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Biomedical subjects

Q Shi

Publications and source records attributed to Q Shi.

At least 19 recordsLinked to original sources
PubMed2007

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases.

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.

Brain Neoplasms↗
PubMed2007

PD-L1 expression analysis in gastric carcinoma tissue and blocking of tumor-associated PD-L1 signaling by two functional monoclonal antibodies.

Programmed death-1 ligand-1 (PD-L1), a member of the B7 family of costimulatory molecules, plays an important role in the regulations of the cellular and humoral immune responses. In this study, two mouse anti-human PD-L1 monoclonal antibodies named 10E10 and 2H11 were successfully generated and further characterized. Monoclonal antibody 10E10 bound to distinct PD-L1 epitope comparing an available anti-PD-L1 monoclonal antibody on a series of malignant cell lines, activated T lymphocytes, B lymphocytes and dendritic cells. Then, by using immunohistochemistry staining with monoclonal antibody 2H11, the expression of PD-L1 was found in human gastric carcinoma specimens but not in normal or gastric adenoma tissues. Additional data show that PD-L1 can be regarded as a decisive factor in evaluating gastric carcinoma prognosis and anti-human PD-L1 monoclonal antibody 10E10 could inhibit T-cell apoptosis induced by tumor-associated PD-L1. Taken together, these results showed that the two functional mouse anti-human PD-L1 monoclonal antibodies we generated might be of great value for further exploration of the costimulatory molecule regulating network and immunointervention for tumor immunotherapy.

Animals↗
PubMed2006

Evidence for two distinct pathways in TNFalpha-induced membrane and soluble forms of ICAM-1 in human osteoblast-like cells isolated from osteoarthritic patients.

OBJECTIVE: The present study aimed to investigate the modulation of membrane-bound intercellular adhesion molecule-1 (mICAM-1) and soluble ICAM-1 (sICAM-1) expression by tumor necrosis factor-alpha (TNFalpha) in human osteoarthritic (OA) osteoblasts. METHODS: Cultured human primary osteoblasts were stimulated with increasing concentrations of human recombinant TNFalpha. Expression of mICAM-1 and sICAM-1 was evaluated by immunocytochemistry, enzyme-linked immunosorbent assay and semi-quantitative reverse transcriptase-polymerase chain reaction. In addition, we investigated the molecular mechanisms underlying ICAM-1 induction by TNFalpha, focusing on the activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB) pathways. RESULTS: Our data showed that TNFalpha dose-dependently increased mICAM-1 and sICAM-1 expression at the protein and mRNA levels in OA osteoblasts. The inhibitor of de novo mRNA synthesis, actinomycin D, suppressed TNFalpha-induced mICAM-1 and sICAM-1 expression. Upon examination of the signaling components, we found that TNFalpha was a potent activator of p38, p44/42, p54/46 MAPK, and IkappaBalpha (IkappaBalpha). The chemical inhibitors of p38, p44/42 MAPK, and NF-kappaB blocked TNFalpha-induced mICAM-1 expression but not that of sICAM-1. Transfection experiments revealed that p38 MAPK or IkappaB kinase alpha (IKKalpha) overexpression enhanced TNFalpha-induced mICAM-1 production. Furthermore, osteoblasts treatment with a chemical inhibitor of metalloproteinase-9 (MMP-9) activity, a proteolytic enzyme involved in ICAM-1 cleavage, evoked a significant 25% decrease of TNFalpha-induced sICAM-1 release. CONCLUSION: Taken together, these findings illustrate the central role played by TNFalpha in the regulation of ICAM-1. We suggest that TNFalpha differentially regulates sICAM-1 and mICAM-1 expression and that sICAM-1 release involves, in part, the proteolytic cleavage of mICAM-1 by MMP-9. The capacity of the MMP-9 inhibitor to prevent sICAM-1 production may be useful for the development of novel therapeutic approaches relevant to OA.

Dactinomycin↗
PubMed2006

Cerebrovascular disease among patients from the Indian subcontinent.

In this study, the authors document the characteristics of South Asian (SA) cerebrovascular patients. A retrospective medical record review comparing SA (n = 99) and European-American (n = 106) patients was performed. SA patients were younger and had a greater prevalence of diabetes, but lower prevalences of hyperlipidemia and tobacco use. SA patients experienced a 75% lower risk of cardiogenic infarctions, but a threefold increased risk of intracranial atherothrombosis. Risk factor modifications and secondary prevention strategies may differ for SA patients.

Aged↗
PubMed2006

Regulated release of VWF and FVIII and the biologic implications.

von Willebrand factor (VWF) performs a critical function in platelet binding at the site of vascular injury and also serves as the carrier protein for coagulation factor FVIII (FVIII), protecting it from proteolytic degradation in plasma. Both proteins undergo rapid, regulated release in response to DDAVP administration in patients with mild hemophilia A or von Wille-brand disease. Here, we attempt to summarize our current understanding of the establishment of the regulated storage pool of VWF and FVIII. The data presented indicate that regulated secretion of both proteins occurs only if there is endogenous synthesis of FVIII together with VWF.

Coagulants↗
PubMed2006

Reticulon proteins: emerging players in neurodegenerative diseases.

Reticulons (RTNs) are a group of integral membrane proteins that have a uniquely conserved C-terminal domain named RHD. In mammalian genomes, transcripts are produced from four genes, rtn1 to rtn4, under the regulation of tissue or cell-type-specific expression. The presence of alternative promoters for gene expression and multiple cryptic splicing sites have resulted in large numbers of genes/proteins that are classified among the reticulon family. Although this family exists in almost all eukaryotes, only the rtn4 gene product, Nogo (RTN4), has gained relatively more in-depth attention. Despite predominant localization in the endoplasmic reticulum, Nogo on the cell surface appears to play a critical role as an inhibitory molecule for axonal growth and regeneration in humans and rodents. Recently, studies have expanded the biological functions of RTNs to other facets including modulating the enzymatic activity of beta-secretase in Alzheimer's disease. In this review, we summarize the accumulated findings concerning the structural and functional aspects of RTNs and speculate on their linkage to the pathogenesis of neurodegenerative diseases.

Animals↗
PubMed2006

Characterization and application of two novel monoclonal antibodies against human OX40: costimulation of T cells and expression on tumor as well as normal gland tissues.

OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is a critical costimulatory receptor during the immune response. Here, we newly generated two specific mouse antihuman OX40 monoclonal antibodies (mAbs) (2G2 and 1F7), whose specificities are quite different from the available OX40 mAb (ACT35) by competition assay. It was also found that both mAbs could enhance the proliferation, activation and differentiation of T lymphocytes primed by anti-CD3 mAb. These results evidenced that both were functional antihuman OX40 mAbs. Furthermore, stained by 2G2 and 1F7, FCM and immunohistochemistry detected the constitutive expression of OX40 on tumor cell lines from epithelium, breast cancer and glioma tissues. Meanwhile, the non-tumor tissues (thyroid gland, stomach gland) were also found OX40 expression. These results suggested that OX40 is not only expressed in activated T cells, but also in some tumors as well as normal gland tissues. Such expression pattern indicated that OX40 may be a valuable surface antigen in unveiling its expression and function outside the immune system. Briefly, these novel antibodies may contribute to the evaluation of the mechanism of tumor metastasis and eventually shed light on further study of tumor immunotherapy and autoimmune diseases.

Animals↗
PubMed2006

Changes in serum cardiac troponins following a 21-km run in junior male runners.

AIM: This study was designed to examine the appearance and clearance characteristics of serum cardiac troponin T (cTnT) and I (cTnI) in junior runners after an exhaustive 21-km run. The dependence of the alternations of the cardiac troponins on the runners' training status reflected in training years, running ability and physiological profile at ventilatory threshold (Th(vent)) was also examined. METHODS: Ten trained male adolescents (16.2+/-0.6 years) performed 21-km run and graded treadmill exercise with maximum effort on two different days. cTnT and cTnI immediately before and 2, 4 and 24 hours after exercise were measured in the 21-km trial. The parameters at Thvent including the running speed (Th(vent)-Speed) and VO2 (Th(vent)-VO2) were identified in the graded exercise trial. RESULTS: Serum cTnT and cTnI in 6 of the 10 subjects measured 4 hours after the 21-km run were above the myocardial injury cutoffs of 0.03 and 0.09 ng x mL(-1), respectively, but returned towards pre-exercise levels within 24 hours that were not in the same manner observed in the clinical situation of myocardial infraction. The 6 subjects' training status was generally lower than that of the rest 4. Further, subjects' 4-h serum cTnT and cTnI were negatively related to their training years, Th(vent)-Speed and Th(vent)-VO2, and positively related to their personal best in half- and full-marathon races (r2 = or > 36%, n = 10). CONCLUSIONS: Such findings implied that clinicians based the diagnosis of long-distance run-induced myocardial infraction in novice junior runners upon the transient postexercise elevations of cardiac troponins alone should be with caution.

Adolescent↗
PubMed2005

Subchondral and trabecular bone metabolism regulation in canine experimental knee osteoarthritis.

OBJECTIVE: To determine trabecular and subchondral bone metabolic changes in experimental canine osteoarthritis (OA). METHODS: OA was induced in 19 dogs by transection of the anterior cruciate ligament (ACL) of the right knee through a stab wound. Dogs were sacrificed at 8 (n=7) and 12 weeks (n=12) after surgery. Non-operated normal dogs (n=6) were used as controls. After sacrifice, samples were obtained from the weight-bearing area of medial tibial plateaus. Explants and cell cultures were prepared from subchondral and trabecular bone. Osteocalcin (Oc), cellular alkaline phosphatase (ALPase), urokinase plasminogen-activator (uPA), prostaglandin E2 (PGE2), metalloproteinase (MMP) and nitric oxide (NO) were measured using standard procedures. RESULTS: ALPase production was significantly increased only at week 12 in subchondral and trabecular bone, while an increase in Oc was noted at week 8. uPA and MMP activity were increased significantly at week 12 in subchondral bone, while PGE2 levels were significantly higher in subchondral and trabecular bone at week 12 compared to normal. A decrease in NO production appeared late at week 12 in trabecular bone, whereas NO levels from subchondral bone were significantly increased compared to normal at week 8. DISCUSSION: Intense bone remodeling takes place in both subchondral and trabecular bone in the knee following ACL transection. This process seems to occur around week 12, although Oc and NO appeared to be involved earlier at 8 weeks. These results suggest that not only subchondral but also trabecular bone metabolism is altered in this OA model.

Alkaline Phosphatase↗
PubMed2005

Characterization and application of two novel monoclonal antibodies against 2IgB7-H3: expression analysis of 2IgB7-H3 on dendritic cells and tumor cells.

2IgB7-H3 has recently been identified as a new member of the B7 family. Its expression at the protein level remains largely unknown due to the lack of the specific monoclonal antibody (mAb). To characterize the expression of 2IgB7-H3, we newly generated two mouse antihuman 2IgB7-H3 mAbs (4H7 and 21D4). We found the constitutive expression of 2IgB7-H3 on a series of tumor cell lines. Furthermore, the expression was examined on monocyte-derived dendritic cells (Mo-DCs) and DCs from CD34(+) hematopoietic progenitor cells (HPC) by means of mAb staining. The results showed that 2IgB7-H3 was expressed on Mo-DCs at a high and stable level during differentiation in vitro. With the maturation of DCs from CD34(+) HPCs, the expression of the molecule was upregulated. However, the 2IgB7-H3 was not expressed on fresh isolated T and B lymphocytes, monocytes, or CD34(+) HPCs. These results suggested that 2IgB7-H3 may be a valuable surface antigen for the detection of DCs.

Animals↗
PubMed2005

Driver landmark and traffic sign identification in early Alzheimer's disease.

OBJECTIVE: To assess visual search and recognition of roadside targets and safety errors during a landmark and traffic sign identification task in drivers with Alzheimer's disease. METHODS: 33 drivers with probable Alzheimer's disease of mild severity and 137 neurologically normal older adults underwent a battery of visual and cognitive tests and were asked to report detection of specific landmarks and traffic signs along a segment of an experimental drive. RESULTS: The drivers with mild Alzheimer's disease identified significantly fewer landmarks and traffic signs and made more at-fault safety errors during the task than control subjects. Roadside target identification performance and safety errors were predicted by scores on standardised tests of visual and cognitive function. CONCLUSIONS: Drivers with Alzheimer's disease are impaired in a task of visual search and recognition of roadside targets; the demands of these targets on visual perception, attention, executive functions, and memory probably increase the cognitive load, worsening driving safety.

Aged↗
PubMed2004

Expression modulation of multiple cytokines in vivo by cyanobacteria blooms extract from Taihu Lake, China.

Cyanobacterial blooms that generate microcystins (MCs) are being increasingly recognized as a potent health hazard in aquatic ecosystems. However, immunomodulation induced by cyanotoxins has not been well documented. This paper reports the in vivo data on the immune disorder caused by crude microcystin (MC) extract of cyanobacteria blooms collected from Taihu Lake, China, with respect to cytokine mRNA levels. Using reverse-transcriptional polymerase chain reaction (RT-PCR), the expression of multiple cytokines, including proinflammatory (IL-1beta, TNF-alpha, and IL-6) and Th1/Th2-related cytokines (IL-2, IL-4 and IL-10), was evaluated following the cyanobacteria blooms extract containing MCs (CBE) exposure at four doses of 23, 38, 77, 115 mg lyophilized algae cells/kg body weight. The results showed that the mRNA levels of TNF-alpha, IL-1beta, IL-2 and IL-4 decreased significantly following injection of all doses as compared to the control (LPS or ConA only), while the IL-6 level was unaffected. Contrast to this decrease, the level of IL-10 mRNA was, however, transiently up regulated following injection of the lowest dose of CBE. The distinct patterns of expression of these cytokines suggested a modulation of cytokine network, the essential component of the host immune system. We further developed a mathematical model to simulate the interaction of T helper cell subsets and related cytokines, which proved to be a good approach to study the kinetics of the interaction of cells and cytokines in microcystin immunosuppression.

Animals↗
PubMed2004

Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells.

The platinum compound oxaliplatin has been shown to be an effective chemotherapeutic agent for the treatment of colorectal cancer. In this study, we investigate the molecular mechanisms of action of oxaliplatin to identify means of predicting response to this agent. Exposure of colon cancer cells to oxaliplatin resulted in G2/M arrest and apoptosis. Immunofluorescent staining demonstrated that the apoptotic cascade initiated by oxaliplatin is characterised by translocation of Bax to the mitochondria and cytochrome c release into the cytosol. Oxaliplatin treatment resulted in caspase 3 activation and oxaliplatin-induced apoptosis was abrogated by inhibition of caspase activity with z-VAD-fmk, but was independent of Fas/FasL association. Targeted inactivation of Bax or p53 in HCT116 cells resulted in significantly increased resistance to oxaliplatin. However, the mutational status of p53 was unable to predict response to oxaliplatin in a panel of 30 different colorectal cancer cell lines. In contrast, the expression profile of these 30 cell lines, assessed using a 9216-sequence cDNA microarray, successfully predicted the apoptotic response to oxaliplatin. A leave-one-out cross-validation approach was used to demonstrate a significant correlation between experimentally observed and expression profile predicted apoptosis in response to clinically achievable doses of oxaliplatin (R=0.53; P=0.002). In addition, these microarray experiments identified several genes involved in control of apoptosis and DNA damage repair that were significantly correlated with response to oxaliplatin.

Antineoplastic Agents↗
PubMed2004

Driver route-following and safety errors in early Alzheimer disease.

OBJECTIVE: To assess navigation and safety errors during a route-following task in drivers with Alzheimer disease (AD). DESIGN/METHODS: Thirty-two subjects with probable AD (by National Institute of Neurological and Communicative Disorders criteria) of mild severity and 136 neurologically normal older adults were tested on a battery of visual and cognitive tests of abilities that are critical to safe automobile driving. Each driver also performed a route-finding task administered on the road in an instrumented vehicle. Main outcome variables were number of 1) incorrect turns; 2) times lost; and 3) at-fault safety errors. RESULTS: The drivers with mild AD made significantly more incorrect turns, got lost more often, and made more at-fault safety errors than control subjects, although their basic vehicular control abilities were normal. The navigational and safety errors were predicted using scores on standardized tests sensitive to visual and cognitive decline in early AD. CONCLUSIONS: Drivers with Alzheimer disease made more errors than neurologically normal drivers on a route-following task that placed demands on driver memory, attention, and perception. The demands of following route directions probably increased the cognitive load during driving, which might explain the higher number of safety errors.

Aged↗
PubMed2004

Pulsatile pump perfusion of pancreata before human islet cell isolation.

Machine pulsatile perfusion for whole pancreas preservation might improve yield, viability, and function of human islets recovered after prolonged cold ischemia times. Four human pancreata were procured from cadaver donors (1 non-heart-beating donor) and stored in cold University of Wisconsin (UW) solution for a mean 13 hours prior to placement on a machine pulsatile perfusion device. The four pancreata were perfused for 4 hours with UW solution before undergoing islet isolation. Islets were quantified, viability was assessed, and insulin secretion was measured. Results were compared with nonpumped islet isolations stratified for cold ischemia time (CIT) <8 hours or cold ischemia time >8 hours. The islet yield for the four pumped pancreata was 3435 (+/-1951) islet equivalents/gram pancreas tissue (IEQ/g), compared with a mean yield of 5134 (+/-2700) IEQ/g and 2640 (+/-1000) IEQ/g from pancreas with <8 hours and >8 hours CIT, respectively. The mean viability after machine pulsatile perfusion was 86% (vs 74% and 74% for the <8 hour and >8 hour CIT groups). The mean viable yield (total yield x viability) was 2937 IEQ/g for machine perfusion, compared with 3799 IEQ/g and 1937 IEQ/g from pancreata with <8 hours and >8 hours CIT, respectively. The insulin secretion index of islets after machine perfusion was 6.4, compared with indices of 1.9 and 1.8 for the <8 hour and >8 hour CIT groups. This preliminary data indicates that low-flow machine pulsatile perfusion of pancreata with prolonged cold ischemia time can result in excellent yield, viability, and function.

Adenosine↗
PubMed2004

Characterization and functional study of five novel monoclonal antibodies against human OX40L highlight reverse signalling: enhancement of IgG production of B cells and promotion of maturation of DCs.

OX40 ligand (OX40L), a molecule originally identified as human gp34, is an important co-stimulatory molecule during immune response. In this study, we report on five functional mouse anti-human OX40L monoclonal antibodies named as 9H10, 4C12, 8D10, 4H4 and 1G1, characterized by means of flow cytometry, Western blot and competition assay. These monoclonal antibodies bound to distinct OX40L epitopes on activated B cells and dendritic cells (DCs) and two of them could suppress the proliferation of T lymphocytes co-stimulated by mature DCs. Furthermore, we demonstrated that our monoclonal antibodies, such as 9H10 and 4C12, could trigger OX40L reverse signal that enhanced IgG production of B cells and promoted maturation of DCs as evidenced by the upexpression of CD80, CD86, CD83 and CXCR4 and monoclonal antibody 9H10 could also promote anti-CD40 monoclonal-antibody-stimulated DCs in order to induce T cells to secrete more interleukin-2 and interferon-gamma, which suggested that OX40L signals could strengthen the effect of CD40 signals on promoting Th1 differentiation.

Animals↗
PubMed2004

Targeting platelet GPIbalpha transgene expression to human megakaryocytes and forming a complete complex with endogenous GPIbbeta and GPIX.

Bernard-Soulier Syndrome (BSS) is a severe congenital platelet disorder that results from a deficiency of the platelet membrane glycoprotein (GP) Ib/IX complex that is composed of four subunits (GPIbalpha, GPIbbeta, GPIX, and GPV). Mutations in either GPIbalpha, GPIbbeta, or GPIX can result in BSS with many of the known mutations occurring in GPIbalpha. In this study, we have developed a gene therapy strategy to express hemagglutinin (HA)-tagged GPIbalpha in megakaryocytes and potentially correct a hereditary deficiency. To direct GPIbalpha expression in megakaryocytic lineage cells, we designed a GPIbalpha cassette where human GPIbalpha cDNA was placed under control of the megakaryocytic/platelet-specific alphaIIb promoter and inserted into a lentiviral vector. Human CD34+ peripheral blood cells (PBC) and Dami cells were transduced with alphaIIb-HA-GPIbalpha-WPT virus. Flow cytometry analysis demonstrated that 50.1% of the megakaryocytes derived from CD34+ stem cells and 97.3% of Dami cells were transduced and expressed transgene GPIbalpha protein. Immunoprecipitation with Western blot analysis demonstrated that transgene protein associated with endogenous GPIbbeta and GPIX proteins. To address further the lineage-specific expression of the alphaIIb-HA-GPIbalpha construct, three cell lines, Dami, AtT-20 and HepG2, were transfected with GPIbalpha expression plasmids and analyzed by confocal microscopy. The results demonstrated that among these three cell lines, the tissue-specific alphaIIb promoter was active only in Dami cells. Thus, GPIbalpha can be efficiently and specifically expressed in the megakaryocytic compartment of hematopoietic cells and the transgene product associates with endogenous GPIbbeta and GPIX forming a complete complex. This strategy could potentially be utilized for gene therapy of BSS.

Antigens, CD34↗