Biomedical subjects

L Zhang

Publications and source records attributed to L Zhang.

At least 55 records · Page 3Linked to original sources

PubMed2006

Inhibition of growth and increase of alkaline phosphatase activity in cultured human oral cancer cells by all-trans retinoic acid.

In this study, the effects of all-trans retinoic acid (ATRA) on human oral cancer cells with regard to cell growth, the cell cycle, and alkaline phosphatase (ALP) activity were evaluated. Human oral cancer KB cells were treated with various concentrations of ATRA, and cell growth was then determined using the MTT viability assay. The cell-cycle distribution and ALP activity were analysed using a flow cytometer and chemical analyser, respectively. The KB cells were inhibited by ATRA at concentrations of 1-16 microM (1 microM, P<0.05; 2 microM, P<0.01; 4, 8 and 16 microM, P<0.001) in a dose-dependent manner. ATRA arrested KB cells in the G0/G1 phase. The ALP activity in KB cells was increased by ATRA. This is one of the first studies to focus on the expression of ALP in human head-and-neck carcinoma cells treated with retinoids. These findings suggest that the anti-tumour effects of ATRA on human oral cancer are associated with G0/G1 phase arrest and an increase in ALP activity.

Alkaline Phosphatase↗

PubMed2006

A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease.

INTRODUCTION: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease (CD). PATIENTS AND METHODS: Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates. RESULTS: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry. CONCLUSIONS: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.

Adult↗

PubMed2006

An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen.

Little is known of the underlying biology of estrogen receptor-negative, progesterone receptor-negative (ER(-)/PR(-)) breast cancer (BC), and few targeted therapies are available. Clinical heterogeneity of ER(-)/PR(-) tumors suggests that molecular subsets exist. We performed genome-wide expression analysis of 99 primary BC samples and eight BC cell lines in an effort to reveal distinct subsets, provide insight into their biology and potentially identify new therapeutic targets. We identified a subset of ER(-)/PR(-) tumors with paradoxical expression of genes known to be either direct targets of ER, responsive to estrogen, or typically expressed in ER(+) BC. Differentially expressed genes included SPDEF, FOXA1, XBP1, CYB5, TFF3, NAT1, APOD, ALCAM and AR (P<0.001). A classification model based on the expression signature of this tumor class identified molecularly similar BCs in an independent human BC data set and among BC cell lines (MDA-MB-453). This cell line demonstrated a proliferative response to androgen in an androgen receptor-dependent and ER-independent manner. In addition, the androgen-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of the unique ER(-)/PR(-) subclass of human tumors. This subset of BCs, characterized by a hormonally regulated transcriptional program and response to androgen, suggests the potential for therapeutic strategies targeting the androgen signaling pathway.

Androgens↗

PubMed2006

Regulation of PUMA-alpha by p53 in cisplatin-induced renal cell apoptosis.

Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Depending on its concentration, cisplatin induces necrosis or apoptosis of tubular cells in the kidneys, whereas the underlying injury mechanism is unclear. Our recent work has suggested a critical role for p53 in cisplatin-induced tubular cell apoptosis; nevertheless, the apoptotic events triggered by p53 remain elusive. The current study has examined Bcl-2 family proteins, critical regulators of apoptosis that may be subjected to p53 regulation. Following cisplatin treatment, the expression of Bcl-xL, an antiapoptotic molecule, was suppressed, while the expression of Bak, a proapoptotic molecule, increased slightly. Of interest, PUMA-alpha, a newly identified p53-responsive proapoptotic Bcl-2 family protein, was drastically induced by cisplatin. PUMA-alpha induction preceded or paralleled the development of apoptosis. Induced PUMA-alpha was localized in mitochondria and appeared to antagonize Bcl-xL via molecular interaction. PUMA-alpha induction during cisplatin treatment was attenuated by pifithrin-alpha, a pharmacological inhibitor of p53, which was accompanied by the amelioration of Bax activation, cytochrome c release and apoptosis. Moreover, PUMA-alpha induction was suppressed by dominant-negative p53. Importantly, cisplatin-induced apoptosis was ameliorated in PUMA-alpha knockout cells. In vivo, cisplatin induced PUMA-alpha in the kidneys, and the inductive response was abrogated in p53-deficient animals. Together, this study has demonstrated the first compelling evidence for the involvement of PUMA-alpha in p53-mediated renal cell apoptosis during cisplatin nephrotoxicity.

Animals↗

PubMed2006

Epidural cooling for selective brain hypothermia in porcine model.

BACKGROUND: Hypothermia has been shown to be neuroprotective in many animal models and several human trials of brain ischemic and trauma. However systemic hypothermia may result in fatal complications. This study was undertaken to test epidural cooling as a new method of inducing selective brain hypothermia. METHOD: Six adult swine (mean mass, 33.8+/-3.6 kg) were studied. Anesthesia was maintained with pentobarbital sodium (25 mg kg-1, i.v.) and pancuronium bromide (0.5 mg kg-1 h-1, i.v.). Five probes were placed in the rectum, deep brain, brain surface, epidural space, and room air for temperature monitoring respectively. Epidural cooling was performed using cold-saline (4 degrees C) perfusion into the epidural space through a flexible double-lumen catheter. The dripping speed of cold saline was controlled to maintain the target temperature. The changes of the epidural space pressure, complete blood counts, basic metabolic panels, tests for fibrinolysis and coagulation status were monitored to assess hypothermia-induced changes. FINDINGS: Following the epidural cooling perfused with cold-saline (4 degrees C) at mean dripping speed of 720 ml per hour, the local brain surface temperature could decrease rapidly to 17.3-21.6 degrees C within one minute, and deep brain temperature decreased to 27.2-29.7 degrees C within 5 minutes. The target temperatures were easily controlled by the dripping speed of cold saline (from mild to deep hypothermia). The rectal temperature was maintained at normal range within 6 perfusion hours. No arrhythmia was observed, and all hematological variables were within the normal range for swine. No increased intracranial pressure was induced by the cooling method. CONCLUSIONS: The data demonstrate that epidural space cooling was technically feasible and useful for selective brain hypothermia, and the target temperatures are easily controlled. The induction of hypothermia was rapid and maintained for a long period of time, whereas the body temperature was maintained within the normal range and without hemodynamic instability.

Animals↗

PubMed2006

Oncolysis and suppression of tumor growth by a GFP-expressing oncolytic adenovirus controlled by an hTERT and CMV hybrid promoter.

One of the challenges of oncolytic virotherapy is the inability to easily track or monitor virus activity during treatment. Here we describe the construction and functional characterization of Ad/hTC-GFP-E1, an oncolytic virus whose transgenes GFP and E1A are both under the control of a synthetic promoter (hTC). This promoter consists of sequences from the human telomorase reverse transcriptase promoter and a minimal cytomegalovirus (CMV) early promoter. The tumor-specific expression of E1A and GFP was demonstrated by Western blot and fluorescent microscope analyses, and the tumor-specific cytotoxicity by crystal-violet staining and cell viability assays. Viral replication and tumor cell lysis occurred at multiplicities of infection (MOI) as low as 100 viral particles per cell in sensitive cell lines. No overt cytotoxic effect was observed in normal human fibroblasts, even at MOIs over 2000 vp. The presence of oncolytic vector was easily visualized and quantitated in vitro and in vivo, in correlation with viral replication. Intralesional administration of the virus into subcutaneous H1299 (NSCLC) tumor xenografts significantly suppressed tumor growth and provided a survival benefit. Together, these results demonstrate that an hTERT-specific oncolytic adenovirus expressing an hTERT-specific transgene is applicable for cancer therapy.

Adenoviridae↗

PubMed2006

Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG.

In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Ultralong Raman fiber lasers as virtually lossless optical media.

By transforming the optical fiber span into an ultralong cavity laser, we experimentally demonstrate quasilossless transmission over long (up to 75 km) distances and virtually zero signal power variation over shorter (up to 20 km) spans, opening the way for the practical implementation of integrable nonlinear systems in optical fiber. As a by-product of our technique, the longest ever laser (to the best of our knowledge) has been implemented, with a cavity length of 75 km. A simple theory of the lossless fiber span, in excellent agreement with the observed results, is presented.

Journal Article↗

PubMed2006

Adaptive control of laser modal properties.

An adaptive optical system for precise control of a laser beam's mode structure has been developed. The system uses a dynamic lens based on controlled optical path deformation in a dichroic optical element that is heated with an auxiliary laser. Our method is essentially aberration free, has high dynamic range, and can be implemented with high average power laser beams where other adaptive optics methods fail. A quantitative model agrees well with our experimental data and demonstrates the potential of our method as a mode-matching and beam-shaping element for future large-scale gravitational wave detectors.

Journal Article↗

PubMed2006

Combination effect of oncolytic adenovirotherapy and TRAIL gene therapy in syngeneic murine breast cancer models.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and oncolytic adenovirotherapy have been investigated extensively in xenografic human tumor models established in immunocompromised nude mice. However, the effects of these therapies on syngeneic murine tumors in immunocompetent settings were not well documented. We hypothesized that TRAIL gene therapy used with an oncolytic adenovirus would overcome the weaknesses of the two therapies used individually. In this study, we evaluated the antitumor effects of an oncolytic adenovirus, Delta24, in both human and murine breast cancer cell lines. We also analyzed the effects of TRAIL gene therapy combined with oncolytic virotherapy in these cancer cells. Our results showed that Delta24 can replicate and help the E1-deleted adenovector replicate in murine cancer cells. We also found that these two therapies combined had greater antitumor activity than either one alone in both human and murine breast cancer cells lines and in the syngeneic breast cancer models established in immunocompetent mice. Moreover, Delta24 virotherapy alone and combined with TRAIL gene therapy dramatically reduced the spontaneous liver metastasis that originated in the subcutaneous 4T1 tumor established in Balb/c mice. These findings provide important considerations in the development and preclinical assessments of oncolytic virotherapy.

Adenoviridae↗

PubMed2006

Iodide sensitizes genetically modified non-small cell lung cancer cells to ionizing radiation.

While external ionizing radiation has been used for treating non-small cell lung cancer (NSCLC), improved efficacy of this modality would be an important advance. Ectopic expression of the sodium iodide symporter (NIS) and thyroperoxidase (TPO) genes in NSCLC cells facilitated concentration of iodide in NSCLC cells, which markedly induced apoptosis in vitro and in vivo. Pre-incubation of the NIS/TPO-modified NSCLC cells in iodide followed by ionizing radiation generates bystander tumoricidal effects and potently enhances tumor cell killing. This iodide-induced bystander effect is associated with enhanced gap junction intercellular communication (GJIC) activity and increased connexin-43 (Cx43) expression. Thus, iodide may serve as an enhancer to markedly improve the efficacy of radiation therapy in combined therapeutic modalities.

Apoptosis↗

PubMed2006

Interference of cyclosporine on glucose metabolism: potential role in chronic transplantation kidney fibrosis.

OBJECTIVES: To explore the fibrosis induction effects of cyclosporine (CsA) on renal tubular epithelial cells, as well as the potential mechanisms of CsA-mediated alterations of glucose metabolism in chronic allograft nephropathy (CAN). METHODS: The rat renal tubular epithelial cell line NRK-52E cells were cultured in medium with 50 mmol/L of D-glucose for 7, 14, or 28 days. The expression of TGF-beta1, CTGF, Smad3, and Smad7, which are involved in the fibrosis signal pathway, was detected by immunofluorescence and reverse-transcriptase polymerase chain reaction. Meanwhile, cells were cultured in various concentration of CsA in glucose-free medium for 24 hours followed by the addition of D-[3-(3)H]-glucose for 30 minutes; glucose uptake was detected by examining the radiation intensity. RESULTS: The expression of TGF-beta1, Smad3, Smad7, and CTGF of NRK-52E cells were up-regulated significantly (P < .05) after culture with 50 mmol/L glucose for 7 days compared with those in 25 mmol/L glucose. At 14 and 28 days, TGF-beta1 was slightly decreased compared with 7 days, but CTGF, Smad3, and Smad7 increased robustly (P < .05). CsA significantly stimulated glucose uptake at various concentrations, with an absorption peak at 60 minutes that decreased at 75 minutes. Furthermore, CsA may have dose-dependent effects on glucose uptake. CONCLUSION: High glucose concentrations may play an important role in the NRK-52E cell fibrosis during the CAN process due to an interference of CsA on glucose metabolism.

Animals↗

PubMed2006

Nuclear translocation of SMAD3 may enhance the TGF-beta/SMADS pathway in high glucose circumstances.

OBJECTIVES: Posttransplant diabetes mellitus is one of the most frequent complications after kidney transplantation. It is considered to be one cause of chronic allograft nephropathy. This study sought to investigate the effects of high glucose on the expression and nuclear translocation of Smad3, which is an important signal mediator involved in the fibrotic signal pathway. METHODS: The established rat renal mesangial cell line HBZY-1 was cultured in medium with various concentrations of glucose (4.5 mg/mL, 9.0 mg/mL, or 13.5 mg/mL), which was collected at 7, 14, or 21 days. The total expression of Smad3, including both inner and outer nucleus proteins was examined by Western blot analysis. The nuclear translocated Smad3, representing only the inner nucleus protein, was detected by immunofluorescence staining observed under a laser confocal scanning microscope. RESULTS: No significant difference in the total Smad3 expression was demonstrated by Western blot analysis among the three groups of HBZY-1 cells at various concentration of glucose after 7, 14, or 21 days. There was no fluorescence detected in the nucleus at day 7 by immunofluorescence staining; however, robust positive expression of Smad3 was detected at days 14 and 21. CONCLUSION: As a restricted Smads member, Smad3 protein might not be upregulated in the presence of high glucose. However, with prolonged culture time, Smad3 translocates from cytoplasm to nucleus, which may be a pivotal step in the fibrotic signal pathway.

Animals↗

PubMed2006

The C-terminal peptide of connective tissue growth factor blocks the full molecule binding to tubular epithelial cell.

OBJECTIVES: Interstitial fibrosis is a critical pathologic change in chronic allograft nephropathy. The cytokine connective tissue growth factor (CTGF, also CCN2) plays an important role in epithelial-mesenchymal transformation (EMT) of tubular epithelial cells to renal interstitial fibrosis. The hexadeca-peptide within the C-terminal of CTGF (named P2) contains the unique binding domain of CTGF to its potential receptor, integrin alphavbeta3. This study examined whether P2 bound preferentially to the receptor and served as an inhibitor of CTGF. METHODS: All studies used an established rat kidney tubular epithelial cell line NRK-52E. Chemically synthesized P2 was purified, and some of it labeled with FITC. The affinity of CTGF or P2 to NRK-52E cells was examined by a solid-phase cell adhesion assay. Competitive binding between P2 and CTGF to NRK-52E cells was examined with flow cytometric analysis. RESULTS: Both P2 and CTGF bound to the NRK-52E cells, mediating cell adhesion. When the cells were incubated in the mixture of P2 and CTGF, P2 bound to the cells preferentially. Furthermore, when cells were preincubated with excessive CTGF, it became difficult for subsequent P2 binding to occur. CONCLUSIONS: P2 and CTGF seemed to bind to cell membranes at the same binding domain. P2 competitively blocked CTGF binding, acting as a CTGF inhibitor.

Animals↗

PubMed2006

Construction and characterization of a cDNA library from liver tissue of Chinese Banna minipig inbred line.

A xenograft that performs efficient functions is an essential premise for successful xenotransplantation. Our early study indicated that Chinese Banna minipig inbred line (BMI) was an ideal xenograft donor. However, the activities of some proteins synthesized by the BMI liver are different from the human, which could lead to functional disorders in coagulation, fibrinolysis, and anticoagulation after liver xenotransplantation. Therefore, it is important to investigate the genetic background of protein incompatibility and to provide new strategies for gene manipulation. In this study we constructed a cDNA expression library using BMI liver tissue to obtain an understanding of nucleic acid and protein differences between the two species. We extracted total RNA and purified mRNA of the liver tissue from one of the sixteenth inbred generation of BMI/JS 151 substrain. After double-strand cDNA synthesis, we fractionated it on a CHROMA APIN-400 column; ligated the longer than 500bp cDNA into a ZAP Express Vector; and performed a lambda: phage packaging reaction, library amplification, and titer. We randomly picked 12 plaques and tested the length of inserts. The titers of the primary and amplified libraries were 1.0 x 10(6) pfu/mL and 5.0 x 10(9) pfu/mL, respectively. The percentages of recombinants were 97.0% in the primary library and 98.0% in the amplified library. The lengths of most inserts were between 750 bp and 2.0 kb. Thus, we successfully constructed a cDNA expression library from BMI liver tissue. Using the library, we hope to get a full-length cDNA of some important genes and conduct further studies on porcine liver function in xenotransplantation.

Animals↗

PubMed2006

Factors related to post-liver transplantation acute renal failure.

Acute renal failure (ARF) after liver transplantation (OLT) is a common complication with severe impact on early and late prognosis of recipients. Factors predicting its incidence have not been fully identified due to the lack of a universal standard as well as the variance of data between transplant centers. To identify factors related to post-OLT ARF, we retrospectively collected materials on 89 patients, who underwent OLT from 1999 to 2001 in our center. Factors associated with post-OLT ARF were identified using univariate logistic regression. Significant factors were then entered into a multivariate logistic regression to identify factors independently associated with post-OLT ARF. Upon univariate analysis, intraoperative volume of blood transfusion (P = .041) and duration of operation (P = .005) were significant. ARF was associated with a poor prognosis (P < .001). Only duration of operation (P = .026) was an independent factor predicting the development of ARF. In conclusion, intraoperative volume of blood transfusion and duration of operation were factors contributing to post-OLT ARF in which the duration of the operation was an independent risk factor. The incidence of post-OLT ARF greatly increased recipient mortality in the early postoperative period.

Acute Kidney Injury↗

PubMed2006

Preparation of apoptotic tumor cells with replication-incompetent HSV augments the efficacy of dendritic cell vaccines.

The use of dendritic cells (DCs) loaded with apoptotic tumor cells is an attractive approach to tumor vaccination in the absence of well-characterized tumor antigens. Apoptotic tumor cells are a convenient source of polyvalent tumor antigen, but may induce only weak immunization. We tested the role of replication-incompetent recombinant herpes simplex virus (HSV) d106 lacking all immediate early genes except ICP0 in the generation of apoptotic cells for tumor vaccination, using ID8-VEGF, a syngeneic mouse model of ovarian carcinoma expressing high levels of VEGF, and TC-1, a human papillomavirus (HPV) 16 E6- and E7-transformed adenocarcinoma. HSVd106 killed tumor cells by apoptosis. Tumor cells infected by HSVd106 were engulfed more avidly by immature DCs, and induced DC maturation more efficiently than tumor cells killed by ultraviolet B (UVB) radiation. HSVd106 infection induced stronger upregulation of heat shock protein (Hsp) 70 and glucose-related protein (GRP) 94 than UVB in cells undergoing apoptosis. Immunization of mice with DCs loaded with HSVd106-killed cells elicited stronger antitumor T-cell response, including tumor-reactive interferon-gamma-secreting and cytotoxic T cells, and resulted in significantly stronger delay in tumor growth than immunization with DCs loaded with UVB-killed tumor cells. Moreover, in the TC-1 model, a protective effect of vaccination (40% tumor free animals) was observed only after immunization with DCs loaded with HSVd106-killed cells. Thus, the use of replication-incompetent HSV strains lacking immediate early genes except ICP0 offers possible advantages in the preparation of whole tumor cell antigen for DC-based tumor vaccination.

Animals↗

PubMed2006

Adenoviral delivery of human CDC5 promotes G2/M progression and cell division in neonatal ventricular cardiomyocytes.

Heart failure results from the cumulative death of cardiomyocytes, and the inability of remaining cells to regenerate. Efforts toward transcriptional reprogramming of cardiomyocytes by overexpressing E1A or E2F1 have been limited by the inability of cardiomyocytes to enter and complete mitosis. Human CDC5 (hCDC5), a component of the pre-mRNA splicing complex, has been shown to regulate G2/M transit in asynchronously dividing cells. We now show that co-infection of recombinant adenoviruses expressing E1A/E1B and hCDC5 promotes cell cycle re-entry and G2/M progression in post-mitotic cardiomyocytes. Co-expression of E1A/E1B and hCDC5 induced nuclear localization of cyclin-dependent kinase 1 and cyclin B1, and was sufficient to promote mitotic entry as determined by an increase in mitotic index only in co-infected cells. E1A/E1B and hCDC5 promoted cell division, as evidenced by an increase in the number of cardiomyocytes following co-infection. Thus, overexpression of E1A/E1B and hCDC5 resulted in cell cycle re-entry, DNA synthesis, cell division, and an increase in cardiomyocyte number, suggesting the formation of new cardiomyocytes. These studies suggest that G1/S-phase transcriptional regulators, in combination with pre-mRNA splicing factors, such as CDC5, that regulate rate-limiting G2/M target genes may prove useful in developing therapies to stimulate myocardial regeneration.

Adenoviridae↗