Biomedical subjects
Publications and source records attributed to C Tang.
Six brands of black inks on paper were examined by FT-Raman spectrometry. The results showed that the black inks could be discriminated by FT-Raman spectrometry. As the method is easy, quick and undestructive to samples, it is useful in black ink examination.
HER2 (erbB-2) proto-oncogene amplification and/or overexpression correlate with poor prognosis in many malignancies. The precise biological role of this oncogenic signaling pathway (which also involves the HER4 gene) in breast cancer is unclear. One property conferred by this oncogene relates to response to drug therapy. Clinical studies support an association between HER2 overexpression and resistance to alkylating agents (cisplatinum and cyclophosphamide). Data from the Cancer and Leukemia Group B 8869/8541 study indicate enhanced dose responsiveness to doxorubicin (Adriamycin) in patients who overexpress the HER2 receptor. Heregulin beta-2, a naturally occurring ligand that activates the HER2 receptor by inducing its heterodimerization with the HER4 receptor, has recently been cloned. The ability of this ligand to phosphorylate the HER2 receptor exogenously allows us to study the effect of HER2 activation on cancer cell behavior. To study the relationship between chemotherapy response and activation of HER2, MCF-7 cells expressing biologically active heregulin were assessed for response to doxorubicin and etoposide, both of which are topoisomerase IIalpha (topo IIalpha) inhibitors. Several clones show markedly increased sensitivity to these drugs. In addition, the same wild-type MCF-7 cells transfected with heregulin beta-2 under the control of an inducible promoter also show this dose-response relationship to doxorubicin after the expression of heregulin beta-2 is activated by zinc. The modulation of topo IIalpha was studied in the cell lines transfected with heregulin. topo IIalpha mRNA and protein (total protein and enzymatic decatenating activity) were found to be up-regulated in heregulin beta-2-transfected cells. Moreover, topo IIalpha promoter activity was also modestly increased in heregulin beta-2-transfected cells. Because up-regulation of topo IIalpha in vitro and in clinical specimens is associated with increased response to doxorubicin (presumptively by an increase in drug substrate), this may be the mechanism of the increased sensitivity to doxorubicin seen in heregulin beta-2-transfected cells. This implies that activation of HER2 or one of the other members of the receptor family may increase sensitivity to doxorubicin by up-regulation of topo IIalpha. This finding suggests the use of receptor/ligand expression to direct patient-specific therapeutic choices (e.g., doxorubicin versus alkylator-based regimens) and the use of biological agents (such as heregulin) in combination with certain chemotherapeutic agents to enhance response to treatment in breast cancer patients.
Regional cerebral blood flow (rCBF) was measured by single photon emission computed tomography in 10 patients with schizotypal personality disorder (SPD) and nine age- and sex-matched normal volunteers. Subjects performed both the Wisconsin Card Sort Test (WCST) and a control task, the Symbol Matching Test (SMT). Four-way analyses of variance were performed to assess relative rCBF of the prefrontal cortex and of the medial temporal region. Normal volunteers showed more marked activation in the precentral gyrus, while SPD patients showed greater activation in the middle frontal gyrus. Relative flow in the left prefrontal cortex was correlated with better WCST performance in normal volunteers. SPD patients, however, showed no such correlations in the left prefrontal cortex, but demonstrated correlations of good and bad performance with CBF in the right middle and inferior frontal gyrus, respectively. Thus, at least some SPD patients demonstrate abnormal patterns of prefrontal activation, perhaps as a compensation for dysfunction in other regions.
Interleukin-3 (IL-3)-dependent murine 32D cells do not detectably express epidermal growth factor receptors (EGFRs) and do not proliferate in response to EGF, heregulin (HRG) or other known EGF-like ligands. Here, we report that EGF specifically binds to and can be crosslinked to 32D transfectants co-expressing ErbB2 and ErbB3 (32D.E2/E3), but not to transfectants expressing either ErbB2 or ErbB3 individually. [125I]EGF-crosslinked species detected in 32D. E2/E3 cells were displaced by HRG and betacellulin (BTC) but not by other EGF-like ligands that were analyzed. EGF, BTC and HRG also induced receptor tyrosine phosphorylation, activation of downstream signaling molecules and proliferation of 32D.E2/E3 cells. 32D transfectants were also generated which expressed an ErbB3-EGFR chimera alone (32D.E3-E1) or in combination with ErbB2 (32D. E2/E3-E1). While HRG stimulation of 32D.E3-E1 cells resulted in DNA synthesis and receptor phosphorylation, EGF and BTC were inactive. However, EGF and BTC were as effective as HRG in mediating signaling when ErbB2 was co-expressed with the chimera in the 32D.E2/E3-E1 transfectant. These results provide evidence that ErbB2/ErbB3 binding sites for EGF and BTC are formed by a previously undescribed mechanism that requires co-expression of two distinct receptors. Additional data utilizing MDA MB134 human breast carcinoma cells, which naturally express ErbB2 and ErbB3 in the absence of EGFRs, supported the results obtained employing 32D cells and suggest that EGF and BTC may contribute to the progression of carcinomas that co-express ErbB2 and ErbB3.
A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.
Position emission tomography using 6-FDOPA as a marker of presynaptic dopaminergic activity was used to investigate the role of the dopamine system in stuttering. Three patients with moderate to severe developmental stuttering were compared with six normal controls. Stuttering subjects showed significantly higher 6-FDOPA uptake than normal controls in medial prefrontal cortex, deep orbital cortex, insular cortex, extended amygdala, auditory cortex and caudate tail. Elevated 6-FDOPA uptake in ventral limbic cortical and subcortical regions is compatible with the hypothesis that stuttering is associated with an overactive presynaptic dopamine system in brain regions that modulate verbalization.
It has been hypothesized that a decrease in dopaminergic presynaptic activity during abstinence or withdrawal is related to relapse in cocaine-dependent subjects (Dackis and Gold 1985; Markou and Koob 1991). This study measured striatal 6-fluorodopa (6-FDOPA) uptake, an index of dopaminergic presynaptic activity, using positron emission tomography (PET) in 11 drug-free cocaine addicts compared to eight normal subjects. Middle abstinence cocaine addicts (n = 5, off cocaine 11-30 days) had significantly lower striatal 6-FDOPA uptake compared to normal controls or early abstinence cocaine addicts (n = 6, off cocaine 1-10 days). The cocaine-dependent subjects (n = 11) showed a significant negative correlation between days off cocaine and striatal 6-FDOPA uptake. The results suggest that during abstinence from cocaine there is a delayed decrease in dopamine terminal activity in the striatum.
Recent studies have demonstrated that following estrogen ablation, estrogen responsive breast cancer cells undergo apoptosis. In addition, estrogen receptor (ER) expression has been strongly correlated with the expression of the bcl-2 gene product, p26Bcl-2 protein, which is known to inhibit apoptosis. In the present studies, we investigated whether estrogen affects the intracellular levels of p26Bcl-2 and thereby modulates taxol-induced apoptosis of estrogen responsive human breast cancer MCF-7 cells. Transfer of MCF-7 cells to a culture-medium without estrogens reduced their intracellular p26Bcl-2 levels by 50%. Inclusion of 0.1 microM estradiol in the medium produced approximately a four-fold increase in p26Bcl-2, but not p29Bcl-x1, or p21Bax levels; the expression of the c-myc and mdr-1 genes remained unchanged. Estradiol-induced four-fold increase in the ratio of the p26Bcl-2 to p21Bax levels caused a significant decline in the lethal, kilobase size DNA fragments of apoptosis, which had resulted when MCF-7 cells were cultured in a medium without estrogen. In addition, in MCF-7 cells, estradiol-induced increase in the intracellular p26Bcl-2 to p21Bax ratios was associated with a significant reduction in the large-sized DNA fragmentation induced by treatment with taxol. The increased ratios also protected MCF-7 cells against taxol-mediated cytotoxicity as assessed by the MTT assay. These results suggest that by modulating p26Bcl-2 levels, estrogens may affect the antitumor activity of taxol and potentially of other anti-breast cancer drugs against estrogen responsive human breast cancer cells.
Boron magnetic resonance imaging (MRI) and spectroscopy (MRS) are being developed for use in boron neutron capture therapy (BNCT). With continued development, boron MRI may be used to locate BNCT agents in vivo, evaluate the pharmacokinetics of BNCT agents, and aid in treatment planning.
Gut hormones that modulate the growth of normal pancreas may also modulate the growth of cancers originating from pancreas. This study visualized and compared the receptors for cholecystokinin (CCK), bombesin (BBS), secretin and vasoactive intestinal peptide (VIP) in tumour-free tissue sections of human pancreas (n = 10) and pancreatic ductal adenocarcinomas (n = 12) with storage phosphor autoradiography using radioligands. CCK-B receptors, present in control pancreata, were not detected in any of the pancreatic cancers. BBS receptors were visualized in control pancreata, but they were absent in 10 of 12 pancreatic cancers. In 5 of 12 pancreatic cancers, receptors for secretin were visualized, while binding for secretin was present in all tumour-free pancreata. Conversely, no specific binding of VIP was detected in control pancreata but was identified in 3 of 12 pancreatic cancer specimens. It is concluded that the expression of gut peptide receptors in pancreatic cancer differs from that in tumour-free pancreas. Receptors for these peptides are present in only a minority of pancreatic cancer specimens.
Overexpression of P-glycoprotein (PGP), MRP or LRP has been characterized as the 'proximal', while overexpression of the anti-apoptosis Bcl-2 or Bcl-xL relative to the pro-apoptosis Bax protein has been recognized as the 'distal' mechanism of multidrug resistance in human AML cells. In the present studies, we examined whether these mechanisms can co-exist in human AML HL-60 cells. We also determined how these mechanisms would affect the accumulation and cytotoxicity of a PGP substrate, such as Taxol (paclitaxel). For this, immunoblot analyses were performed to determine the expression of PGP, MRP, Myc, Bcl-2, Bcl-xL and Bax on either the multidrug-resistant HL-60 sublines created under the selection pressure of doxorubicin (HL-60/AR), paclitaxel (HL-60/TAX1000) or vincristine (HL-60/VCR), or sublines created by transfection and overexpression of the bcl-2 (HL-60/Bcl-2) or bcl-xL gene (HL-60/Bcl-xL). As compared to the control HL-60, HL-60/AR cells possess high MRP while HL-60/TAX1000 and HL-60/VCR cells express high levels of the mdr-1 encoded PGP. In addition, these multidrug-resistant cells possess 1.5- to 2.5-fold higher Bcl-2, while their Bax and Myc levels are similar to those in the control HL-60 cells. HL-60/TAX1000 and HL-60/VCR cells also express three- and 2.5-fold higher Bcl-xL levels. PGP, but not MRP, overexpression significantly impaired paclitaxel accumulation and paclitaxel-induced apoptosis, as well as reduced its cytotoxic effects as determined by the MTT assay. In contrast, enforced and much higher expression of Bcl-2 in HL-60/Bcl-2 (five-fold) or Bcl-xL in HL-60/Bcl-xL cells (10-fold) significantly reduced paclitaxel-induced apoptosis and the loss of cell viability, without affecting its intracellular accumulation. These results confirm the possibility of co-expression of multiple mechanisms of multidrug resistance in human leukemic cells which had been selected by exposure to a single drug. The results also indicate that MRP overexpression does not confer resistance against paclitaxel. In addition, these findings suggest that, for Bcl-2 and Bcl-xL, enforced overexpression to high levels is necessary to induce paclitaxel resistance in HL-60 cells.
Alterations in the distribution of alpha-adrenergic receptors (alpha ARs) in two subcellular organelles, the sarcolemmal membrane and the light vesicle, of rat heart during the progression of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). alpha ARs were assayed by using [3H]prazosin binding and photoaffinity labeling with [125I]arylazidoprazosin in combination with polyacrylamide gel electrophoresis. Septic rat hearts exhibit two distinct phases: an initial hypercardiodynamic (9 h after CLP; early sepsis) followed by a hypocardiodynamic (18 h after CLP; late sepsis) phase. [3H]prazosin binding studies show that during early sepsis, the Bmax (maximal binding capacity) was increased by 21.4% in sarcolemma but was decreased by 22.5% in light vesicles, while during late sepsis, the Bmax was decreased by 25.4% in sarcolemma but was increased by 60.8% in light vesicles. The photoaffinity labeling studies revealed three binding peptides with M(r) of 77, 68, and 39 kDa. The total binding for the three label peptides during early sepsis was increased by 25.5% in sarcolemma but was decreased by 40% in light vesicles, while during late sepsis, the total binding was decreased by 32.1% in sarcolemma but was increased by 35.8% in light vesicles. These data indicate that alpha ARs in the rat heart were externalized from light vesicles to sarcolemma during early hypercardiodynamic phase while they were internalized from surface membranes to intracellular compartment during late hypocardiodynamic phase of sepsis. Because alpha ARs play an important role in regulating myocardial contractility, an initial externalization followed by internalization of alpha ARs may contribute to the development of the initial hypercardiodynamic and the subsequent hypocardiodynamic states during sepsis.
Allergen-specific cytokine responses in the airways are thought to play a critical role in the pathogenesis of atopic asthma. This study examined whether there is a quantitative difference in bronchoalveolar lavage (BAL) cell allergen-induced IL-5 production between atopic subjects with and without asthma which may relate to a difference in airway response induced by allergen exposure. Twelve atopic asthmatics (AA), nine atopic non-asthmatics (AN) and 10 normal controls (N) underwent inhalation challenge with house dust mite allergen (HDM) extract. AA differed from AN in having late airway reactions (LAR) after HDM inhalation (P < 0.01), which correlated with an increased percentage of BAL eosinophils and increased BAL cell IL-5 production after in vivo or in vitro HDM challenge for the AA group (P < 0.01). IL-5 production by PBMC from both atopic groups was elevated with HDM stimulation in vitro, but AA again had a higher level under baseline conditions than AN (P < 0.02). Furthermore, there was a greater effect of BAL fluid from AA on ECP release by eosinophils compared to that for AN (P < 0.01). These findings suggest that increased IL-5 production in atopic asthmatic airways contributes to the increased physiological response to allergen inhalation, by modulating local eosinophil recruitment and activation.
A new type of endocardial bipolar pacing lead has been designed to overcome the potential drawbacks of the conventional coaxial bipolar pacing lead. We prospectively evaluated the new co-radial bipolar pacing leads (Intermedics Thin-Line), which are thinner (5 Fr vs 6-8 Fr) than standard coaxial bipolar leads. X-ray visibility and lead handling were subjectively assessed (excellent, good, adequate, or poor) at implant; lead impedance, sensitivity threshold, and pacing threshold were measured at implant, then at 1, 3, 6, 12, and 18 months. The results were as follows: 103 patients (51 M; age 63.8 +/- 17.4 years) received 71 atrial (A) and 89 ventricular (V) leads. X-ray visibility was excellent in 59/103; good in 23/103; adequate in 11/103; and poor in 10/103. Overall handling was excellent in 56/71 A and 69/89 V; good in 11/71 A and 18/89 V; adequate in 3/71 A and 1/89 V; poor in 1/71 A and 1/89 V. There were two perioperative complications. At implant: impedance in A and V were 370.1 +/- 74.7 and 501.5 +/- 124.4 omega, sensing thresholds in A and V were 3.0 +/- 1.5 and 9.9 +/- 5.0 mV, pacing thresholds at 0.45 ms in A and V were 0.59 +/- 0.21 and 0.41 +/- 0.15 volt, respectively. At 1, 3, 6, 12, and 18 months of follow-up: no pacing lead related complications were reported; pacing lead characteristics remained outstanding and stable. This new lead appears to have significant clinical advantages over the conventional coaxial bipolar pacing lead. Long-term follow-up is required to confirm its reliability and chronic performance characteristics.
Atrial and ventricular attachments of accessory atrioventricular connections have classically been localized to adjacent atrial and ventricular tissues, and this principle is responsible for the widespread success of radiofrequency catheter ablation. We present anatomical evidence of an unusually located accessory atrioventricular connection, which bridged the atrioventricular ring epicardially, directly from the base of the right atrial appendage to the right ventricle. This observation might offer a new insight into unusual accessory atrioventricular connection locations and may explain why some endocardial radiofrequency catheter ablation procedures might fail.
BACKGROUND: Gut peptides are known to influence hormone release and growth of endocrine tumours of the pancreas. Although information on somatostatin receptors has been provided recently, little is known on the receptor status of other gastrointestinal hormones in such tumours. AIMS: To analyse the spectrum of gut hormone receptors on endocrine tumours of pancreas. SUBJECTS: Four types of endocrine tumours from eight patientS. METHODS: The receptors for bombesin, secretin, vasoactive intestinal peptide, cholecystokinin, and somatostatin have been visualised and quantified with storage phosphor autoradiography. RESULTS: Bombesin receptors were present in all five gastrinomas and two primary VIPomas. Secretin receptors were expressed in four primary gastrinomas and one primary VIPoma from pancreas. Vasoactive intestinal peptide receptors were identified in four primary gastrinomas and all VIPomas. Furthermore, all VIPomas expressed cholecystokinin-B (gastrin) receptors, whereas, gastrinomas did not contain cholecystokinin-B receptors. The receptors for somatostatin were detected in all gastrinomas and VIPomas. Both somatostatinoma and glucagonoma were negative for all five types of peptide receptors studied. CONCLUSIONS: Besides somatostatin receptors, most of gastrinomas and VIPomas also express receptors for bombesin, secretin, and vasoactive intestinal peptide.
The study was designed to characterize restitution kinetics in atrial repolarization of rabbits and to examine effects of K+ or Ca2+ channel blockers on restitution. Action potentials were recorded from rabbit atrial tissue. Restitution curves of phase I amplitude and action potential duration at 50 and 90% repolarization (APD50, APD90) were defined at a basic cycle length of 0.5 s during control and with interventions. Restitution of phase I amplitude had a monoexponential function with a time constant of 2.8 +/- 0.2 s. The curves of APD50 frequently had a monoexponential function and time constants were 1.8 +/- 0.1 s. Restitution curves of APD90 were biphasic: a descending phase followed by an ascending phase. The blocker of Ito1 (a 4-aminopyridine-sensitive component of the transient outward current), 4-aminopyridine, flattened the restitution curves of phase I amplitude, and APD50 and APD90 curves became monophasic. Sotalol, a selective IKr (a rapid component of the delayed rectifier K+ current) blocker, did not alter curves of phase I amplitude and APD50 but shifted APD90 curves upward. Cadmium, a Ca2+ blocker shifted curves of phase I amplitude and APD50 downward and abolished the ascending phase of APD90 curves. We conclude that kinetics of Ito1 and ICa (calcium current) may account for characteristics of restitution of atrial repolarization in rabbit.
The peptide galanin (GAL) exists in dense concentrations within the medial hypothalamus and is synthesized in a population of neurons within the paraventricular nucleus (PVN). This peptide has been linked to energy homeostasis through its behavioral, metabolic and endocrine actions, including pancreatic insulin secretion. This investigation examined whether circulating insulin, in turn, has impact on hypothalamic GAL production, GAL mRNA and peptide concentrations in the hypothalamus. Streptozotocin (STZ)-induced diabetic rats, compared to control subjects, were tested with or without insulin replacement. After STZ treatment, the rats exhibited hyperglycemia, increased food and water intake, and decreased weight gain compared to controls. These changes were reversed by daily, subcutaneous injections of insulin. Measurements of GAL mRNA, via solution hybridization/nuclease protection assay, revealed a 6-fold elevation after STZ treatment compared to controls, accompanied by a similar rise in GAL peptide levels. This increase in GAL message and peptide was reversible by insulin and was detected in a mediodorsal hypothalamic (MDH) dissection which contains the PVN. It was not seen in a dissection of the mediobasal hypothalamus that includes the GAL-synthesizing neurons of the arcuate nucleus. Measurements of GAL in discrete hypothalamic nuclei of STZ diabetic rats showed a 100% increase in peptide concentrations (p < 0.05) in the PVN that was insulin responsive. Other hypothalamic areas examined failed to exhibit any change in peptide. These findings are consistent with other evidence indicating an inverse association, between circulating insulin and GAL message or peptide in the PVN, that may have physiological relevance in the control of energy balance.