected with Ret. Temporary blockade of Ret expression in embryos using Ret antisense oligonucleotides (Ret-AS-ODN) in vivo led to reduced striatal DA content and a decrease of tyrosine hydroxylase (TH) positive fibers in the striatum. Additionally, some DA neurons in the substantia nigra (SN) underwent apoptotic cell death following the Ret-AS-ODN treatment. Taken together, the data suggest that normal function of Ret is required in vivo for the maturation of DA neurons, in particular for cell survival and fiber innervation. We further demonstrated Ret-induced expression of DAT in vitro.

Animals↗
PubMed2006

Acoustic waves generated by a laser line pulse in a hollow cylinder.

A theoretical solution is proposed to predict acoustic waves generated in a homogeneous and isotropic hollow cylinder by a laser line source under either ablation or thermoelastic regime. The Fourier series expansion is introduced for one spatial coordinate to solve this transient response problem. Theoretical displacements are obtained in both regimes for aluminum hollow cylinders with various thickness including a rod of the same size. The corresponding displacements are observed experimentally by the laser ultrasonic technique. Agreement has been found in the time arrival, shape and relative amplitude of surface waves and various longitudinal and transverse bulk waves. These acoustic waves are further identified by the ray trajectory analysis. This work will be helpful when dealing with the inverse problem of the nondestructive evaluation of hollow cylindrical parts.

Journal Article↗
PubMed2006

Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients.

Although the selective tyrosine kinase inhibitor imatinib is successfully used in the treatment of chronic myeloid leukemia (CML), inherent mechanisms confer primary resistance to leukemic patients. In order to search for potentially useful genes in predicting cytogenetic response, a retrospective gene expression study was performed. Leukocyte RNA isolated before imatinib from interferon-alpha-pretreated chronic phase CML patients (n=34) with or without major cytogenetic remission (< or =35% Philadelphia (Ph)+ metaphases) during the first year of treatment was comparatively analyzed using Affymetrix U133A chips. Using support vector machines for gene classification, an outcome-specific gene expression signature consisting of 128 genes was identified. Comparative expression data of specific genes point to changes in apoptosis (e.g. casp9, tumor necrosis factor receptor-associated protein 1, hras), DNA repair (msh3, ddb2), oxidative stress protection (glutathione synthetase, paraoxonase 2, vanin 1) and centrosomes (inhibitor of differentiation-1) within primary resistant patients. Independent statistical approaches and quantitative real-time reverse transcriptase-polymerase chain reaction studies support the clinical relevance of gene profiling. In conclusion, this study establishes a candidate predictor of imatinib resistance in interferon-alpha-pretreated CML patients to be subjected to future investigation in a larger independent patient cohort. The resulting expression signature point to involvement of BCR-ABL-independent mechanisms of resistance.

Antineoplastic Agents↗
PubMed2006

Trimethyltin-induced apoptosis is associated with upregulation of inducible nitric oxide synthase and Bax in a hippocampal cell line.

Trimethyltin (TMT) produces selective neuronal degeneration in the central nervous system (CNS), in which the hippocampus is the most sensitive area. Since previous studies have been conducted in either non-neural cells or mixed primary cultures, an immortalized hippocampal neuronal cell line (HT-22 cell) was used to assess the mechanism and mode of death produced by TMT. The compound produced a time- and concentration-dependent apoptotic death that was caspase-mediated. Excessive generation of reactive oxygen species (ROS) and subsequent reduction of mitochondrial membrane potential (DeltaPsim) were involved in the cytotoxicity. Scavenging of ROS by a free radical trapping agent or inhibition of the mitochondrial permeability transition (MPT) pore significantly reduced cell death. Additionally, TMT increased expression of inducible nitric oxide synthase (iNOS) by activation of the redox-sensitive transcription factor NFkappaB. Pharmacologic inhibition studies showed that the iNOS-mediated NO generation increased expression of Bax and then mitochondrial-mediated apoptosis. It was concluded that excessive ROS generation initiated the apoptotic cell death by upregulating iNOS followed by increased Bax expression which then led to loss of DeltaPsim and caspase-executed cell death. This study is the first to report in a neuronal cell model that TMT stimulates induction of iNOS, which then increases cellular levels of reactive nitrogen species (RNS) to initiate apoptotic death.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Efficacy of local dipyridamole therapy in a porcine model of arteriovenous graft stenosis.

Perivascular delivery of antiproliferative drugs has been proposed as an approach to prevent neointimal hyperplasia associated with hemodialysis polytetrafluoroethylene (PTFE) grafts. We examined this approach to deliver dipyridamole in a porcine graft model. PTFE grafts were implanted between the carotid artery and external jugular vein bilaterally in pigs. During the surgery or 1 week post-graft placement, dipyridamole (0.26-52 mg) alone or incorporated in microspheres was mixed with an injectable polymeric gel and applied to the graft-arterial and graft-venous anastomoses on one side, whereas the contralateral control graft received no treatment. Three or four weeks after operation, the grafts and adjacent vessels were explanted en bloc and cross-sections of the anastomoses were examined histologically. The degree of neointimal hyperplasia was quantified by planimetry. In separate experiments, dipyridamole was extracted from the explanted tissues and assayed by spectrofluorometry. The normalized median hyperplasia areas of the treated and control graft-venous anastomoses were 0.45 (25th-75th percentile, 0.30-0.86) and 0.24 (0.21-0.30), respectively (N=7; P=0.08). The median hyperplasia areas of the treated and control graft-arterial anastomoses were 0.12 (0.07-0.39) and 0.11 (0.09-0.13), respectively (N=7; P=0.31). The dipyridamole levels in the vascular walls around the anastomoses were at or above the in vitro inhibitory concentrations for approximately 3 weeks. These results suggest that the local perivascular sustained delivery of dipyridamole, even at high dosages, was ineffective in inhibiting neointimal hyperplasia associated with PTFE grafts in a porcine model.

Animals↗
PubMed2006

Effect of cilnidipine on left ventricular function in hypertensive patients as assessed by tissue Doppler Tei index.

Tissue Doppler Tei index is pointed to be more effective in the evaluation of global cardiac function than systolic and diastolic measurements alone in various heart diseases. This study was designed to assess the effect of cilnidipine on left ventricular function in hypertensive patients by using this index. A group of 40 hypertensives (mean age 55+/-8 years, range: 35-65) and 16 controls (mean age 52+/-9 years, range: 36-65) were included. Hypertensives were classified into non-left ventricular hypertrophy (NLVH) group (25 patients) and left ventricular hypertrophy (LVH) group (15 patients), and treated with cilnidipine for 2 months. Before and after treatment, the participants were examined by echocardiography. Tissue Doppler Tei index was calculated as diastolic time interval measured from end of late diastole to origin of early diastole (a') minus systolic Sm duration (b') divided by b', that is Tei index = (a'-b')/b'. Thirty-seven hypertensive patients finished the treatment. Tei index was significantly higher in NLVH and LVH groups than in control group, and in LVH group than in NLVH group (0.44+/-0.07 vs 0.28+/-0.06, P < 0.001; 0.51+/-0.13 vs 0.28+/-0.06, P < 0.001; 0.51+/-0.13 vs 0.44+/-0.07, P < 0.05). After treatment, Tei index was significantly decreased (0.40+/-0.11 vs 0.46+/-0.10, P < 0.0001); systolic blood pressure and diastolic blood pressure were also decreased significantly. In conclusion, Tei index is impaired in hypertensives before development of ventricular hypertrophy and impairment is more prominent in hypertrophy. Cilnidipine can improve left ventricular function. Tissue Doppler Tei index is gaining importance in evaluating LV function after drug intervention in hypertensive patients.

Calcium Channel Blockers↗
PubMed2006

The mechanomyography of persons after stroke during isometric voluntary contractions.

This study was to investigate the properties of mechanomyography (MMG), or muscle sound, of the paretic muscle in the affected side of hemiplegic subjects after stroke during isometric voluntary contractions, in comparison with those from the muscle in the unaffected side of the hemiplegic subjects and from the healthy muscle of unimpaired subjects. MMG and electromyography (EMG) signals were recorded simultaneously from the biceps brachii muscles of the dominant arm of unimpaired subjects (n=5) and the unaffected and affected arms of subjects after stroke (n=8), when performing a fatiguing maximal voluntary contraction (MVC) associated with the decrease in elbow flexion torque, and then submaximal elbow flexions at 20%, 40%, 60% and 80% MVCs. The root mean squared (RMS) values, the mean power frequencies (MPF, in the power density spectrum, PDS) of the EMG and MMG, and the high frequency rate (HF-rate, the ratio of the power above 15Hz in the MMG PDS) were used for the analysis. The MMG RMS decreased more slowly during the MVC in the affected muscle compared to the healthy and unaffected muscles. A transient increase could be observed in the MMG MPFs from the unaffected and healthy muscles during the MVC, associated with the decrease in their simultaneous EMG MPFs due to the muscular fatigue. No significant variation could be seen in the EMG and MMG MPFs in the affected muscles during the MVC. The values in the MPF and HF-rate of MMG from the affected muscles were significantly lower than those from the healthy and unaffected muscles (P<0.05) at the high contraction level (80% MVC). Both the MMG and EMG RMS values in the healthy and unaffected groups were found to be significantly higher than the affected group (P<0.05) at 60% and 80% MVCs. These observations were related to an atrophy of the fast-twitch fibers and a reduction of the neural input in the affected muscles of the hemiplegic subjects. The results in this study suggested MMG could be used as a complementary to EMG for the analysis on muscular characteristics in subjects after stroke.

Adult↗
PubMed2006

Molecular characterisation of non-absorptive and absorptive enterocytes in human small intestine.

BACKGROUND AND AIMS: Perturbation of differentiation of the crypt-villus axis of the human small intestine is associated with several intestinal disorders of clinical importance. At present, differentiation of small intestinal enterocytes in the crypt-villus axis is not well characterised. SUBJECTS AND METHODS: Expression profiling of microdissected enterocytes lining the upper part of crypts or the middle of villi was performed using the Affymetrix X3P arrays and several methods for confirmation. RESULTS: A total of 978 differentially expressed sequences representing 778 unique UniGene IDs were found and categorised into four functional groups. In enterocytes lining the upper part of crypts, cell cycle promoting genes and transcription/translation related genes were predominantly expressed, whereas in enterocytes lining the middle of villi, high expression of cell cycle inhibiting genes, metabolism related genes, and vesicle/transport related genes was found. CONCLUSION: Two types of enterocytes were dissected at the molecular level, the non-absorptive enterocyte located in the upper part of crypts and the absorptive enterocyte found in the middle of villi. These data improve our knowledge about the physiology of the crypt-villus architecture in human small intestine and provide new insights into pathophysiological phenomena, such as villus atrophy, which is clinically important.

Adult↗