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Biomedical subjects

S Carlin

Publications and source records attributed to S Carlin.

At least 19 recordsLinked to original sources
PubMed2001

Mechanisms of airway remodeling. Airway smooth muscle.

The airway smooth muscle cell can contract; relax; participate in allergic and inflammatory responses by expressing adhesion molecules, releasing cytokines, and producing matrix proteins and proteases; and, as has been reported, undergo migration. These properties enable the muscle cell to be a key component in the airway wall remodeling that accompanies persistent asthma. Evidence is emerging that identifies the pivotal steps in the signal transduction pathways that lead to the excessive proliferation of the muscle observed in vitro in airway smooth muscle cells from subjects with asthma. The contractile, biochemical, and growth characteristics of muscle from allergic subjects are different from those of nonallergic subjects. In addition, the allergic response impacts on the extracellular matrix in which the muscle is embedded, by altering the profile of matrix proteins released. Once the relationships between allergy and inflammation of the smooth muscle and its extracellular matrix are better defined, opportunities to prevent or reverse airway remodeling will become available.

Allergens↗
PubMed2000

A gene therapy approach to enhance the targeted radiotherapy of neuroblastoma.

BACKGROUND: The aims of this study were to determine whether the introduction and expression of the noradrenaline transporter (NAT) gene into NAT-negative neuroblastoma cell lines would make them amenable to targeted radiotherapy using [(131)I]MIBG. PROCEDURE: Neuroblastoma cell lines were transfected with a eukaryotic expression vector containing the bovine noradrenaline transporter cDNA under the expression of the CMV promoter. Stable transfectants were created by selection in geneticin (G418) and were characterised for their MIBG uptake ability and susceptibility to [(131)I]MIBG therapy. RESULTS: The cell line SK-N-MC, which normally shows no ability to take up MIBG, was successfully transfected with bNAT. SK-N-MC.bNAT transfectants exhibited uptake and release kinetics similar to those of the natural NAT-expressing cell line SK-N-BE(2c). Levels of [(131)I]MIBG uptake were 33% of those of the highest naturally NAT-expressing cell line SK-N-BE(2c). Growth delay assays using multicellular spheroids indicated that this degree of [(131)I]MIBG uptake was sufficient to inhibit growth at radioactive concentrations of 4 Mbq/ml. CONCLUSIONS: These results demonstrate the feasibility of combining gene therapy with targeted radiotherapy to enhance uptake, and hence radiation dose, to neuroblastoma tumours using [(131)I]MIBG. With the appropriate delivery vehicle and tumour-specific control of expression, the introduction of noradrenaline transporter molecules may be a viable means of enhancing the response of neuroblastoma tumours to [(131)I]MIBG therapy.

Carrier Proteins↗
PubMed2000

Experimental targeted radioiodide therapy following transfection of the sodium iodide symporter gene: effect on clonogenicity in both two-and three-dimensional models.

To evaluate the potential of the expression of the sodium/iodide symporter (NIS) as a means of targeting radioiodine to tumor cells, we have employed plasmid-mediated transfection of the NIS gene into a range of mammalian cell hosts. We observed perchlorate-inhibitable iodide uptake up to 41-fold over control in all NIS-transfected cells. We assessed the effect of NIS expression followed by exposure to 131I- on the clonogenic survival of UVW glioma cells. After exposure of two-dimensional monolayer cultures of UVW-NIS cells to 131I- at a radioactive concentration of 4 MBq/mL, clonogenic survival was reduced to 21%. Similar treatment of UVW-NIS cells in three-dimensional spheroid cultures resulted in a reduction of clonogenic survival to 2.5%. This increase in sensitivity to 131I- exposure is likely to be due to a radiological bystander effect. These results are very encouraging for the development of a novel cytotoxic gene-therapy strategy in which a radiological bystander effect plays a significant role in tumor cell sterilization.

Adenocarcinoma↗
PubMed2000

The production of extracellular matrix proteins by human passively sensitized airway smooth-muscle cells in culture: the effect of beclomethasone.

Airway remodeling is a key feature of persistent asthma. Part of the remodeling process involves the laying down of extracellular matrix (ECM) proteins within the airways. In this study we compared the production of ECM proteins by human airway smooth-muscle (ASM) cells in culture after exposure to 10% serum from an asthmatic individual or 10% serum from a nonasthmatic individual with or without beclomethasone (0.01 to 100 nM). Enzyme-linked immunosorbent assays were done with antibodies to human fibronectin; perlecan; elastin; the laminin beta(1), gamma(1), beta(2), alpha(1) chains; thrombospondin; chondroitin sulfate; collagen types I, III, IV, and V; versican; and decorin. Serum from the asthmatic individual, when compared with that from the nonasthmatic individual, caused a significant increase in the production of fibronectin, perlecan, laminin gamma(1), and chondroitin sulfate. Beclomethasone caused a significant reduction in the number of cells exposed to serum from either the asthmatic or nonasthmatic individual, but did not reverse the increase in ECM protein induced by the former. These results suggest an interaction between the ASM and the allergic process that may alter components of the airway wall in asthma, and that corticosteroids may not prevent the fibrosis induced by resident cells within the airways.

Adult↗
PubMed2000

An antisense of protein kinase C-zeta inhibits proliferation of human airway smooth muscle cells.

We hypothesized that an atypical isoform of protein kinase (PK) C, PKC-zeta, is essential for proliferation of human airway smooth muscle (HASM) cells in primary culture. Recombinant replication-deficient E1-deleted adenoviruses (100 plaque-forming units [pfu]/cell) expressing the antisense of PKC-zeta and the wild-type PKC-zeta (Ad-CMV-PKC-zeta) were added to actively growing cells that were subsequently incubated for 48 h in platelet-derived growth factor (PDGF) 40 ng/mL or 10% fetal bovine serum (FBS). Expression of the antisense at a virus concentration of 100 pfu/cell produced a significant (n = 3, P<0.05) decrease in the mean manual cell count in the presence of PDGF to 37+/-5% relative to that in cells with no virus (100%), whereas in cells infected with virus containing no construct, this figure was 102+/-13%. The increase in cell number in response to FBS, however, was not affected by the presence of the antisense. Corresponding values for cells in 10% FBS were 100+/-22%, 85+/-22%, and 122+/-18%. Western blotting revealed decreased levels of PKC-zeta protein, but not PKC-alpha or PKC-epsilon protein, in cells infected with the antisense when compared with levels in control cells. Thus, in HASM cells, PKC-zeta is involved in proliferation in response to PDGF, but not in response to FBS, for which alternate signal transduction pathways independent of PKC-zeta must exist.

Adenoviridae↗
PubMed2000

Applications of gene transfer to targeted radiotherapy.

For targeted radionuclide therapy to succeed as a single modality treatment, schemes must be devised which will enable the deposition in malignant cells of sterilising doses of radiation. Until such methods have been perfected, it is necessary to combine targeted radiotherapy in a rational manner with conventional anti-cancer treatments. Several means of delivery of therapeutic radionuclides are being evaluated but none of these yet appears to be as powerful as the simplest and most effective example, viz: sodium [131I]iodide treatment of disseminated thyroid carcinoma. The radiopharmaceutical [131I]meta-iodobenzylguanidine ([131I]MIBG) is an effective single agent for the treatment of neuroblastoma. However, uptake of the drug in malignant sites is heterogeneous, suggesting that this therapy alone is unlikely to cure disease. A growing body of experimental evidence indicates exciting possibilities for the integration of gene transfer with radionuclide targeting. This review covers aspects of the combination of gene manipulation and targeted radiotherapy, emphasising the potential of gene transfer to facilitate tumour targeting with low molecular weight radiopharmaceuticals.

3-Iodobenzylguanidine↗
PubMed1999

The development of a quality of life instrument for use with post-menopausal women with urogenital atrophy in the UK and Sweden.

Many post-menopausal women suffer from oestrogen deficiency. This can cause urogenital atrophy which leads to symptoms such as dyspareunia, dysuria, vaginal dryness and urge incontinence. Even though urogenital atrophy is a common condition, little attempt has been made to investigate the impact that the condition has on the quality of life of the women concerned. A quality of life instrument specifically for use with women with urogenital atrophy was developed. The needs-based approach to quality of life was adopted, which states that quality of life is the extent to which an individual is able to satisfy her needs. The development work was undertaken simultaneously in the UK and Sweden. The measure was found to be acceptable and relevant to women in both countries and to have good levels of test-retest reliability (0.92 in the UK and 0.85 in Sweden), internal consistency (alpha coefficients 0.90 in both countries) and construct validity. It is suitable for use in clinical trials and for monitoring the progress of patients in clinical practice.

Adult↗
PubMed1999

Protein kinase C isoforms in human airway smooth muscle cells: activation of PKC-zeta during proliferation.

Protein kinase C (PKC) is implicated in the regulation of smooth muscle contractility and growth. We have previously described the pattern of isoform expression of PKC in canine airway smooth muscle. This study identified the isoforms present in human cultured airway smooth muscle cells and also addressed the question of whether mitogenesis in these cells is associated with changes in a specific isoform, PKC-zeta. Western blot analysis revealed the presence of PKC-alpha, -betaI, and -betaII of the conventional group; PKC-delta, -theta, -epsilon, and -eta of the novel group; and PKC-zeta, -mu, and -iota of the atypical group. There was a significant increase in density of the Western blot for PKC-zeta in cells proliferating in response to 10% fetal bovine serum (FBS) to 372 +/- 115% of control values (P < 0.05; n = 3 patients) in the cytosolic fraction. Platelet-derived growth factor (PDGF) produced increases in PKC-zeta in both the cytosolic and membrane fractions to 210 +/- 49 and 443 +/- 227%, respectively, of control values (P < 0.05; n = 4 patients). There was no change in expression of PKC-alpha, -betaI, -betaII, -theta, -epsilon, -eta, -delta, or -iota in response to the same stimuli. PGE2 (1 microM) added to the cells 30 min before PDGF reduced incorporation of [3H]thymidine from 5,580 +/- 633 (SE) to 3, 980 +/- 126 dpm (P < 0.05; n = 3 patients) and, in addition, reduced expression of PKC-zeta in the membrane fraction as determined by Western blotting from 266 +/- 66 to 110 +/- 4% of control values (P < 0.05; n = 3 patients). PKC-zeta activity in stimulated cells (10% FBS), as assessed by immunoprecipitation and phosphorylation of glycogen synthase peptide, was approximately 3-fold greater than that in unstimulated cells, and the amount of PKC-zeta protein correlated with isoenzyme activity (r2 = 0.91; P < 0.02; n = 4 patients). In conclusion, this study 1) provides the first description of which isoforms of PKC are present in human cultured airway smooth muscle cells and 2) shows that proliferation of these cells is associated with upregulation of PKC-zeta. Whether activation of PKC-zeta is a primary or secondary event in airway smooth muscle cell proliferation remains to be determined.

Bronchi↗
PubMed1998

Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma.

BACKGROUND: Patients with clinically localized, intermediate- or high-grade non-Hodgkin's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. METHODS: We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone. RESULTS: Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). CONCLUSIONS: Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Genesis and acid/base.

Perhaps the enigmatic etiology of cell specialization ultimately leading to organogenesis can be explained by the unusual combine application of some common mechanisms. Perhaps the combination of control of variable pH through compartmentalization, dialysis/diffusion gradients, and an electrophoresis plane impacts cells in zones causing the developmental patterns. Possibly pH is even manipulated at times to change the charge on molecules in order that attraction of opposite charges can be utilized.

Adult↗
PubMed1994

Diseased cells and pH.

Diseased cells may alter their intracellular pH. This could explain such diverse activities as resistance to hormones, resistance to medications, and preferential metastasis to the same locations.

Animals↗
PubMed1994

Alterations in EGF-dependent proliferative and phosphorylation events in squamous cell carcinoma cell lines by a tyrosine kinase inhibitor.

The epidermal growth factor (EGF) receptor is overexpressed in squamous cell carcinoma and the EGF receptor has been proposed as a potential target for new therapeutic agents in this tumour type. We have utilized a tyrphostintype inhibitor of the EGF receptor tyrosine kinase domain (RG50864) to study EGF-dependent proliferation and phosphorylation in two human squamous cell carcinoma cell lines. There were selected on the basis that whereas both cell lines have a large number of EGF receptors, one is growth inhibited by EGF (A431) while the proliferation of the other cell line (B2A4) is stimulated by EGF. EGF induced receptor autophosphorylation in each of the two cell lines; however, the level of phosphorylation was greater in the A431 cells than in the B2A4 cells. The pattern of proteins phosphorylated in response to EGF was different in the two squamous cell lines. RG50864 antagonized the EGF-dependent proliferation of B2A4 cells, but was unable to reverse the inhibitory effect of EGF on A431 cell growth. RG50864 partially inhibited EGF receptor autophosphorylation in both cell lines and completely inhibited the EGF-dependent phosphorylation of other cellular proteins, one of which co-migrated with MAP2kinase in both cell lines. Moreover, different dose-response relationships for the inhibition of phosphorylation of various proteins were observed in A431 versus B2A4 cells. As a substrate competitive inhibitor of the EGF receptor tyrosine kinase, the primary mode of action of RG50864 may be to prevent the association and/or phosphorylation of multiple specific substrates of the receptor in a fashion which may be cell line dependent. The precise relationship of these phosphorylation events to tyrphostin sensitivity remains to be established.

Antineoplastic Agents↗
PubMed1993

Possible etiology for euthyroid sick syndrome.

Euthyroid sick syndrome is possibly due to an increase in Triac (a T3 analogue) and/or Tetrac (a T4 analogue). Triac and/or Tetrac possibly feed back on the pituitary/hypothalamus region and cause a secondary hypothyroidism. This is possibly analogous to such diverse conditions as fetal thyroid function and black bear hibernation.

Animals↗