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1. Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With NPM1 and FLT3 Mutations

Author

Russell, Nigel H., primary, Wilhelm-Benartzi, Charlotte, additional, Othman, Jad, additional, Dillon, Richard, additional, Knapper, Steven, additional, Batten, Leona M., additional, Canham, Joanna, additional, Hinson, Emily L., additional, Betteridge, Sophie, additional, Overgaard, Ulrik Malthe, additional, Gilkes, Amanda, additional, Potter, Nicola, additional, Mehta, Priyanka, additional, Kottaridis, Panagiotis, additional, Cavenagh, Jamie, additional, Hemmaway, Claire, additional, Arnold, Claire, additional, Freeman, Sylvie D., additional, Dennis, Mike, additional, Kallenbach, Maria, additional, Severinsen, Marianne, additional, Holm, Mette, additional, Maxwell Norgaard, Jan, additional, Beier Ommen, Hans, additional, Culligan, Dominic, additional, Tighe, Jane, additional, Craig, Jenny, additional, Crawley, Charles, additional, Krishnamurthy, Pramila, additional, Sadik, Walid, additional, Smith, Jeffery, additional, Dasgupta, Ranjit, additional, Berkhan, Leanne, additional, Bowett, Peter, additional, Doocey, Richard, additional, Emmett, Shannon, additional, Hawkins, Timothy, additional, Patton, Nigel, additional, Pemberton, Lucy, additional, Milne, Alison, additional, Roy, Ashok, additional, Simpson, Sylwia, additional, Cuthbert, Robert, additional, Finnegan, Damian, additional, Francis McMullin, Mary, additional, Pechey, Victoria, additional, Lovell, Richard, additional, Milligan, Donald, additional, Paneesha, Shankara, additional, Cahalin, Paul, additional, Kelsey, P., additional, Ackroyd, Sam, additional, Wiliams, Adrian, additional, Evely, Roger, additional, Marks, David, additional, Fletcher, Andrew, additional, Al-Ani, Maryam, additional, Ahmed, Khalil, additional, Lush, Richard, additional, Rye, Adam, additional, Cutting, Robert, additional, Welch, Emma, additional, Wodzinski, Mark, additional, Butler, Andrew, additional, Fernyhough, Liam, additional, Ganly, Peter, additional, Gibbons, Steve, additional, Smith, Mark, additional, Spearing, Ruth, additional, Peniket, Andy, additional, Hatcliffe, Faye, additional, Patel, Amit, additional, Lindsay, Kathrine, additional, Brearton, Gillian, additional, Tuegar, Salah, additional, Gandhi Anna Cowley, S., additional, Copplestone, Adrian, additional, Hunter, Hannah, additional, Medd, Patrick, additional, Nokes, Tim, additional, Rule, Simon, additional, Thomas, Wayne, additional, Joseph, Joe, additional, Kaul, Stuti, additional, Sorour, Youssef, additional, Chvuka, Shingi, additional, Mangos, Hilda, additional, Neylon, Annette, additional, Farrell, Katrina, additional, Edwards, Hugh, additional, Hanlon, Katharine, additional, Fail, Tom, additional, Goodrick, Margaret, additional, Heartin, Earnest, additional, Hoyle, Christine, additional, Carr, Robert, additional, Raj, Kavita, additional, Krogh Jensen, Morten, additional, Janmohamed, Riaz, additional, Kaczmarski, Richard, additional, Sugai, Taku, additional, Ademokun, Debo, additional, Chalmers, Isobel, additional, Hodson, Andrew, additional, Gomez, Cesar, additional, Sadullah, Shala, additional, Kwan, Mark, additional, Longmuir, Karyn, additional, Wilson-Morkeh, Isaac, additional, Hunter, Ann, additional, Martin, Murray, additional, Saravanamuttu, Kandeepan, additional, Sidra, Gamal, additional, Burns, Sarah, additional, Gibbs, Simon, additional, Tholouli, Eleni, additional, Aldouri, Maadh, additional, Andrews, Vivienne, additional, Eden, Ayed, additional, Dungarwalla, Moez, additional, White, Denise, additional, Laird, Jane, additional, Mitchell, Lindsey, additional, Murphy, John, additional, Paterson, Pamela, additional, Raafat, Alaeddin, additional, Mannari, Deepak, additional, Davies, Simon, additional, Austen, Belinda, additional, Allford, Sarah, additional, Kakalamudi, Sudhakar, additional, Basu, Supratik, additional, Hada, Sunil, additional, Jacob, Abraham, additional, MacWhonell, Alan, additional, McCaig, Alison, additional, Gelly, Keith, additional, Kerr, Ron, additional, Meiklejohn, David, additional, Tauro, Sudhir, additional, Lawes, Matthew, additional, Bowen, Angela, additional, Krishnamurthy, Suchitra, additional, Byrne, Jenny, additional, Dasgupta, Emma, additional, Russell, Nigel, additional, Stokley, Simone, additional, Friis, Lone, additional, Marcher, Claus, additional, Bake, Bart, additional, Chapple, Mary, additional, Moreton, Paul, additional, Omran, Asad, additional, Patil, Kavita, additional, Wright, David, additional, Jack, Fergus, additional, Maddams, Rebecca, additional, Corser, Robert, additional, Cranfield, Tanya, additional, Dignum, Helen, additional, Ganczakowski, Mary, additional, Jones, Christopher, additional, Craddock, Charles, additional, Moss, Paula, additional, Murray, Jim, additional, Craig, Joanne, additional, Forsyth, Peter, additional, Lush, Chris, additional, Wei Bjerrum, Ole, additional, Borregaard, Niels, additional, Kampmann, Peter, additional, Kjeldsen, Lars, additional, Juul Nielsen, Ove, additional, Niemann, Carsten, additional, Lykke Petersen, Soeren, additional, Udby Peter Møller, Lene, additional, Alfred, Arun, additional, Barker, Helen, additional, Went, Richard, additional, Groch, Henri, additional, Mucklow, Stuart, additional, Sampson, Rebecca, additional, Chacko, Joseph, additional, Hall, Rachel, additional, Walewska, Renata, additional, Creach, Desmond, additional, Pottinger, Bryson, additional, Addada, Juanah (Jo), additional, Hamilton, Malcolm, additional, Kerr, Paul, additional, Ngu, Loretta, additional, Rudin, Claudius, additional, Ruell, Jackie, additional, Dalley, Chris, additional, Kaur, Harpreet, additional, Reilly, John, additional, Snowden, John, additional, Ferguson, Paul, additional, Dyer, Peter, additional, Chandra, Deepak, additional, DeVos, Johannes, additional, Grey-Davies, Elisabeth, additional, Hendry, Louise, additional, Corbett, Timothy, additional, Crowe, Josephine, additional, Knechtli, Christopher, additional, Wexler, Sarah, additional, Fernandes, Savio, additional, Neilson, Jeff, additional, Houghton, John, additional, Jowitt, Simon, additional, Thomas-Dewing, Rowena, additional, Williams, Mark, additional, Zaman, Sonya, additional, Cullis, Jonathan, additional, Everington, Tamara, additional, Grand, Effie, additional, Hasan, Yasmin, additional, Murrin, Richard, additional, Wandoo, Farooq, additional, Ismail, Saad, additional, Mohite, Unmesh, additional, Sati, Hamdi, additional, Jenner, Matthew, additional, Orchard, Kim, additional, Richardson, Deborah, additional, McCloskey, Kayleigh, additional, Xu Chin, Kate, additional, Fenella Willis, Neoh, additional, Sud, Amit, additional, Gharib, Maged, additional, Nicholson, Toby, additional, Bowen, David, additional, Janes, Sarah, additional, Eagleton, Helen, additional, O'Hea, Anne-Marie, additional, Pattinson, Jonathan, additional, Hervey, Victoria, additional, Lyons, Simon, additional, Marshall, Scott, additional, Nicolle, Annette, additional, Vavyla, Maria, additional, Burgess, Jordan, additional, Somervaille, Tim, additional, Somerfield, Sven, additional, Mamat, Mohd, additional, Tomlins, Jo, additional, Salesh, Sana, additional, David, Marianna, additional, Maddox, Jamie, additional, Plews, Diane, additional, Dang, Ray, additional, Potter, Mike, additional, Ellis, Lauren, additional, Nicholson, Emma, additional, Keat, Sally, additional, Ahmed Alhassani, Thubeena M., additional, Anjum, Farahn, additional, Chatterjee, Poulami, additional, Stanchev, Atanas, additional, Peters, Jayne, additional, Lindsay-Holmes Srividhya, Sarah, additional, Chodhouri, Senthil S., additional, Eve, Heather, additional, Smith, Steve, additional, Roberts, Patrick, additional, Rymes, Nicholas, additional, Zhao New Oo, Rui, additional, Ardeshna, Kirit, additional, Blombery, Piers, additional, Khwaja, Asim, additional, Linch, David, additional, Popat, Rakesh, additional, Virchis, Andres, additional, Yong, Kwee, additional, McIntyre, Victoria, additional, Horne, Gillian, additional, Bokhari, Syed, additional, Borg, Anton, additional, Chapman, Oliver, additional, Harrison, Beth, additional, Jackson, Nicholas, additional, Jobanputra, Shailesh, additional, Narayanan, Mekkali, additional, Rose, Peter, additional, Oun, Hajer, additional, Powell, Matthew, additional, Gilles, Julie, additional, Laing, Alison, additional, Devanny, Ian, additional, Haskins, Lea, additional, Micallef-Eynaud, Paul, additional, Maclean, Peter, additional, Alvares, Caroline, additional, Kell, Jonathan, additional, Knapper, Steve, additional, Davidson, Kerri, additional, McLintock, Lorna, additional, Rogers, Stephen, additional, Williamson, Peter, additional, Corbett, Gillian, additional, Goodman, Hugh, additional, Islam, Shahid, additional, Pullon, Humphrey, additional, Johnson, Peter, additional, Roddie, P.H., additional, Maughan, Elizabeth, additional, Mills, Juliet, additional, Shafeek, Salim, additional, Narat, Santosh, additional, Aitchison, Robin, additional, Bond, Lee, additional, Munro, Laura, additional, and Edwards, David, additional

Published
2024
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2. Left/right asymmetry in the early avian embryo

Author

Hoyle, Christine Irma

Subjects
571.8
Abstract

Left/right asymmetry was investigated during the development of the early avian embryo with particular reference to the normal asymmetry of the heart, which loops to the embryo's right-hand side. The structure of the pre-looped and post-looped heart was studied using light and electron microscopy. In the pre-looped heart, the right and left myocardial wall were of equal thickness. In the looping heart the right wall had thinned in comparison to the left. The direction of rotation in right and left looped hearts was examined using fluorescent carbocyanine dyes and viewed with a confocal microscope. The direction of rotation was found to be the same as the direction of looping. The situs of multiple embryos was studied by dividing the unincubated quail blastoderm in ovo. Singles, twins and triplet embryos were formed. Twins and triplets showed great variation in their orientation to each other. The majority of embryos had normal situs of the heart and body but 14% showed left-hand looping of the heart. No universal mechanism controlling situs was found at this stage. Areas of precardiac mesoderm were exchanged in the stage 4-6 embryo, in order to form double-right and double-left sided embryos. At stage 6, double-left sided embryos and controls formed right-sided loops, whereas the situs of hearts in double-right sided embryos approximated randomness. Left-handed heart loops were formed by cutting the right splanchnopleure at stage 8-9. following the work of Lepori. Teratological agents were applied both in ovo and in vitro. Retinoic acid was applied systemically and locally to form a right/left gradient using formate beads. Retinoic acid gave a dose-dependent and stage-related spectrum of heart malformations, including altering the situs. No significant difference was found in heart shape resulting from a right or left gradient. Methoxamine, βFGF, heparininase and ultraviolet light caused malformations of the heart but no significant alteration in the situs of the heart.

Published
1992

6. Identification of triptolide, a natural diterpenoid compound, as an inhibitor of lung inflammation

Author

Hoyle, Gary W., Hoyle, Christine I., Chen, Jing, Chang, Weiyuan, Williams, Ronald W., and Rando, Roy J.

Subjects
Lung diseases -- Care and treatment, Lung diseases -- Genetic aspects, Inflammation -- Health aspects, Inflammation -- Research, Tachykinins -- Health aspects, Tachykinins -- Research, Biological sciences
Abstract

Inflammation is associated with various pulmonary diseases and contributes to the pathogenesis of acute lung injury. We previously identified a proinflammatory signaling pathway triggered by G protein-coupled receptors (GPCRs) in which stimulation of [G.sub.q]-coupled GPCRs results in activation of the transcription factor NF-[kappa]B. Because damage to the lung causes the release of multiple mediators acting through [G.sub.q]-coupled GPCRs, this signaling pathway is likely to contribute to inflammatory processes in the injured lung. In an effort to identify novel inhibitors of lung inflammation, the National Institutes of Health Clinical Collection, a library of 446 compounds, was screened for inhibitory activity toward production of IL-8 induced by stimulation of the [G.sub.q]-coupled tachykinin 1 receptor with substance P in A549 cells. Twenty-eight compounds that significantly inhibited substance P-induced IL-8 production were identified. The most potent inhibitor was triptolide, a diterpenoid compound from Tripterygium wilfordii Hook F, a vine used in traditional Chinese medicine for the treatment of autoimmune diseases. Triptolide inhibited IL-8 production induced by substance P with an [IC.sub.50] of 2.3 x [10.sup.-8] M and inhibited NF-[kappa]B activation in response to an agonist of the protease-activated receptor 2 with an [IC.sub.50] of 1.4 x [10.sup.-8] M. Anti-inflammatory effects of triptolide were assessed in vivo using a chlorine gas lung injury model in mice. Triptolide inhibited neutrophilic inflammation and the production of KC (Cxcl1) in the lungs of chlorine-exposed mice. The results demonstrate that triptolide exhibits anti-inflammatory activity in cultured lung cells and in an in vivo model of acute lung injury. chlorine gas; acute lung injury; substance P; nuclear factor-[kappa]B; tachykinin 1 receptor doi: 10.1152/ajplung.00014.2010.

Published
2010

7. Make your strep diagnosis spot on

Author

Hoyle, Christine

Subjects
Strep throat -- Diagnosis, Strep throat -- Care and treatment, Strep throat -- Distribution, Company distribution practices, Health
Published
2009

15. Multiple cycles of high dose chemotherapy supported by hematopoietic progenitor cells as treatment for patients with advanced malignancies

Author

Long, Gwynn D., Negrin, Robert S., Hoyle, Christine F., Kusnierz-Glaz, Claus R., Schriber, Jeffrey R., Blume, Karl G., and Chao, Nelson J.

Subjects
Breast cancer -- Care and treatment, Chemotherapy -- Usage, Non-Hodgkin's lymphomas -- Care and treatment, Hematopoietic stem cells -- Health aspects, Health
Abstract

Background. Retrospective studies suggest that dose intensity is an important determinant of outcome in the treatment of patients with a variety of malignant diseases such as breast cancer, ovarian cancer, and lymphoma. Unfortunately, these results have not been clearly substantiated in prospective randomized trials. One problem with these studies may be that the degree of dose escalation is not sufficient to result in an improved outcome because the chemotherapy doses are limited by hematopoietic toxicity. In an attempt to deliver more dose-intensive therapy, the feasibility of the administration of multiple cycles of high dose chemotherapy with hematopoietic progenitor cell and growth factor support was investigated in patients with advanced malignancies. Methods. Nineteen patients with metastatic breast cancer and six patients with refractory non-Hodgkin's lymphoma were initially treated with etoposide (VP-16) (2 gm/[m.sup.2]) and granulocyte-colony stimulating factor (G-CSF). Peripheral blood hematopoietic progenitor cells were collected by leukapheresis and cryopreserved as the patients' leukocyte counts recovered from the nadir induced by VP-16. Patients were then treated with four cycles of mitoxantrone (18 mg/[m.sup.2]), thiotepa (150-200 mg/[m.sup.2]) and cyclophosphamide (4500-5000 mg/[m.sup.2]) as a 48-72 hour continuous infusion followed by infusion of one-quarter of their progenitor cells 48 hours later. All patients also received G-CSF (5 [micro]g/kg/day) until engraftment. Results. A total of 88 of a planned 100 cycles of therapy were administered to these 25 patients. The median time to recovery of an absolute neutrophil count of 500/[micro]l or greater was 13-14 days (range, 7-18 days) and time to recovery of a platelet count of 20,000/[micro]l or greater was 13-14 days (range, 7-16 days) after the initiation of each cycle of chemotherapy. The median number of platelet transfusions required after each cycle was 2-3 (range, 0-18 transfusions) and the number of erythrocyte transfusions was 4 (range, 0-10). The most common toxicity was diarrhea. Prophylactic intravenous antibiotics were administered to avoid fever with neutropenia. Two patients developed interstitial pneumonitis and one patient died. One heavily pretreated patient failed to engraft after the first cycle. Reversible veno-occlusive disease of the liver developed in one patient after the fourth cycle of therapy. Four patients progressed while on therapy. Eight patients were disease free and 13 patients had a partial response or had a positive bone scan as the only evidence of disease at the completion of therapy. Seven patients, two with lymphoma and five with breast cancer (28%), remain progression free with a median follow-up of 24.7 months (range, 17-28 months). Conclusions. Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high dose chemotherapy, resulting in a significant increase in dose intensity with acceptable toxicity. Cancer 1995; 76:860-8. Key words: hematopoietic progenitor cells, growth factors, dose intensity, dose response.

Published
1995

23. Molecular Characterization of the t(15;17)(q22;21) in Epirubicin-Related Acute Promyelocytic Leukaemia

Author

Mays, Ashley Nicole, primary, Osheroff, Neil, additional, Felix, Carolyn, additional, Byl, Jo Ann, additional, Saravanamuttu, Kandeepan, additional, Peniket, Andrew, additional, Corser, Robert, additional, Chang, Cherry, additional, Hoyle, Christine, additional, Parker, Anne N, additional, Hasan, Syed K, additional, Lo-Coco, Francesco, additional, Solomon, Ellen, additional, and Grimwade, David, additional

Published
2008
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36. Differential heat shock protein localization in chronic lymphocytic leukemia

Author

Dempsey, Nina C., Leoni, Francesca, Ireland, H. Elyse, Hoyle, Christine, and Williams, John H. H.

Abstract

Levels of Hsp90 and Hsp27 in CLL patients correlate with stage of disease or apoptosis, while Hsp72 in serum is affected by corticosteroid treatment. Mechanisms behind carcinogenesis and resistance of tumor cells to treatment regimes remain elusive. The major stress proteins Hsp72, Hsp90, and Hsp27 are credible candidates to provide this resistance, as their overexpression in many cancer types is well documented. In addition to being present inside tumor cells, where they confer resistance to apoptosis, Hsp72, in particular, is presented externally, embedded in the cell membrane of cancer cells. This study aimed to investigate the localization of Hsp72, Hsp90, and Hsp27 in leukocytes from patients with CLL and age‐matched control subjects. CLL patients were found to express significantly higher levels of iHsp90 (CLL=2463 MFI; control=748 MFI) and iHsp27 (CLL=2190 MFI; control=1031 MFI) in lymphocytes than that expressed by lymphocytes from control subjects. Furthermore, expression of iHsp90 was shown to be related to stage of disease, and expression of iHsp27 correlated with levels of active caspase‐3. Patients were found to express very high levels or very low levels of sHsp72 and iHsp72 in CD5+/CD19+cells, although surface and intracellular datasets did not correlate. Levels of extracellular Hsp72 circulating in the serum were found to correlate with internal levels of Hsp72 and were also found to be significantly lower in patients receiving corticosteroid treatment than in patients not receiving corticosteroid treatment. Finally, analysis of the number of circulating Tregs revealed significantly elevated numbers in CLL patients compared with control subjects.

Published
2010
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37. The development of asymmetry: the sidedness of drug-induced limb abnormalities is reversed in situs inversus mice

Author

Brown, Nigel A., Hoyle, Christine I., McCarthy, Afshan, and Wolpert, Lewis

Abstract

We are studying the development of handedness, in particular the relationships between handed structures with bilateral symmetry, for example the limbs, and those with lateral asymmetry, such as the heart, lungs and gut. Asymmetric (unilateral) developmental limb abnormalities can be induced by chemical treatment of mouse embryos, either in utero by acetazolamide, or in culture by misonidazole. We have examined these effects in mice homozygous for the iv gene. The development of bilateral symmetry in iv/iv mice is normal, but the control of asymmetry appears to be random, that is 50 % develop normally (situs solitus), 50 % with laterally inverted viscera (situs inversus). We find that the handedness of induced asymmetric limb defects is highly correlated with embryonic visceral situs. Right limb defects are induced in situs solitus embryos, left-sided defects in situs inversus. This suggests that the mechanism of induction of asymmetric defects is not related to any intrinsic difference between the development of left and right limbs, but is connected to visceral asymmetry. In addition, the high correlation of limb defects with situs was observed in culture as well as in utero suggesting that the maternal environment plays no role in the development of asymmetry.

Published
1989
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38. Development of left/right handedness in the chick heart

Author

Hoyle, Christine, Brown, Nigel A., and Wolpert, Lewis

Abstract

The chick heart tube develops from the fusion of the right and left areas of precardiac mesoderm and in almost all cases loops to the embryo’s right-hand side. We have investigated whether any intrinsic difference exists in the right and left areas of precardiac mesoderm, that influences the direction of looping of the heart tube. Chick embryos incubated to stages 4,5 and 6 were cultured by the New method. Areas of precar-diac mesoderm were exchanged between donor and host embryos of the same stage and different stages to form control, double-right and double-left sided embryos. Overall, double-right sided embryos formed many more left-hand loops than double-left sided embryos. At stages 4 and 5 a small percentage of double-right embryos formed left-hand loops (13%) whereas at stage 6 almost 50% of hearts had left-hand loops. Control embryos formed right-hand loops in 97% of cases. The stability of right-hand heart looping by double-left sided embryos, may be related to the process of ‘conversion’, whereas the direction of looping by double-right sided embryos has become randomised. There is some indication that an intrinsic change occurred in the precar-diac mesoderm between stages 5 and 6 that later influenced the direction of looping of the heart tube. The direction of body turning is suggested to be linked to the direction of heart looping.

Published
1992
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39. A Ki-1 (CD30)-Positive Human Cell Line (Karpas 299) Established From a High-Grade Non-Hodgkin's Lymphoma, Showing a 2;5 Translocation and Rearrangement of the T-Cell Receptor β-Chain Gene

Author

Fischer, Patricia, Nacheva, Elisabeth, Mason, David Y., Sherrington, Paul D., Hoyle, Christine, Hayhoe, Frank G.J., and Karpas, Abraham

Abstract

We describe the characterization of a new human cell line, Karpas 299 (K299), established from blast cells in the peripheral blood of a 25-year-old white man. His illness, which began with enlarged occipital and axillary nodes and weight loss, ended after 7 months with generalized lymph-adenopathy, pleural effusion, and bone marrow involvement. A lymph node biopsy showed a large cell lymphoma mainly sinusoidal in distribution. The blast cells with pleomorphic nuclei resembled primitive histiocytes. The cells, which expressed the T-cell-associated markers CD4 and CD5, were positive for HLA-DR, epithelial membrane antigen, and CD30 (Ki-1 antigen). The karyotype was aneuploid and included a translocation 2,5. The site of translocation on chromosome 5 (at 5q35.1) is in the region of the locus of the c-fmsoncogene (receptor of the monocyte-macrophage colony-stimulating factor MCSF or CSF-1). The cell line Karpas 299 has the same karyotype and pattern of antigen expression as the patient's cells. Northern blot analysis of RNA showed an active rearrangement of the T-cell receptor β-chain gene. This is to our knowledge the first Ki-1 antigen-positive line to be established from a case of non-Hodgkin's lymphoma.

Published
1988
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40. Expansion of Philadelphia Chromosome–Negative CD3+CD56+Cytotoxic Cells From Chronic Myeloid Leukemia Patients: In Vitro and In Vivo Efficacy in Severe Combined Immunodeficiency Disease Mice

Author

Hoyle, Christine, Bangs, Charles D., Chang, Pearl, Kamel, Onsi, Mehta, Bela, and Negrin, Robert S.

Abstract

We have developed culture conditions for the efficient expansion of cytotoxic effector cells from peripheral blood mononuclear cells (PBMNCs) by the timed addition of interferon-γ (IFN-γ), interleukin-2 (IL-2), and the monoclonal antibody (MoAb) OKT3. These cells, termed cytokine-induced killer (CIK) cells, are composed primarily of T cells, and the population of cells with the greatest cytotoxic activity is an otherwise rare population of CD3+CD56+cells that expand dramatically under these culture conditions. CIK cells were expanded from PBMNCs from 13 patients with chronic myeloid leukemia (CML). These cultures contained a variable number of T cells at the start of the culture (median 44%, range 1% to 64%), yet after 21 to 28 days of culture, virtually all of the cells were CD3+T cells (median 97%, range 90% to 99%). The CD3+CD56+subset of cells expanded significantly (median 25-fold, range 2.2- to 525-fold). CIK cells from all patients showed cytotoxicity against the tumor cell lines OCI-LY8 and K562. In four patients the expanded CIK cells suppressed colony growth of autologous CML blast cells and myeloid progenitor cells. Allogeneic CIK cells from normal donors also suppressed CML colony growth but did not inhibit growth of normal hematopoietic colonies. Twelve of the 13 cultures were exclusively composed of Philadelphia (Ph)-negative cells and one culture had 1 out of 20 Ph-positive metaphases after 4 weeks in culture. Intracellular cytokine production was assayed by fluorescence-activated cell sorter (FACS), and the expanded T-cell cultures produced IL-2, IFN-γ, and tumor necrosis factor-α (TNF-α), but not IL-4. Both the CD4+and CD8+subsets secreted this cytokine profile. To test the in vivo activity of the expanded CIK cells, CML was engrafted into severe combined immunodeficiency disease (SCID) mice using matrigel. After 4 weeks, 4 × 107autologous CIK cells were injected intravenously by tail vein injection into groups of mice, and the animals were sacrificed after a total of 18 weeks. Bcr-abl was detected in the bone marrow or spleen of 5 out of 6 control mice and only 2 out of 13 mice who received the autologous CIK cells (P= .02). In an additional series of animals, the mice did not engraft with CML but instead developed large human Epstein-Barr virus–associated lymphomas by 12 weeks. The mice who received autologous CIK cells at 4 weeks had either no tumor (5) or small tumors (5), whereas all 10 mice that received CIK cells at week 8 developed lymphomas; however, these were not as large as in the 10 control mice who did not receive CIK cells (P= .03). This study shows that CIK cells, which are Ph chromosome–negative, can be expanded from patients with CML and have potent in vitro and in vivo efficacy against autologous tumor cells.

Published
1998
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45. Localisation of heat shock proteins in haematological malignancies

Author

Dempsey, Nina Claire, Williams, John H. H., and Hoyle, Christine

Subjects
616.15, heat shock proteins
Abstract

Although a number of HSPs have been shown to be up-regulated in a wide range of human cancers, the full significance of this remains to be determined. The localisation of HSPs seems to be critical in determining their role in cancer cell survival; High intracellular levels (iHsp) appear to be advantageous to the tumour cell, inhibiting key steps in apoptosis, while in some circumstances, surface expression (sHsp) appears to be detrimental to the cell, aiding immune recognition by various effector cells. Consequently, clarifying the importance of HSP cellular location in the cancer setting may lead to the development of novel therapies based upon manipulation of HSP localisation. This thesis had two major aims; (1) to investigate the cellular localisation of HSPs in leukocytes from patients with both myelocytic and lymphocytic malignancies in order to establish relationships between apoptosis and stage of disease (2) to study the synergistic effect of four chemotherapeutic drugs with membrane fluidising agents, compounds which have the potential to modulate HSP localisation. Hsp90 and Hsp27 expression was shown to be restricted to the inside of peripheral blood leukocytes, while Hsp72 was localised both intracellularly and on the cell surface. In CLL, iHsp90 and iHsp27 levels were found to be significantly higher than in control subjects, while surface and intracellular Hsp72 was shown to be expressed either at very high levels or at very low levels. Furthermore, iHsp90 levels were found to be associated with stage of disease, while iHsp27 levels were shown to negatively correlate with levels of apoptosis. CLL patients with stable disease were found to express higher levels of iHsp72 than patients with progressive disease. However, in AML and MDS, levels of all HSPs in peripheral blood were found to be similar to those seen in control subjects, but disease patients showed a much wider range of expression. In AML, levels of sHsp72 positively correlated in all cell types, an observation not made in MDS patients or control subjects. HSP localisation was shown to be affected by membrane fluidising agents, with a movement of Hsp72 and Hsp60 to the cell surface. This effect was not due to proteotoxicity and supports data implicating the cell membrane in the regulation of HSP responses. This manipulation of HSP localisation and the increase in membrane fluidity resulted in increased sensitivity of CLL cells to three chemotherapeutic agents and points to the possibility that manipulation of membrane fluidity, may have significant value in the development of new treatment regimes.

Published
2009
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46. Analysis of heat-shock protein localisation using flow cytometry.

Author

Dempsey NC, Leoni F, Hoyle C, and Williams JH

Subjects
Animals, HSP70 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins metabolism, Humans, Receptors, Cell Surface analysis, Flow Cytometry methods, HSP70 Heat-Shock Proteins analysis, HSP90 Heat-Shock Proteins analysis
Abstract

The use of flow cytometry in heat-shock protein (HSP) research is increasing rapidly due to the high sensitivity and versatility of the technique. The method allows the simultaneous analysis of multiple proteins within numerous cell types in a heterogeneous sample, providing advantages over alternative techniques, such as ELISA and Western blotting. As a result, flow cytometry is becoming the leading technique used in this area of research. The current chapter describes the methodology for preparing samples for this technique and outlines two protocols for the analysis of surface- and intracellular-localised HSPs.

Published
2011
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