Biomedical subjects

Z Fan

Publications and source records attributed to Z Fan.

At least 91 records · Page 5Linked to original sources

PubMed1999

Cross-reactive anti-chicken CD4 and CD8 monoclonal antibodies suggest polymorphism of the turkey CD8alpha molecule.

To measure turkey CD4 and CD8 T cell levels, the cross-reactivity of mouse anti-chicken CD4 and CD8 monoclonal antibodies (mAb) with turkey leucocytes was tested by flow cytometric analysis of blood obtained from individuals in five turkey lines. The turkey lines used included a randombred control population (RBC2), a subline (F) of RBC2 selected for increased 16-wk BW, and a sire line (A, B, and C) from each of three commercial turkey breeders. Peripheral blood lymphocytes were isolated and stained with single or dual color staining. The CT8 mAb (anti-chicken CD8alpha) failed to detect the CD8alpha molecule in some turkeys, and there were large line differences in ability to detect the CD8alpha molecule. However, certain anti-chicken CD8alpha mAb (3-298, 3-292, and 11-39) had good cross-reactivity with the turkey CD8alpha molecule. These present data indicate that the turkey CD8alpha molecule is polymorphic. Some anti-chicken CD4 mAb (CT4, 2-6, 2-35, and 7-125) were also cross-reactive with the turkey CD4 molecule. Immunoprecipitation and Western blotting showed that the 3-298 mAb precipitated a 33- to 35-kDa polypeptide from the turkey splenocyte lysate under reducing conditions. The availability of cross-reactive anti-chicken CD4 and CD8 mAb will facilitate the studies of immune responses in turkeys.

Animals↗

PubMed1999

Intrathecal gadolinium-enhanced MR myelography and cisternography: a pilot study in human patients.

OBJECTIVE: This study was designed to evaluate the safety, MR imaging characteristics, and clinical response to intrathecal gadopentetate dimeglumine (gadolinium) administration in human patients. SUBJECTS AND METHODS: Eleven adult patients were included in this prospective study. Via lumbar puncture, a single dose of either 0.2 ml, 0.5 ml, or 1.0 ml of gadolinium (500 mmol/l) mixed with 5 ml of previously removed CSF was slowly injected into the lumbar subarachnoid space. Immediate and delayed MR imaging were subsequently carried out using a 1.0-T magnet. RESULTS: No patient manifested gross behavioral changes, neurologic alterations, or seizure activity. The intrathecal gadolinium-enhanced MR myelography revealed disk herniation (n = 4), posttraumatic spinal stenosis (n = 3), postsurgical noncommunicating cyst (n = 1), myelitis (n = 1), intradural extramedullary mass formation (n = 1), and intradural vascular malformation (n = 1). CONCLUSION: This pilot study shows the relative safety and feasibility of low-dose intrathecal gadolinium administration. The potential clinical applications include the evaluation of obstructions and communications of the subarachnoid space, spontaneous or traumatic CSF leaks, and CSF dynamics. Additional animal and human studies must be performed to further evaluate the long-term safety and to prove the clinical applications of this procedure in a larger number of subjects.

Adult↗

PubMed1999

Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225.

Epidermal growth factor (EGF)-related proteins such as transforming growth factor alpha (TGF-alpha) control cancer cell growth through autocrine and paracrine pathways. Overexpression of TGF-alpha and/or its receptor (EGFR) has been associated with a more aggressive disease and a poor prognosis. The blockade of EGFR activation has been proposed as a target for anticancer therapy. Monoclonal antibody (MAb) C225 is an anti-EGFR humanized chimeric mouse MAb that is presently in Phase II clinical trials in cancer patients. Previous studies have suggested the potentiation of the antitumor activity of certain cytotoxic drugs, such as cisplatin and doxorubicin, in human cancer cell lines by treatment with anti-EGFR antibodies. We have evaluated in human ovarian, breast, and colon cancer cell lines, which express functional EGFR, the antiproliferative activity of MAb C225 in combination with topotecan, a cytotoxic drug that specifically inhibits topoisomerase I and that has shown antitumor activity in these malignancies. A dose-dependent supraadditive increase of growth inhibition in vitro was observed when cancer cells were treated with topotecan and MAb C225 in a sequential schedule. In this respect, the cooperativity quotient, defined as the ratio between the actual growth inhibition obtained by treatment with topotecan followed by MAb C225 and the sum of the growth inhibition achieved by each agent, ranged from 1.2 to 3, depending on drug concentration and cancer cell line. Treatment with MAb C225 also markedly enhanced apoptotic cell death induced by topotecan. For example, in GEO colon cancer cells, 5 nM topotecan, followed by 0.5 microg/ml MAb C225, induced apoptosis in 45% cells as compared with untreated cells (6%) or to 5 nM topotecan-treated cells (22%). Treatment of mice bearing established human GEO colon cancer xenografts with topotecan or with MAb C225 determined a transient inhibition of tumor growth because GEO tumors resumed the growth rate of untreated tumors at the end of the treatment period. In contrast, an almost complete tumor regression was observed in all mice treated with the two agents in combination. This determined a prolonged life span of the mice that was significantly different as compared with controls (P < 0.001), to MAb C225-treated group (P < 0.001), or to the topotecan-treated group (P < 0.001). All mice of the topotecan plus MAb C225 group were the only animals alive 14 weeks after tumor cell injection. Furthermore, 20% of mice in this group were still alive after 19 weeks. The combined treatment with MAb C225 and topotecan was well tolerated by mice with no signs of acute or delayed toxicity. These results provide a rationale for the evaluation of the anticancer activity of the combination of topoisomerase I inhibitors and anti-EGFR blocking MAbs in clinical trials.

Animals↗

PubMed1999

Specific in vitro association between the hepatitis C viral genome and core protein.

Little is known about the molecular interactions required for hepatitis C virion assembly. The 5' noncoding region (5'NCR) of the RNA genome is highly conserved and has extensive secondary structure. The highly basic core protein is rich in arginine and lysine residues. We postulate that a specific interaction between these structures may be important for virion assembly. Using an RNA gel mobility shift assay, a specific interaction has been demonstrated between the RNA of the 5'NCR and recombinant core protein. Proteins from other regions of the virus do not interact with the viral RNA. The interaction is inhibited competitively by unlabelled sense polarity RNA, but antisense 5'NCR RNA and nonspecific RNAs compete only at much higher concentrations. These data suggest that there is a specific interaction between the 5'NCR of the hepatitis C virus (HCV) genome and HCV core protein. This interaction may be important for the specific encapsidation of the viral genome during HCV replication.

5' Untranslated Regions↗

PubMed1999

Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells.

Low levels of p27Kip1 in primary prostate cancer specimens have been shown to be associated with higher rates of disease recurrence and poor rates of disease-free survival in patients with localized disease. In this study, we provide the first direct evidence showing that dihydrotestosterone (DHT), a major proliferation regulator of prostate cancer, can down-regulate p27Kip1 and stimulate cyclin-dependent kinase-2 (CDK2) activity in established prostate cancer cell lines. We investigated the cooperative effects of DHT and epidermal growth factor (EGF) on the proliferation of androgen-responsive MDA PCa 2a and MDA PCa 2b prostate cancer cells. DHT and EGF each stimulated proliferation of these cells, but exposure of the cells to DHT and EGF together stimulated greater proliferation. Stimulation of cell proliferation by DHT and/or EGF was associated with increased CDK2 activity and a decreased level of p27Kip1. There seems to be a positive feedback stimulation loop between androgen-induced gene transcription and EGF-stimulated signal transduction, as one could stimulate the synthesis of the receptors for the other. Dual blockade of androgen receptor function with the antiandrogen hydroxyflutamide and EGF receptor superfamily-mediated signal transduction with the anti-EGF receptor monoclonal antibody C225 and the anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells. Our results demonstrate the importance of counteracting both androgen receptors and EGF receptors in the development of novel therapies for prostate cancer.

Androgen Antagonists↗

PubMed1999

Effects of Kupffer cells stimulated by triglyceride and very low-density lipoprotein on proliferation of rat hepatic stellate cells.

OBJECTIVE: To study the effects of triglyceride, very low-density lipoprotein (VLDL), and Kupffer cell-conditioned medium (KCCM) derived from triglyceride and VLDL treatment on proliferation of rat hepatic stellate cells (HSC). METHODS: HSC and Kupffer cells were isolated and cultured from liver of Wistar rats by in situ perfusion with proteinase and collagenase, and density gradient centrifugation with Nycodenz; HSC and Kupffer cells were identified by immunohistochemistry, endocytosis, and ultrastructure, etc. Kupffer cells were incubated with triglyceride (25 micrograms/ml) and VLDL (25 micrograms/ml) for 24 hours, KCCM were prepared, and MTT colorimetric assay was detected for HSC proliferation. RESULTS: HSC proliferation was 0.1894 +/- 0.0316 (12.5 micrograms/ml), 0.1637 +/- 0.0243 (25 micrograms/ml), 0.1450 +/- 0.0264 (50 micrograms/ml), 0.1212 +/- 0.0275 (100 micrograms/ml), 0.1226 +/- 0.0138 (200 micrograms/ml) and 0.0990 +/- 0.0163 (400 micrograms/ml) in the presence of triglyceride and was 0.1583 +/- 0.0314 (6.25 micrograms/ml), 0.1642 +/- 0.0269 (12.5 micrograms/ml), 0.1834 +/- 0.0498 (25 micrograms/ml), 0.1964 +/- 0.0287 (50 micrograms/ml) and 0.2202 +/- 0.0284 (100 micrograms/ml) in presence of VLDL, respectively. Compared with the control, HSC proliferation at 400 micrograms/ml of triglyceride was lower (P < 0.01), but at 12.5 micrograms/ml of triglyceride and 25, 50, 100 micrograms/ml of VLDL higher (P < 0.05 or 0.01); HSC proliferation was 0.1569 +/- 0.0144, 0.1924 +/- 0.0113 and 0.1871 +/- 0.0116 in the presence of KCCM, KCCM + triglyceride and KCCM + VLDL, respectively. Compared with the control and KCCM, KCCM + triglyceride and KCCM + VLDL might promote HSC proliferation (P < 0.01); there was no statistical significance between KCCM + triglyceride and KCCM + VLDL (P > 0.05); KCCM was greater in HSC proliferation than the control, but there was no significant change (P > 0.05). CONCLUSIONS: Triglyceride, VLDL, and KCCM stimulated by triglyceride and VLDL might promote HSC proliferation and be associated with fatty liver and hepatic fibrogenesis.

Animals↗

PubMed1999

[Effects of Kupffer cells stimulated by triglyceride and very low-density lipoprotein on proliferation of rat hepatic stellate cells].

OBJECTIVE: To study the effects of Kupffer cell-conditioned medium (KCCM) derived from triglyceride and very low-density lipoprotein (VLDL) treatment on proliferation of rat hepatic stellate cells (HSC). METHODS: HSC and Kupffer cells were isolated from liver of Wistar rats by in situ perfusion with pronase and collagenase and density gradient centrifugation with Nycodenz and then cultured. KCCM was prepared and MTT colorimetric assay was used to detect HSC proliferation. RESULTS: HSC and Kupffer cells were isolated successfully with high purity. 12.5 mg/L of triglyceride and 25 - 100 mg/L of VLDL promoted HSC proliferation (P < 0.05 or 0.01); KCCM + triglyceride and KCCM + VLDL might promote HSC proliferation as compared with a control group (P < 0.01). There was no significant difference between KCCM + triglyceride and KCCM + VLDL (P > 0.05). CONCLUSION: The technique for isolation of HSC and Kupffer cells described here is simple and reliable. Triglyceride, VLDL and KCCM stimulated by them may promote HSC proliferation and be associated with fatty liver and hepatic fibrogenesis.

Animals↗

PubMed1999

[Study on thermodynamic interactions between polyoctene-1 and solvents using gas chromatography].

Polymer of long chain alpha-olefins is a kind of comb-like polymer with special properties. In this paper, the thermodynamic interactions of polyoctene-1 with eight solvents have been studied by using gas chromatography. The eight Flory-Huggins interaction parameters chi 1 were calculated. The results indicated that chi 1 decreases with increase of the carbon number of linear alkane, but when the carbon number is larger than 8, chi 1 tends to increase with the carbon number. It was also shown that the interaction of polyoctene-1 with cyclohexane is the strongest among all the studied solvents, and that with n-octane is the strongest among the linear alkanes. The relation of interaction parameter (polyoctene-1/n-octane) with temperature T was also determined: chi 1 = 1.697-523.1/T. It was shown that the dissolution of polyoctene-1 in n-octane is an exothermic process with an enthalpy change of -4.84 kJ/mol. The solubility parameter delta 2 of polyoctene-1 is 27.42 (J/mL)1/2, determined from the interaction parameters chi 1.

English Abstract↗

PubMed1999

[Comprehensive evaluation of medical process by constructed polynory function].

This paper describes the concept of "medical process evaluation" and presents a model which is based on constructed polynory function by using the Fuzzy Set theory. This model frame has been used for the prognostic evaluation of patients recovering from acute myocardial infarction and for the comprehensive evaluation of efficacy in treatments of pneumoconiosis. The results are satisfactory. This model frame can be generalized to other medical process evaluation.

Fuzzy Logic↗

PubMed1999

[The effect of age on the regional blood flow of neck of femur in normal Chinese].

This study aimed to assess the effect of age on the regional blood flow of neck of femur in normal Chinese. 133Xe washout method was adopted. The result showed that the femur regional blood flow of normal Chinese decreased slowly with the increase of their age. The relation between age and femur blood flow might be expressed as F = -0.042Y + 9.01(F refers to blood flow, Y refers to age). The average femur regional blood flow of normal Chinese was 7.37 +/- 0.62 ml.(100 g.min)-1 for 21-40 years old. The authors suggest this result can be considered to stand for regional femur blood flow of young healthy adults.

Adolescent↗

PubMed1998

Anti-HIV type 1 memory cytotoxic T lymphocyte responses associated with changes in CD4+ T cell numbers in progression of HIV type 1 infection.

We investigated memory cytotoxic T lymphocyte (CTLm) responses to HIV-1 as a determinant of HIV-1 disease progression, in relation to plasma HIV-1 load and T lymphocyte numbers in a longitudinal study of 14 homosexual men with incident HIV-1 infection. Study participants were selected who exhibited failure of T cell homeostasis, i.e., a downward inflection in CD3+ T cells that occurs in >75% of persons 1.5 to 2.5 years before development of AIDS, and compared with participants who developed low CD4+ T cell counts associated with possible T cell homeostasis failure, a subject who progressed rapidly to AIDS without well-defined T cell inflection, and subjects who had long-term preservation of T cell homeostasis (nonprogressors). High CTLm responses against Gag, but not Pol or Env, soon after seroconversion were associated with a slower loss of CD4+ T cells 1-4 years after seroconversion. Anti-Env CTLm responses decreased in most subjects around the time that T cell homeostasis failed. Plasma HIV-1 RNA increased exponentially (1.59-fold per year) over the 5 years preceding failure of T cell homeostasis, and there was a shift from a non-syncytium-inducing/CCR5 coreceptor phenotype of HIV-1 to a syncytium-inducing/CXCR4 phenotype, regardless of high or increasing levels of anti-HIV-1 CTLm during this time. These observations suggest that decreases in CTLm and increasing virus load are independent factors contributing to HIV-1 disease progression.

CD4 Lymphocyte Count↗

PubMed1998

Measurement of feline cytokine gene expression by quantitative-competitive RT-PCR.

We have developed a method to quantitate feline cytokine gene expression using competitive RT-PCR. Feline cytokine specific primers were developed that encompass an intron, thus allowing differentiation of cDNA vs. genomic DNA amplification products. The PCR products of the primers were verified by sequencing and Southern blot analysis. For quantitation, a non-homologous RNA competitor was created for each cytokine of interest. The competitor was designed to yield an RT-PCR product 10-20% larger than the native sequence, thereby allowing differentiation of the two products by electrophoresis on an agarose gel. Both competitor and native sequences used the same primer sequences for RT (oligo dT) and PCR (cytokine specific). The amplification efficiency of the competitor and native sequence was shown to be identical which allowed comparison at any point during the amplification, including the plateau phase. The quantity of starting cytokine mRNA was determined by interpolation from a standard curve. As little as 1 microgram of total cellular RNA was required per cytokine determination. The assay can routinely quantify as few as 1000 copies of template and spans a range of up to 4 log.

Animals↗

PubMed1998

Tissue factor regulates plasminogen binding and activation.

Tissue factor (TF) has been implicated in several important biologic processes, including fibrin formation, atherogenesis, angiogenesis, and tumor cell migration. In that plasminogen activators have been implicated in the same processes, the potential for interactions between TF and the plasminogen activator system was examined. Plasminogen was found to bind directly to the extracellular domain of TF apoprotein (amino acids 1-219) as determined by optical biosensor interaction analysis. A fragment of plasminogen containing kringles 1 through 3 also bound to TF apoprotein, whereas isolated kringle 4 and miniplasminogen did not. Expression of TF on the surface of a stably transfected Chinese hamster ovary (CHO) cell line stimulated plasminogen binding to the cells by 70% more than to control cells. Plasminogen bound to a site on the TF apoprotein that appears to be distinct from the binding site for factors VII and VIIa as judged by a combination of biosensor and cell assays. TF enhanced two-chain urokinase (tcuPA) activation of Glu-plasminogen, but not of miniplasminogen, in a dose-dependent, saturable manner (half maximal stimulation at 59 pmol/L). TF apoprotein induced an effect similar to that of relipidated TF, but a relatively higher concentration of the apoprotein was required (half maximal stimulation at 3.8 nmol/L). The stimulatory effect of TF on plasminogen activation was confirmed when plasmin formation was examined directly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In accord with this, TF inhibited fibrinolysis by approximately 74% at a concentration of 14 nmol/L and almost totally inhibited the binding of equimolar concentrations of plasminogen to human umbilical vein endothelial cells and human trophoblasts. Further, CHO cells expressing TF inhibited uPA-mediated fibrinolysis relative to a wild-type control. TF apoprotein and plasminogen were found to colocalize in atherosclerotic plaque. These data suggest that plasminogen localization and activation may be modulated at extravascular sites through a high-affinity interaction between kringles 1 through 3 of plasminogen and the extracellular domain of TF.

Animals↗

PubMed1998

Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature.

We have established stably transfected HEK 293 cell lines expressing high levels of functional human ether-a go-go-related gene (HERG) channels. We used these cells to study biochemical characteristics of HERG protein, and to study electrophysiological and pharmacological properties of HERG channel current at 35 degrees C. HERG-transfected cells expressed an mRNA band at 4.0 kb. Western blot analysis showed two protein bands (155 and 135 kDa) slightly larger than the predicted molecular mass (127 kDa). Treatment with N-glycosidase F converted both bands to smaller molecular mass, suggesting that both are glycosylated, but at different levels. HERG current activated at voltages positive to -50 mV, maximum current was reached with depolarizing steps to -10 mV, and the current amplitude declined at more positive voltages, similar to HERG channel current expressed in other heterologous systems. Current density at 35 degrees C, compared with 23 degrees C, was increased by more than twofold to a maximum of 53.4 +/- 6.5 pA/pF. Activation, inactivation, recovery from inactivation, and deactivation kinetics were rapid at 35 degrees C, and more closely resemble values reported for the rapidly activating delayed rectifier K+ current (I(Kr)) at physiological temperatures. HERG channels were highly selective for K+. When we used an action potential clamp technique, HERG current activation began shortly after the upstroke of the action potential waveform. HERG current increased during repolarization to reach a maximum amplitude during phases 2 and 3 of the cardiac action potential. HERG contributed current throughout the return of the membrane to the resting potential, and deactivation of HERG current could participate in phase 4 depolarization. HERG current was blocked by low concentrations of E-4031 (IC50 7.7 nM), a value close to that reported for I(Kr) in native cardiac myocytes. Our data support the postulate that HERG encodes a major constituent of I(Kr) and suggest that at physiological temperatures HERG contributes current throughout most of the action potential and into the postrepolarization period.

Action Potentials↗

PubMed1998

Three-dimensional structure of a human Fab with high affinity for tetanus toxoid.

BACKGROUND: The wide range of antibody specificity and affinity results from the differing shapes and chemical compositions of their binding sites. These shapes range from discrete grooves in antibodies elicited by linear oligomers of nucleotides and carbohydrates to shallow depressions or flat surfaces for accommodation of proteins, peptides and large organic compounds. OBJECTIVES: To determine the Fab structure of a high-affinity human antitoxin antibody. To explore structural features which enable the antibody to bind to intact tetanus toxoid, peptides derived from the sequence of the natural immunogen and antigenic mimics identified by combinatorial chemistry. To explain why this Fab shows a remarkable tendency to produce crystals consistently diffracting to d spacings of 1.7-1.8 A. To use this information to engineer a strong tendency to crystallize into the design of other Fabs. STUDY DESIGN: The protein was crystallized in hanging or sitting drops by a microseeding technique in polyethylene glycol (PEG) 8000. Crystals were subjected to X-ray analysis and the three-dimensional structure of the Fab was determined by the molecular replacement method. Interactive computer graphics were employed to fit models to electron density maps, survey the structure in multiple views and discover the crystal packing motif of the protein. RESULTS: Exceptionally large single crystals of this protein have been obtained, one measuring 5 x 3 x 2 mm (l x w x d). The latter was cut into six irregular pieces, each retaining the features of the original in diffracting to high resolution (1.8 A) with little decay in the X-ray beam. In an individual Fab, the active site is relatively flat and it seems likely that the protein antigen and derivative peptides are tightly held on the outer surface without significant penetration into the interior. There is no free space to accommodate even a dipeptide between VH and VL. One of the unique features of the B7-15A2 Fab is a large aliphatic ridge dominating the center of the active site. The CDR3 of the H chain contributes significantly to this ridge, as well as to adjoining regions projected to be important for the docking of the antigen. Both the ease of crystallization and the favorable diffraction properties are mainly attributable to the tight packing of the protein molecules in the crystal lattice. DISCUSSION: The B7-15A2 active site provides a stable and well defined platform for high affinity docking of proteins, peptides and their mimotopes. The advantages for future developments are suggested by the analysis of the crystal properties. It should be possible to incorporate the features promoting crystallization, close packing and resistance to radiation damage into engineered human antibodies without altering the desired specificities and affinities of their active sites.

Amino Acid Sequence↗

PubMed1998

Stability of access resistance during haemodialysis.

BACKGROUND: Access blood flow (Qac) is considered a useful indicator in the surveillance of haemodialysis access function. However, changes in Qac may be due to changes in blood pressure and/or to changes in access resistance (AR). METHODS: Weekly readings of Qac, cardiac output, and arterial blood pressure measured early and late during haemodialysis were obtained in 11 patients for a period of 3 weeks. Qac was determined from thermodilution of extracorporeal blood returning to the patient with reversed placement of blood lines and by measurement of arterial and venous blood temperatures in the extracorporeal circulation. Data are given as mean +/- SE. RESULTS: Qac dropped as mean arterial pressure (MAP) and total peripheral resistance (TPR) decreased, but increased when MAP and TPR increased. Linear regressions between the change in access flow and the change in MAP (deltaQac%=0.80*deltaMAP%-1.6, r2=0.39), and the change in TPR (deltaQac%= 0.54*deltaTPR%-9.2, r2=0.35) respectively, were significant (P<0.001). Whereas Qac significantly decreased (-8.4+/-3.3%, P<0.01) during the same treatment, AR remained unchanged (4.7+/-3.2%; P=NS). AR for all studies was 16.5+/-1.0 peripheral resistance units (1 PRU=2.226 kPa min l(-1)). There was a trend for resistance to increase (5.1+/-2.6%, P=NS) and for flow to decrease (-6.1+/-2.3%, P=NS) during the 3 weeks of the study. CONCLUSION: Qac measured during haemodialysis is variable and depends on haemodynamics, but AR is constant. AR is related to the physical structure of the peripheral access. Because of its intradialytic stability AR may be better suited as an indicator of access function.

Blood Pressure↗

PubMed1998

Therapeutic application of anti-growth factor receptor antibodies.

The application of monoclonal antibodies for the treatment of human cancer has been under extensive study for nearly two decades. With the advent of recombinant antibody technology, which makes humanized antibody or human-mouse chimeric antibody available for clinical trials, significant progress has been made in the past several years. In this article, we present an overview of recent research on anti-growth factor receptor antibodies. This research aims to modulate the function of growth factor receptors or to exploit the overexpression of these receptors on cancer cells for targeted therapy. The pharmacologic blockade of receptors with antireceptor antibody has been explored as anticancer therapy, both alone and in combination with conventional chemotherapy, or with novel inhibitors acting on various steps of signal transduction pathways. There also has been progress in research on intracellular antibodies, bispecific antibodies, antibody-fusion molecules, and antireceptor antibodies as a means of nonviral gene therapy. This review focuses primarily on monoclonal antibodies directed against the epidermal growth factor receptor family.

Animals↗

PubMed1998

Temperature dependence of early and late currents in human cardiac wild-type and long Q-T DeltaKPQ Na+ channels.

Na+ current (INa) through wild-type human heart Na+ channels (hH1) is important for normal cardiac excitability and conduction, and it participates in the control of repolarization and refractoriness. INa kinetics depend strongly on temperature, but INa for hH1 has been studied previously only at room temperature. We characterized early INa (the peak and initial decay) and late INa of the wild-type hH1 channel and a mutant channel (DeltaKPQ) associated with congenital long Q-T syndrome. Channels were stably transfected in HEK-293 cells and studied at 23 and 33 degreesC using whole cell patch clamp. Activation and inactivation kinetics for early INa were twofold faster at higher temperature for both channels and shifted activation and steady-state inactivation in the positive direction, especially for DeltaKPQ. For early INa (<24 ms), DeltaKPQ decayed faster than the wild type for voltages negative to -20 mV but slower for more positive voltages, suggesting a reduced voltage dependence of fast inactivation. Late INa at 240 ms was significantly greater for DeltaKPQ than for the wild type at both temperatures. The majority of late INa for DeltaKPQ was not persistent; rather, it decayed slowly, and this late component exhibited slower recovery from inactivation compared with peak INa. Additional kinetic changes for early and peak INa for DeltaKPQ compared with the wild type at both temperatures were 1) reduced voltage dependence of steady-state inactivation with no difference in midpoint, 2) positive shift for activation kinetics, and 3) more rapid recovery from inactivation. This study represents the first description of human Na+ channel kinetics near physiological temperature and also demonstrates complex gating changes in the DeltaKPQ that are present at 33 degreesC and that may underlie the electrophysiological and clinical phenotype of congenital long Q-T Na+ channel syndromes.

Cell Line↗