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Biomedical subjects

G Doherty

Publications and source records attributed to G Doherty.

13 recordsLinked to original sources
PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗
PubMed2004

Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes.

Sphingosine 1-phosphate (S1P) is a bioactive lysolipid with pleiotropic functions mediated through a family of G protein-coupled receptors, S1P(1,2,3,4,5). Physiological effects of S1P receptor agonists include regulation of cardiovascular function and immunosuppression via redistribution of lymphocytes from blood to secondary lymphoid organs. The phosphorylated metabolite of the immunosuppressant agent FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol) and other phosphonate analogs with differential receptor selectivity were investigated. No significant species differences in compound potency or rank order of activity on receptors cloned from human, murine, and rat sources were observed. All synthetic analogs were high-affinity agonists on S1P(1), with IC(50) values for ligand binding between 0.3 and 14 nM. The correlation between S1P(1) receptor activation and the ED(50) for lymphocyte reduction was highly significant (p < 0.001) and lower for the other receptors. In contrast to S1P(1)-mediated effects on lymphocyte recirculation, three lines of evidence link S1P(3) receptor activity with acute toxicity and cardiovascular regulation: compound potency on S1P(3) correlated with toxicity and bradycardia; the shift in potency of phosphorylated-FTY720 for inducing lymphopenia versus bradycardia and hypertension was consistent with affinity for S1P(1) relative to S1P(3); and toxicity, bradycardia, and hypertension were absent in S1P(3)(-/-) mice. Blood pressure effects of agonists in anesthetized rats were complex, whereas hypertension was the predominant effect in conscious rats and mice. Immunolocalization of S1P(3) in rodent heart revealed abundant expression on myocytes and perivascular smooth muscle cells consistent with regulation of bradycardia and hypertension, whereas S1P(1) expression was restricted to the vascular endothelium.

Anesthesia↗
PubMed2001

Evaluation of the performance and clinical impact of a rapid intraoperative parathyroid hormone assay in conjunction with preoperative imaging and concise parathyroidectomy.

BACKGROUND: (99m)Tc-sestamibi scans and rapid, intraoperative intact parathyroid hormone (PTH) assays allow preoperative identification of diseased glands and intraoperative confirmation of diseased gland removal, respectively. Use of these two new technologies may facilitate simpler, more concise surgery, shorter hospital stays, and decreased costs for frozen-section analysis. One major drawback to this new strategy has been the high cost of rapid point-of-care PTH assays. METHODS: We performed rapid PTH assays with the DPC Turbo PTH assay on the DPC IMMULITE automated analyzer. The number of intraoperative frozen sections, type of anesthesia, surgical approach, length of hospital stay, and pre- and postoperative calcium values were compared between a group of 49 patients undergoing parathyroidectomy where the intraoperative PTH assay was used in conjunction with preoperative imaging, and a historical control group of 55 patients before the use of these two technologies in our institution. RESULTS: Comparison of the Turbo PTH assay to the standard IMMULITE PTH assay gave the following: y = 1.08 x - 4.36 (r = 0.97; n = 48). For the 49 patients, the median turnaround time for each intraoperative PTH determination was 19 min (range, 14-40 min). The median decrease in PTH values from baseline was 88% (range, 33-99%). Thirty-seven patients required two PTH determinations, 7 required three, 4 had four, and 1 required five determinations. The average laboratory cost for the rapid intraoperative PTH assays was < $100 per patient (range, $55 to $113). Compared with the control group, the experimental group had significantly fewer frozen sections (1.4 vs 2.5; P < 0.0001), shorter hospital stays (17 discharged on the day of surgery vs none discharged on the day of surgery; P < 0.0001), greater use of local anesthesia (33% vs 0%; P < 0.001), and more unilateral, rather than bilateral neck explorations (65% vs 0%; P < 0.001). CONCLUSIONS: The combination of intraoperative Turbo PTH assay and preoperative (99m)Tc-sestamibi scans can lead to significant decreases in laboratory and surgical pathology costs, hospital stays, and exposure to general anesthesia by facilitating concise parathyroidectomy surgery.

Adolescent↗
PubMed1999

A new monoclonal antibody that specifically recognises the MDR-3-encoded gene product.

The MDR-3-encoded P-glycoprotein (Pgp) is highly expressed in liver and is thought to function as a hepatic transporter of phospholipids into bile. However its role, if any, in other tissues remains undefined. Although transfection experiments have indicated that it may be unable to confer drug resistance, there is evidence that it may be involved in drug resistance in certain B-cell leukaemias. To date, most work on clinical samples has been performed at the mRNA level; limited work has been performed using polyclonal antibodies raised to MDR-3 and mdr-2 (the murine equivalent of MDR-3). We have generated a new monoclonal antibody, termed 6/1G, which specifically recognises the human MDR-3 gene-encoded product. Antibody 6/1G was produced by in vitro immunisation of spleen cells from BALB/c mice with a synthetic 12-amino acid peptide. Cells from MDR-3 transgenic mice showed consistent membranous staining with antibody 6/1G. Immunoblotting with 6/1G identified a band at 170 kDa on lysates of MDR-3 transgenic cells. Preliminary results with a range of B-cell leukaemias suggest that MDR-3 Pgp positivity may be a marker for a more malignant phenotype in B-CLL. Antibody 6/1G may be useful in defining a role for MDR-3 in malignancy and drug resistance, as well as in certain liver diseases such as progressive familial intracholeostasis.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1998

Preoperative diagnosis and surgical management of neuroendocrine gastroenteropancreatic tumors: general recommendations by a consensus workshop.

In 1996 a consensus workshop on the preoperative diagnosis and surgical treatment of neuroendocrine tumor disease took place in Berlin. Although there was a consensus on the diagnosis and surgical treatment by world experts in neuroendocrine surgery in some areas, it became clear that certain management policies vary among centers. In large part, diverging policies reflect a lack of controlled studies. This paper summarizes the various opinions brought forward during this conference and emphasizes consensus approaches for the diagnosis and therapy of neuroendocrine neoplasms.

Gastrointestinal Neoplasms↗
PubMed1997

The multidrug-resistant human lung tumour cell line, DLKP-A10, expresses novel drug accumulation and sequestration systems.

Drug accumulation studies with the anticancer agents adriamycin and vincristine were carried out on the MDR variant of the human lung cell lines DLKP, DLKP-A10 which overexpresses the MDR associated P-glycoprotein efflux pump. Reduced cellular accumulation of both agents was observed in the resistant variant. The subsequent addition of verapamil and cyclosporin A resulted in partial restoration of cellular accumulation of both drugs in the DLKP-A10 resistant variant while complete restoration of cellular drug levels was observed in the SKMES-1/ADR cell line. These results suggested that the accumulation defect observed in the SKMES-1/ADR cell line was P-glycoprotein mediated and that accordingly, the cells exhibited characteristics consistent with the classical MDR phenotype. In contrast, while P-glycoprotein also appears to mediate a reduction in cellular drug accumulation in the DLKP-A10 cells, an alternative transport mechanism may also be present. No significant increase in the expression of either the MRP or LRP transport proteins was observed in the resistant cells. Metabolic inhibition by antimycin A (but not sodium azide or 2-deoxy-D-glucose) resulted in complete restoration of drug accumulation suggesting the presence of an alternative energy dependent transport mechanism. Fluorescent microscopy studies indicated different cellular localisation of the drug within the parental and resistant cells despite equivalent intracellular concentrations. These studies also revealed the presence of an ATP-dependent, vesicular sequestration mechanism which may be involved in the reduction of nuclear adriamycin accumulation in the DLKP-A10 cell line. This was indicated by observation of the disruption of cytoplasmic vesicles by antimycin A and also inhibition of cytoplasmic drug sequestration by the carboxylic ionophores, monensin and nigericin, accompanied by increased adriamycin accumulation and redistribution of the drug from the cytoplasm to the nucleus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

A new mdr-1 encoded P-170 specific monoclonal antibody: (6/1C) on paraffin wax embedded tissue without pretreatment of sections.

AIMS: The generation and characterisation of a monoclonal antibody that specifically recognises the mdr-1 encoded protein, P-glycoprotein (P-170), on routinely processed formalin fixed, paraffin wax embedded tissue sections. METHODS: The monoclonal antibody, designated 6/1C, was produced following a combination of in vivo and in vitro immunisation regimens in Balb/c mice with a synthetic 12 amino acid peptide that corresponds to amino acids 21-32 (believed to be intracellularly located) of P-170 and has insignificant homology with the mdr-3 encoded P-170. Antibody 6/1C was characterised by western blotting and immunocytochemistry on cytospins of paired multidrug resistant or sensitive cell lines, including mdr-1 and mdr-3 transfected cells, and by immunohistochemistry on normal and malignant formalin fixed paraffin wax embedded tissue sections. RESULTS: Antibody 6/1C showed a single band at 170 kDa on western blots of multidrug resistant cell lysates and mdr-1 transfected cell lysates that was absent on similar preparations of drug sensitive cells and mdr-3 transfected cells. Immunocytochemical studies on cytospins of multidrug resistant cells and mdr-1 transfected cells revealed strong inner plasma membrane/cytoplasmic staining. Staining was negligible on drug sensitive cells and cells transfected with the mdr-3 gene. Immunohistochemical studies on formalin fixed, paraffin wax embedded normal adult kidney, liver, and breast tissue and a range of fetal tissues exhibited staining patterns of a variety of secretory surfaces consistent with documented mdr-1 specific staining. Specific staining of malignant cells in similarly treated sections of breast tumours was seen also with antibody 6/1C. Staining on paraffin wax embedded tissue with this antibody did not require any pretreatment of tissue sections. CONCLUSIONS: This new monoclonal antibody, chosen for its specificity with the mdr-1 encoded P-170 and its reactivity on routinely fixed paraffin wax embedded tissue samples without pretreatment, appears to be useful for the investigation of P-170 in archival material. It is especially useful for retrospective studies on pretreatment and post-treatment tissue sections, and could help establish when and how rapidly mdr-1 associated drug resistance develops during chemotherapeutic regimens. Immunohistochemical assessment of P-170 expression in many cancers has potential for diagnostic purposes and may influence the choice of chemotherapeutic drugs used in the treatment of refractory tumours.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Conversation, co-ordination and convention: an empirical investigation of how groups establish linguistic conventions.

Two experiments are reported which demonstrate the development of co-ordinated description languages in two groups of communicators playing Garrod and Anderson's (1987) maze game. The experiments contrast language co-ordination between speakers who always interact with the same partner (isolated pairs) as compared with speakers who interact with different partners drawn from the same community. Whereas the isolated pairs show higher degrees of inter-speaker convergence than the community pairs at the start of the experiment, the situation reverses by the time they have all played six or more games. The results are discussed at two levels: (1) in terms of Lewis's formal theory of conventions, and (2) in relation to a language processing model which abides by the "output/input co-ordination" principle proposed in Garrod and Anderson (1987).

Group Processes↗
PubMed1978

Effects of cue-controlled relaxation, a placebo treatment, and no treatment on changes in self-reported test anxiety among college students.

Twenty-eight test-anxious Ss received either "cue-controlled relaxation therapy," an inert placebo treatment, or no treatment. Once before and twice after the experimental treatment period each S responded to three test-anxiety scales and to one measure of public-speaking anxiety. Once after the treatment, Ss rated the credibility of the procedure to which they had been exposed. Pre- and posttreatment scores on the measure of (untreated) speech anxiety and posttreatment ratings of credibility both showed that the cued relaxation and placebo procedures exerted equivalent experimental demand for improvement. Scores on all three test-anxiety measures showed that, under these conditions of equivalent demand,the placebo procedure reduced self-reports of test anxiety at least as much as did cue-controlled relaxation. Implications are discussed.

Anxiety↗