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Biomedical subjects

Xin Huang

Publications and source records attributed to Xin Huang.

At least 37 records · Page 2Linked to original sources
PubMed2006

Overexpression of glycosylphosphatidylinositol (GPI) transamidase subunits phosphatidylinositol glycan class T and/or GPI anchor attachment 1 induces tumorigenesis and contributes to invasion in human breast cancer.

Based on the oncogenic role of phosphatidylinositol glycan (PIG) class U in human tumors, we explored the role of two additional subunits of the glycosylphosphatidylinositol (GPI) transamidase complex in human breast cancer. We found that PIG class T (PIG-T) and GPI anchor attachment 1 (GPAA1) were overexpressed in breast cancer cell lines and primary tumors. Forced expression of PIG-T and GPAA1 transformed NIH3T3 cells in vitro and increased tumorigenicity and invasion of these cells in vivo. Suppression of PIG-T expression in breast cancer cell lines led to inhibition of anchorage-independent growth. Moreover, we found that PIG-T and GPAA1 expression levels positively correlated with paxillin phosphorylation in invasive breast cancer cell lines. Furthermore, suppression of PIG-T and GPAA1 expression led to a decrease in paxillin phosphorylation with a concomitant decrease in invasion ability. These results suggest that the GPI transamidase complex is composed of a group of proto-oncogenes that individually or as a group contribute to breast cancer growth. This aberrant growth is mediated, at least partially, by phosphorylation of paxillin, contributing to invasion and progression of breast cancer.

Acyltransferases↗
PubMed2006

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

BACKGROUND: No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. METHODS: Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. FINDINGS: 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. INTERPRETATION: We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

Adult↗
PubMed2006

Responses of neurons in the medial superior temporal visual area to apparent motion stimuli in macaque monkeys.

Monkeys fixated a stationary spot during presentation of dot textures that moved in apparent motion defined by the spatial and temporal separations, Deltax and Deltat, between successive flashes of each dot. For each neuron, we assessed the speed tuning for smooth motion (Deltat = 2 or 4 ms) at speeds < or =128 degrees /s and the effect of varying the value of Deltat at speeds of 16 and 32 degrees /s. Many medial superior temporal (MST) neurons, like middle temporal (MT) neurons, were tuned for the speed of smooth motion and showed decreases in firing rate as the value of Deltat increased at a constant speed. A subset of MST neurons, however, showed monotonically increasing firing rates as a function of smooth stimulus speed and responses to apparent motion that paralleled a previously discovered illusion where estimates of target speed increase with the value of Deltat. Opponent firing rate, defined as the difference between responses for motion in the preferred and opposite directions, peaked at values of Deltat that were consistent with the behavioral illusion. Comparison with a new sample of MT neurons recorded with the same stimuli failed to reveal comparable effects. Attempts to map the population responses in MT and MST onto the behavioral illusion of increased speed succeeded by averaging the opponent response across MST neurons, but only by applying vector averaging to determine the preferred speed of the most active MT neurons. We suggest that a vector-averaging computation transforms MT's place code for target speed into the rate code of some MST neurons.

Action Potentials↗
PubMed2006

Dopamine transporter and D2 receptor binding densities in mice prone or resistant to chronic high fat diet-induced obesity.

This study examined the density of dopamine transporter (DAT) and D2 receptors in the brains of chronic high-fat diet-induced obese (cDIO), obese-resistant (cDR) and low-fat-fed (LF) control mice. Significantly decreased DAT densities were observed in cDR mice compared to cDIO and LF mice, primarily in the nucleus accumbens, striatal and hypothalamic regions. D2 receptor density was significantly lower in the rostral part of caudate putamen in cDIO mice compared to cDR and LF mice.

Analysis of Variance↗
PubMed2006

Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.

Administration, Oral↗
PubMed2006

Photoelectron spectroscopy of free multiply charged Keggin anions alpha-[PM12O40]3- (M = Mo, W) in the gas phase.

Two polyoxometalate Keggin-type anions, alpha-PM12O40(3-) (M = Mo, W), were transferred to the gas phase by electrospray; their electronic structure and stability were probed by photoelectron spectroscopy. These triply charged anions were found to be highly stable in the gas phase with large adiabatic electron detachment energies of 1.7 and 2.1 eV for M = Mo and W, respectively. The magnitude of the repulsive Coulomb barrier was measured as approximately 3.4 eV for both anions, providing an experimental estimate for the intramolecular Coulomb repulsion present in these highly charged anions. Density functional theory calculations were carried out and compared with the experimental data, providing insight into the electronic structure and valence molecular orbitals of the two Keggin anions. The calculations indicated that the highest occupied molecular orbital and other frontier orbitals for PM12O40(3-) are localized primarily on the mu2-oxo bridging ligands of the polyoxometalate framework, consistent with the reactivity on the mu2-oxo sites observed in solution. It was shown that the HOMO of PW12O40(3-) is stabilized relative to that of PMo12O40(3-) by approximately 0.35 eV. The experimental adiabatic electron detachment energies of PM12O40(3-) (i.e., the electron affinities of PM12O40(2-)) are combined with recent calculations on the proton affinity of PM12O40(3-) to yield O-H bond dissociation energies in PM12O39(OH)2- as approximately 5.1 eV.

Gases↗
PubMed2006

Pb12 2-: plumbaspherene.

Although Si or Ge is not known to form empty cage clusters such as the fullerenes, we recently found a unique 12-atom icosahedral tin cluster, Sn12 2- (stannaspherene). Here we report photoelectron spectroscopy and theoretical evidence that Pb12 2- is also a highly stable icosahedral cage cluster and bonded by four delocalized radial pi bonds and nine delocalized on-sphere sigma bonds from the 6p orbitals of the Pb atoms. Following Sn12 2-, we coin a name, plumbaspherene, for the highly stable and nearly spherical Pb12 2- cluster, which is expected to be stable in solution and the solid state. Plumbaspherene has a diameter of approximately 6.3 A with an empty interior volume large enough to host most transition metal atoms, affording a new class of endohedral clusters.

Journal Article↗
PubMed2006

Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study.

Mesenchymal stem cells (MSCs) are potential sources of cells for tissue repair. However, little information is available about the time course of homing and differentiation of systemically delivered MSCs after acute myocardial ischemia (MI). In the present study, MSCs were isolated from male rat bone marrow and expanded in vitro. Female rats were divided randomly into three groups. Three hours after coronary ligation, the transplanted group received an infusion of MSCs through the tail vein; at the same time, a coronary-ligated control group was injected with culture medium, and a normal (unligated) group received MSCs. Homing of MSCs to the heart was assessed by expression of the Y chromosome sry gene using fluorescence in situ hybridization (FISH) at 3 days, 1, 4, and 8 weeks after transplantation. Immunofluorescent staining was used to examine markers for cardiomyocytes, endothelial cells, and smooth muscle cells. Hemodynamics in the hearts was also measured to assess cardiac function. At each time point, sry-positive cells were present in the cardiac tissue in transplanted group but not in the hearts of normal and control group animals. The number of sry-positive cells was significantly higher at 1 week compared to 3 days after transplantation. No significant difference was found in the number of sry-positive cells among those of 1, 4, and 8 weeks after transplantation. At 3 days and 1 week after transplantation, the sry-positive cells in the transplanted group lacked troponin, desmin, smooth muscle alpha-actin, and CD31. At the later time points, cardiomyocytes, smooth muscle cells, and endothelial cells bearing sry were identified in the transplanted group. The cardiac function in transplanted group showed higher improvement at 4 and 8 weeks compared to 1 week after transplantation. Our data suggest that intravenously delivered MSCs are capable of homing toward the ischemic myocardium, and the fastigium of homing appeared around 1 week after MI. The differentiation of MSCs to cardiomyocytes, smooth muscle cells, and endothelial cells shows to be time dependent and arises at 1 to 4 weeks after transplantation.

Animals↗
PubMed2006

Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.

Administration, Oral↗
PubMed2006

Sn12(2-): stannaspherene.

Stannaspherene. The Sn122- cluster is discovered to be a highly stable and highly symmetric icosahedral cage bonded by four delocalized radial pi bonds and nine delocalized on-sphere sigma bonds from the 5p orbitals of the Sn atoms. It has a diameter of 6.1 A, with a large empty interior volume, and can host most transition metal atoms inside, giving rise to a large class of endohedral chemical building blocks for cluster-assembled nanomaterials.

Journal Article↗
PubMed2006

Olanzapine differentially affects 5-HT2Aand2C receptor mRNA expression in the rat brain.

This study examined regional changes in rat brain mRNA levels encoding 5-HT(2A) and 5-HT(2C) receptors following chronic olanzapine treatment. The immediate effect (2h after the last treatment) was a down-regulation of 5-HT(2A) receptor mRNA expression, predominantly in the hypothalamus, limbic system and striatum, while a rebound effect was observed 48 h later. 5-HT(2C) receptor mRNA expressions were decreased in the substantia nigra. Correlations between 5-HT(2A) receptor mRNA expression and total food intake, weight gain and energy efficiency were observed.

Analysis of Variance↗
PubMed2006

Regulation of supramolecular chirality and morphology of the LB film of achiral barbituric acid by amphiphilic matrix molecules.

Previously, we have found that an achiral barbituric acid (BA) derivative, 5-(4-(N-methyl-N-hexadecylaminobenzylidene))-2,4,6-(1H,3H)-pyrimidinetrione (BAC16), could form molecular assemblies showing supramolecular chirality through the organization at the air/water interface. To acquire more knowledge of the formation mechanism of such supramolecular assemblies, some achiral molecules, such as stearic acid (SA), octadecylamine (ODA), and an analogue of BA without an alkyl chain, were mixed into the BAC16 system. The effects of these matrix molecules on the supramolecular chirality and surface morphologies of Lanmuir-Blodgett (LB) films were investigated. It was observed that, at a low molar ratio of the matrix molecules (below 10%), the chirality of the BAC16 assemblies could be maintained with only a reduction in the intensity. When the matrix fraction was increased, the supramolecular chirality of the mixed films disappeared. The addition of the matrix molecules can greatly change the surface morphologies of the mixed films. When SA was mixed with BAC16, the spiral nanofibers of BAC16 were changed to long nanofibers. When ODA was mixed, the hydrolytic cleavage reaction of BAC16 took place at the air/water interface and disordered spirals were obtained. When the analogous BA derivate without an alkyl chain was mixed, the phase-separating morphology was observed. These changes in the chirality and surface morphologies indicated firmly that the supramolecular chirality of BAC16 films were formed due to the cooperative arrangement of the molecules. A certain amount of matrix molecules will destroy the cooperative arrangement and thus the chirality.

Journal Article↗
PubMed2006

Cyclodextrin-derived mimic of glutathione peroxidase exhibiting enzymatic specificity and high catalytic efficiency.

To elucidate the relationships between molecular recognition and catalytic ability, we chose three assay systems using three different thiol substrates, glutathione (GSH), 3-carboxyl-4-nitrobenzenethiol (CNBSH), and 4-nitrobenzenethiol (NBSH), to investigate the glutathione peroxidase (GPx) activities of 2,2'-ditellurobis(2-deoxy-beta-cyclodextrin) (2-TeCD) in the presence of a variety of structurally distinct hydroperoxides (ROOH), H2O2, tert-butyl peroxide (tBuOOH), and cumene peroxide (CuOOH), as the oxidative reagent. A comparative study of the three assay systems revealed that the cyclodextrin moiety of the GPx mimic 2-TeCD endows the molecule with selectivity for ROOH and thiol substrates, and hydrophobic interactions are the most important driving forces in 2-TeCD complexation. Furthermore, in the novel NBSH assay system, 2-TeCD can catalyze the reduction of ROOH about 3.4 x 10(5) times more efficiently than diphenyl diselenide (PhSeSePh), and its second-order rate constants for thiol are similar to some of those of native GPx. This comparative study confirms that efficient binding of the substrate is essential for the catalytic ability of the GPx mimic, and that NBSH is the preferred thiol substrate of 2-TeCD among the chosen thiol substrates. Importantly, the proposed mode of action of 2-TeCD imitates the role played by several possible noncovalent interactions between enzymes and substrates in influencing catalysis and binding.

Catalysis↗
PubMed2006

Direct experimental probe of the on-site Coulomb repulsion in the doubly charged fullerene anion C70 2-.

Vibrationally resolved photoelectron spectra were obtained for cold C(70)- and C(70)2-. Accurate values for the first and second electron affinities (EA's) of C(70) were measured as 2.765 +/- 0.010 and 0.002 (+0.01/-0.03)eV, respectively, establishing that C(70)-2 is an electronically stable dianion in the gas phase. The difference between the first and second EA (2.75 eV) provides a direct experimental measure for the on-site Coulomb and exchange interactions between the two excess electrons in C(70)-2. Strong electron correlation effects were also observed between the two excess electrons in C(70)-2.

Journal Article↗
PubMed2006

Proper levels of c-Myb are discretely defined at distinct steps of hematopoietic cell development.

The definitive hematopoietic cell lineages have been proposed to originate from hemogenic endothelial cells during mouse embryogenesis. c-Myb is a transcription factor that is essential for the development of definitive hematopoiesis. To investigate the functional role of c-Myb in hematopoietic cell development from endothelial cells, we introduced a c-myb transgene expressed under the control of a tetracycline-regulated promoter into the c-myb(-/-) embryonic stem (ES) cell line, with the aim of inducing c-Myb expression at any stage and at any level. Induction of c-Myb expression after replating c-myb(-)(/)(-) endothelial cells rescued the generation and proliferation of definitive hematopoietic progenitor cells, suggesting that c-Myb expression in developing endothelial cells is not a prerequisite for their hematogenic potential. Overexpression of c-Myb, however, prevented the terminal differentiation of erythrocytes and megakaryocytes and completely abolished B-lymphocyte development. Our results indicate that c-Myb is a major factor that controls differentiation as well as proliferation of hematopoietic progenitor cells derived from hemogenic endothelial cells, and that appropriate levels of c-Myb protein are strictly defined at distinct differentiation steps of each hematopoietic cell lineage.

Animals↗
PubMed2006

[Expression of key cell cycle markers in squamous cell carcinoma of the cervix positive in human papillomavirus: a comparative study between Chinese and Australian populations].

OBJECTIVE: To investigate the patterns of expression of key cell cycle proteins targeting on the human papillomavirus (HPV) sites E6 and E7 in cervical carcinoma. METHODS: Semiquantitative immunohistochemistry was used to determine the expression of the cell cycle regulatory factor p53, retinoblastoma gene product pRb, cyclin-dependent kinase inhibitors p21(CIP1/WAF1) (p21), p16(INK4A) (p21), and p27(KIP1) (p21), and cyclin D1 targeting on the HPV sites E6 and E7 in 73 HPV 16-positive specimens of cervical squamous cell carcinoma, 35 from Australia patients and 38 age, lymph node status, and grade of tumor-matched Chinese patients. RESULTS: There were no significant differences in age, lymph node status, and grade of tumor between the Chinese and Australian groups, however, the number of the patients in advanced stage (>Stage IIa) was greater in the Chinese group than in the Australian group (19:7). The positive rate of p53 in the Australian group was 3%, significantly lower than that in the Chinese group (23%, P = 0.028). The upregulation rate of pRb, p21, and p27 in the Australian group were 56%, 63% and 34% respectively, all significantly higher than those in the Chinese group (89%, 97%, and 89% respectively, P = 0.01, P < 0.001, and P < 0.001). There were no significant differences in the upregulation rate of p16 and cyclin D1 expression rate between the Australian group and Chinese group (97% versus 100%, and 3% versus 12%, both P > 0.05). In the combined data of both groups, the positive rate of p53 was 13%; and the upregulation rates of pRb, p16, p21, p27, and cyclin D1 were 74%, 99%, 81%, 63% and 7% respectively. CONCLUSION: Cervical carcinoma overexpresses pRb, p16, p21, and p27. Tumors from Chinese patients are significantly more likely to be positive in p53 and to have upregulated pRb, p21, and p27 than their Australian counterparts. The molecular pathways to human papillomavirus-induced cervical cancer may be influenced by ethnicity and further investigation is necessary.

Australia↗