291 results on '"Pamela J, Russell"'
Search Results
2. Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1)
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Mei-Chun Yeh, Brian W. C. Tse, Nicholas L. Fletcher, Zachary H. Houston, Maria Lund, Marianna Volpert, Chelsea Stewart, Kamil A. Sokolowski, Varinder Jeet, Kristofer J. Thurecht, Douglas H. Campbell, Bradley J. Walsh, Colleen C. Nelson, and Pamela J. Russell
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Prostate cancer ,Radionuclide therapy ,Miltuximab® ,Glypican-1 ,MIL-38 ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Purpose Chimeric antibody Miltuximab®, a human IgG1 engineered from the parent antibody MIL-38, is in clinical development for solid tumour therapy. Miltuximab® targets glypican-1 (GPC-1), a cell surface protein involved in tumour growth, which is overexpressed in solid tumours, including prostate cancer (PCa). This study investigated the potential of 89Zr-labelled Miltuximab® as an imaging agent, and 177Lu-labelled Miltuximab® as a targeted beta therapy, in a mouse xenograft model of human prostate cancer. Methods Male BALB/c nude mice were inoculated subcutaneously with GPC-1-positive DU-145 PCa cells. In imaging and biodistribution studies, mice bearing palpable tumours received (a) 2.62 MBq [89Zr]Zr-DFO-Miltuximab® followed by PET-CT imaging, or (b) 6 MBq [177Lu]Lu-DOTA-Miltuximab® by Cerenkov imaging, and ex vivo assessment of biodistribution. In an initial tumour efficacy study, mice bearing DU-145 tumours were administered intravenously with 6 MBq [177Lu]Lu-DOTA-Miltuximab® or control DOTA-Miltuximab® then euthanised after 27 days. In a subsequent survival efficacy study, tumour-bearing mice were given 3 or 10 MBq of [177Lu]Lu-DOTA-Miltuximab®, or control, and followed up to 120 days. Results Antibody accumulation in DU-145 xenografts was detected by PET-CT imaging using [89Zr]Zr-DFO-Miltuximab® and confirmed by Cerenkov luminescence imaging post injection of [177Lu]Lu-DOTA-Miltuximab®. Antibody accumulation was higher (% IA/g) in tumours than other organs across multiple time points. A single injection with 6 MBq of [177Lu]Lu-DOTA-Miltuximab® significantly inhibited tumour growth as compared with DOTA-Miltuximab® (control). In the survival study, mice treated with 10 MBq [177Lu]Lu-DOTA-Miltuximab® had significantly prolonged survival (mean 85 days) versus control (45 days), an effect associated with increased cancer cell apoptosis. Tissue histopathology assessment showed no abnormalities associated with [177Lu]Lu-DOTA-Miltuximab®, in line with other observations of tolerability, including body weight stability. Conclusion These findings demonstrate the potential utility of Miltuximab® as a PET imaging agent ([89Zr]Zr-DFO-Miltuximab®) and a beta therapy ([177Lu]Lu-DOTA-Miltuximab®) in patients with PCa or other GPC-1 expressing tumours.
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- 2020
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3. Human Group IIA Phospholipase A2—Three Decades on from Its Discovery
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Kieran F. Scott, Timothy J. Mann, Shadma Fatima, Mila Sajinovic, Anshuli Razdan, Ryung Rae Kim, Adam Cooper, Aflah Roohullah, Katherine J. Bryant, Kasuni K. Gamage, David G. Harman, Fatemeh Vafaee, Garry G. Graham, W. Bret Church, Pamela J. Russell, Qihan Dong, and Paul de Souza
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eicosanoid ,drug development ,chronic inflammation ,cancer ,prostaglandin ,Organic chemistry ,QD241-441 - Abstract
Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.
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- 2021
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4. Supplementary Data from Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines
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Pamela J. Russell, Jane Chapman, Kim Ow, Yasmin Husaini, and Aparajita Khatri
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Supplementary Data from Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines
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- 2023
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5. Data from Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines
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Pamela J. Russell, Jane Chapman, Kim Ow, Yasmin Husaini, and Aparajita Khatri
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Purpose: To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)–mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 1/Th2 serum cytokine balance with a special focus to assess correlation with tumor burden/survival.Experimental Design: Efficacy of intraprostatic administration of adenovirally delivered murine IL-12 and IL-18 against orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were also assessed. Host immune responses to different treatments were assessed by monitoring 11 serum cytokines using Luminex technology.Results: Our data show that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant reduction in local RM1 tumors and lung colonies with enhanced long-term survival versus individual treatments. A dramatic enhancement of tumor infiltration by a wider repertoire of immune cells and disruption of vasculature implied the combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently associated with lower tumor burden (local and systemic), and this, rather than an increase in Th1 cytokines, better predicted treatment efficacy. In addition, mouse survival correlated with substantially higher cytokine (Th1/Th2) levels after treatment.Conclusion: Locoregional application of CDUPRT-GDEPT and IL-12/IL-18 was effective against local and systemic prostate cancer and improved survival. Monitoring serum levels of IL-4 and MCP-1 may accurately reflect tumor burden and, hence, host response to therapy.
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- 2023
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6. Human Group IIA Phospholipase A2—Three Decades on from Its Discovery
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Fatemeh Vafaee, Kasuni K. Gamage, Shadma Fatima, Ryung Rae Kim, Kieran F. Scott, Pamela J. Russell, Katherine Bryant, Garry G. Graham, David G. Harman, Aflah Roohullah, W. Bret Church, Anshuli Razdan, Qihan Dong, Adam Cooper, Paul de Souza, Timothy J. Mann, and Mila Sajinovic
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chronic inflammation ,Pharmaceutical Science ,Inflammation ,Review ,Bioinformatics ,Group II Phospholipases A2 ,Analytical Chemistry ,QD241-441 ,Phospholipase A2 ,Drug Development ,Neoplasms ,Drug Discovery ,medicine ,cancer ,Humans ,Physical and Theoretical Chemistry ,Cloning ,chemistry.chemical_classification ,biology ,business.industry ,Organic Chemistry ,Prognosis ,Enzyme assay ,Enzyme ,chemistry ,Eicosanoid ,Drug development ,Chemistry (miscellaneous) ,eicosanoid ,biology.protein ,Molecular Medicine ,medicine.symptom ,prostaglandin ,business ,Function (biology) - Abstract
Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.
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- 2021
7. Plant-Derived MINA-05 Inhibits Human Prostate Cancer Proliferation In Vitro and Lymph Node Spread In Vivo
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Kate Vandyke, Melanie Y. White, Terry Nguyen-Khuong, Kim Ow, Sharon C.-W. Luk, Elizabeth A. Kingsley, Alexandra Rowe, Shiu-Fun Pang, Bradley J. Walsh, and Pamela J. Russell
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Prostate cancer ,G2M block ,MINA-05 herbal treatment ,lymph node metastases ,clonogenic assays ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Few treatment options exist for metastatic prostate cancer (PC) that becomes hormone refractory (HRPC). In vitro, plant-derived MINA-05 caused dose-dependent decreases in cell numbers in HRPC cell lines LNCaPC4-2B and PC-3, and in androgen-sensitive LNCaP-FGC, DuCaP, and LAPC-4, by WST-1 assay. MINA-05 pretreatment significantly decreased clonogenic survival in agar and on plastic at 1 × and 2 × IC50 for PC-3 (P < .05 and P < .001, respectively), and at 1/2 ×, 1 ×, and 2 × IC50 for LNCaP-FGC cells (P < .001). MINA-05 also induced G2M arrest of LNCaP-FGC and PC-3 cells (by flow cytometry) and caused some apoptosis in LNCaPFGC (sub-G1, peak on flow, expression of activated caspase-3) but not in PC-3 cells. Western blotting indicated that these cell cycle changes were associated with decreased levels of regulatory proteins cyclin B1 and cdc25C. MINA-05 given daily by gavage for 39 days did not diminish primary orthotopic PC-3 growth in nude mice, but decreased the extent of lymph node invasion at higher doses. We conclude that MINA-05 induces G2M arrest, inhibits cell growth, reduces PC cell re-growth in vitro, and reduces lymph node invasion after orthotopic PC-3 cell implantation in vivo. It has potential as an adjuvant treatment for patients with PC.
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- 2007
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8. Correction: 3D Cultures of Prostate Cancer Cells Cultured in a Novel High-Throughput Culture Platform Are More Resistant to Chemotherapeutics Compared to Cells Cultured in Monolayer.
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Karen F Chambers, Eman M O Mosaad, Pamela J Russell, Judith A Clements, and Michael R Doran
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Medicine ,Science - Published
- 2015
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9. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) gene deletion promotes cancer growth in TRAMP prostate cancer prone mice.
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Yasmin Husaini, Glen P Lockwood, Trung V Nguyen, Vicky Wang-Wei Tsai, Mohammad G Mohammad, Pamela J Russell, David A Brown, and Samuel N Breit
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Medicine ,Science - Abstract
The divergent TGF-β superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-). On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+). Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1) had metastases than TRAMPMIC+/+ mice (p
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- 2015
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10. 3D Cultures of prostate cancer cells cultured in a novel high-throughput culture platform are more resistant to chemotherapeutics compared to cells cultured in monolayer.
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Karen F Chambers, Eman M O Mosaad, Pamela J Russell, Judith A Clements, and Michael R Doran
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Medicine ,Science - Abstract
Despite monolayer cultures being widely used for cancer drug development and testing, 2D cultures tend to be hypersensitive to chemotherapy and are relatively poor predictors of whether a drug will provide clinical benefit. Whilst generally more complicated, three dimensional (3D) culture systems often better recapitulate true cancer architecture and provide a more accurate drug response. As a step towards making 3D cancer cultures more accessible, we have developed a microwell platform and surface modification protocol to enable high throughput manufacture of 3D cancer aggregates. Herein we use this novel system to characterize prostate cancer cell microaggregates, including growth kinetics and drug sensitivity. Our results indicate that prostate cancer cells are viable in this system, however some non-cancerous prostate cell lines are not. This system allows us to consistently control for the presence or absence of an apoptotic core in the 3D cancer microaggregates. Similar to tumor tissues, the 3D microaggregates display poor polarity. Critically the response of 3D microaggregates to the chemotherapeutic drug, docetaxel, is more consistent with in vivo results than the equivalent 2D controls. Cumulatively, our results demonstrate that these prostate cancer microaggregates better recapitulate the morphology of prostate tumors compared to 2D and can be used for high-throughput drug testing.
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- 2014
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11. Reliable Method of Isolating Transfected Clones from the LNCaP Human Prostatic Cell Line
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Suzanne Bennett, Anthony Joshua, and Pamela J. Russell
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Biology (General) ,QH301-705.5 - Published
- 1997
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12. A humanized orthotopic tumor microenvironment alters the bone metastatic tropism of prostate cancer cells
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Boris Michael Holzapfel, Marietta Landgraf, Daniela Loessner, Judith A. Clements, Elizabeth D. Williams, Pamela J. Russell, Christoph Meinert, Nathalie Bock, Abbas Shafiee, Pamela M. Pollock, Jeremy Baldwin, Laure Martine, Gail P. Risbridger, James W. Denham, Dietmar W. Hutmacher, Jacqui A. McGovern, Christoph A. Lahr, and Ferdinand Wagner
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Male ,QH301-705.5 ,Medicine (miscellaneous) ,Bone Neoplasms ,Mice, SCID ,General Biochemistry, Genetics and Molecular Biology ,Article ,Metastasis ,Extracellular matrix ,Prostate cancer ,Mice ,Prostate ,Mice, Inbred NOD ,LNCaP ,Tumor Microenvironment ,Medicine ,Animals ,Humans ,Biology (General) ,Neoplasm Metastasis ,Cancer models ,Tumor microenvironment ,Tissue Engineering ,business.industry ,Cancer ,Prostatic Neoplasms ,medicine.disease ,Primary tumor ,medicine.anatomical_structure ,Cancer research ,sense organs ,General Agricultural and Biological Sciences ,business - Abstract
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, and bone is the most frequent site of metastasis. The tumor microenvironment (TME) impacts tumor growth and metastasis, yet the role of the TME in PCa metastasis to bone is not fully understood. We used a tissue-engineered xenograft approach in NOD-scid IL2Rγnull (NSG) mice to incorporate two levels of humanization; the primary tumor and TME, and the secondary metastatic bone organ. Bioluminescent imaging, histology, and immunohistochemistry were used to study metastasis of human PC-3 and LNCaP PCa cells from the prostate to tissue-engineered bone. Here we show pre-seeding scaffolds with human osteoblasts increases the human cellular and extracellular matrix content of bone constructs, compared to unseeded scaffolds. The humanized prostate TME showed a trend to decrease metastasis of PC-3 PCa cells to the tissue-engineered bone, but did not affect the metastatic potential of PCa cells to the endogenous murine bones or organs. On the other hand, the humanized TME enhanced LNCaP tumor growth and metastasis to humanized and murine bone. Together this demonstrates the importance of the TME in PCa bone tropism, although further investigations are needed to delineate specific roles of the TME components in this context., McGovern et al. establish an orthotopic, humanized prostate cancer model to study bone metastasis. The authors demonstrate that a humanized tumor microenvironment (TME) influences the metastatic spread of cancer cells to tissue-engineered bone, highlighting the importance of the TME in prostate cancer metastasis to bone.
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- 2021
13. KLK4 Induces Anti-Tumor Effects in Human Xenograft Mouse Models of Orthotopic and Metastatic Prostate Cancer
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Pamela J. Russell, Johanna Felber, Jonathan M. Harris, Judith A. Clements, Kamil A. Sokolowski, Brian W.C. Tse, Thomas Kryza, Carina Walpole, Mei-Chun Yeh, Ying Dong, Tobias Dreyer, and Viktor Magdolen
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0301 basic medicine ,Cancer Research ,KLK4 ,tumor xenografts ,lcsh:RC254-282 ,Article ,Intracardiac injection ,Metastasis ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,stomatognathic system ,In vivo ,kallikrein-related peptidase 4 ,Medicine ,metastasis ,Antitumor activity ,Tumor microenvironment ,business.industry ,imaging ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,prostate cancer ,In vitro ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,business - Abstract
Simple Summary The serine protease kallikrein-related peptidase 4 (KLK4) has been reported to potentially play a role in the progression of prostate cancer and other cancer types. However, most of these reports have been limited to in vitro studies. In vivo cancer models offer greater complexity to mimic the characteristics of cancer growth and metastasis in humans. In this study, we used in vivo models of prostate cancer and demonstrated that KLK4 can strongly inhibit the growth of primary prostate tumors as well as bone metastases. To our knowledge, this is the first report of an anti-tumor effect of KLK4 in prostate cancer in vivo. Abstract Recent reports have suggested the role of kallikrein-related peptidase 4 (KLK4) to be that of remodeling the tumor microenvironment in many cancers, including prostate cancer. Notably, these studies have suggested a pro-tumorigenic role for KLK4, especially in prostate cancer. However, these have been primarily in vitro studies, with limited in vivo studies performed to date. Herein, we employed an orthotopic inoculation xenograft model to mimic the growth of primary tumors, and an intracardiac injection to induce metastatic dissemination to determine the in vivo tumorigenic effects of KLK4 overexpressed in PC3 prostate cancer cells. Notably, we found that these KLK4-expressing cells gave rise to smaller localized tumors and decreased metastases than the parent PC-3 cells. To our knowledge, this is the first report of an anti-tumorigenic effect of KLK4, particularly in prostate cancer. These findings also provide a cautionary tale of the need for in vivo analyses to substantiate in vitro experimental data.
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- 2020
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14. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) slows cancer development but increases metastases in TRAMP prostate cancer prone mice.
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Yasmin Husaini, Min Ru Qiu, Glen P Lockwood, Xu Wei Luo, Ping Shang, Tamara Kuffner, Vicky Wang-Wei Tsai, Lele Jiang, Pamela J Russell, David A Brown, and Samuel N Breit
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Medicine ,Science - Abstract
Macrophage inhibitory cytokine-1 (MIC-1/GDF15), a divergent member of the TGF-β superfamily, is over-expressed by many common cancers including those of the prostate (PCa) and its expression is linked to cancer outcome. We have evaluated the effect of MIC-1/GDF15 overexpression on PCa development and spread in the TRAMP transgenic model of spontaneous prostate cancer. TRAMP mice were crossed with MIC-1/GDF15 overexpressing mice (MIC-1(fms)) to produce syngeneic TRAMP(fmsmic-1) mice. Survival rate, prostate tumor size, histopathological grades and extent of distant organ metastases were compared. Metastasis of TC1-T5, an androgen independent TRAMP cell line that lacks MIC-1/GDF15 expression, was compared by injecting intravenously into MIC-1(fms) and syngeneic C57BL/6 mice. Whilst TRAMP(fmsmic-1) survived on average 7.4 weeks longer, had significantly smaller genitourinary (GU) tumors and lower PCa histopathological grades than TRAMP mice, more of these mice developed distant organ metastases. Additionally, a higher number of TC1-T5 lung tumor colonies were observed in MIC-1(fms) mice than syngeneic WT C57BL/6 mice. Our studies strongly suggest that MIC-1/GDF15 has complex actions on tumor behavior: it limits local tumor growth but may with advancing disease, promote metastases. As MIC-1/GDF15 is induced by all cancer treatments and metastasis is the major cause of cancer treatment failure and cancer deaths, these results, if applicable to humans, may have a direct impact on patient care.
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- 2012
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15. Paradoxical Roles of Tumour Necrosis Factor-Alpha in Prostate Cancer Biology
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Brian W. C. Tse, Kieran F. Scott, and Pamela J. Russell
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Tumour necrosis factor (TNF) is a pleiotropic cytokine with dual roles in cancer biology including prostate cancer (PCa). On the one hand, there is evidence that it stimulates tumour angiogenesis, is involved in the initiation of PCa from an androgen-dependent to a castrate resistant state, plays a role in epithelial to mesenchymal plasticity, and may contribute to the aberrant regulation of eicosanoid pathways. On the other hand, TNF has also been reported to inhibit neovascularisation, induce apoptosis of PCa cells, and stimulate antitumour immunity. Much of the confusion surrounding its seemingly paradoxical roles in cancer biology stems from the dependence of its effects on the biological model within which TNF is investigated. This paper will address some of these issues and also discuss the therapeutic implications.
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- 2012
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16. Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model.
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Tzong-Tyng Hung, Jeffrey Chan, Pamela J Russell, and Carl A Power
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Medicine ,Science - Abstract
BACKGROUND: The bisphosphonate, zoledronic acid (ZOL), can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice. METHODS: The model involves intracardiac injection for arterial dissemination of the RM1(BM) cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 µg/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate-resistant acid phosphatase 5b (TRAP 5b) and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots. FINDINGS: Micro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM) cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice. CONCLUSIONS: ZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a requirement for establishment of these bone tumours.
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- 2011
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17. Localised delivery of doxorubicin to prostate cancer cells through a PSMA-targeted hyperbranched polymer theranostic
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Amanda K. Pearce, Nicholas L. Fletcher, Andrew K. Whittaker, Zachary H. Houston, Joshua D. Simpson, Kristofer J. Thurecht, Adrian V. Fuchs, and Pamela J. Russell
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Glutamate Carboxypeptidase II ,Male ,Materials science ,Polymers ,Cell ,Biophysics ,Bioengineering ,02 engineering and technology ,Theranostic Nanomedicine ,Biomaterials ,Mice ,03 medical and health sciences ,Prostate cancer ,Drug Delivery Systems ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Organic chemistry ,Doxorubicin ,Cytotoxicity ,Antibiotics, Antineoplastic ,Microscopy, Confocal ,Optical Imaging ,Prostate ,Prostatic Neoplasms ,Receptor-mediated endocytosis ,021001 nanoscience & nanotechnology ,medicine.disease ,Controlled release ,In vitro ,medicine.anatomical_structure ,Mechanics of Materials ,Delayed-Action Preparations ,030220 oncology & carcinogenesis ,Antigens, Surface ,Ceramics and Composites ,Cancer research ,0210 nano-technology ,medicine.drug - Abstract
The therapeutic potential of hyperbranched polymers targeted to prostate cancer and loaded with doxorubicin was investigated. Polyethylene glycol hyperbranched polymers were synthesised via RAFT polymerisation to feature glutamate urea targeting ligands for PSMA on the periphery. The chemotherapeutic, doxorubicin, was attached to the hyperbranched polymers through hydrazone formation, which allowed controlled release of the drug from the polymers in vitro endosomal conditions, with 90% release of the drug over 36 h. The polymers were able to target to PSMA-expressing prostate cancer cells in vitro, and demonstrated comparable cytotoxicity to free doxorubicin. The ability of the hyperbranched polymers to specifically facilitate transport of loaded doxorubicin into the cells was confirmed using live cell confocal imaging, which demonstrated that the drug was able to travel with the polymer into cells by receptor mediated internalisation, and subsequently be released into the nucleus following hydrazone degradation. Finally, the ability of the complex to induce a therapeutic effect on prostate cancer cells was investigated through a long term tumour regression study, which confirmed that the DOX-loaded polymers were able to significantly reduce the volume of subcutaneous prostate tumours in vivo in comparison to free doxorubicin and a polymer control, with no adverse toxicity to the animals. This work therefore demonstrates the potential of a hyperbranched polymer system to be utilised for prostate cancer theranostics.
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- 2017
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18. Gamma-Tocotrienol Induces Apoptosis in Prostate Cancer Cells by Targeting the Ang-1/Tie-2 Signalling Pathway
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Pamela J. Russell, Kai Dun Tang, Judith A. Clements, Ming-Tat Ling, and Ji Liu
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Male ,Angiogenesis ,Cell Survival ,Down-Regulation ,gamma-tocotrienol and autophagy ,Catalysis ,Article ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Tie-2 ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Angiopoietin-1 ,Autophagy ,Cytotoxic T cell ,Humans ,Vitamin E ,Physical and Theoretical Chemistry ,Chromans ,Protein kinase A ,Molecular Biology ,gamma-Tocotrienol ,lcsh:QH301-705.5 ,Spectroscopy ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Chemistry ,Organic Chemistry ,Prostatic Neoplasms ,General Medicine ,medicine.disease ,prostate cancer ,Receptor, TIE-2 ,3. Good health ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,lcsh:Biology (General) ,lcsh:QD1-999 ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Signal Transduction - Abstract
Emerging evidence suggests that gamma-tocotrienol (&gamma, T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. &gamma, T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. Recently, &gamma, T3 was found to target cancer stem cells (CSCs), leading to suppression of tumour formation and chemosensitisation. Despite its promising anti-cancer potential, the exact mechanisms responsible for the effects of &gamma, T3 are still largely unknown. Here, we report the identification of Ang-1 (Angiopoietin-1)/Tie-2 as a novel &gamma, T3 downstream target. In prostate cancer cells, &gamma, T3 treatment leads to the suppression of Ang-1 at both the mRNA transcript and protein levels. Supplementing the cells with Ang-1 was found to protect them against the anti-CSC effect of &gamma, T3. Intriguingly, inactivation of Tie-2, a member receptor that mediates the effect of Ang-1, was found to significantly enhance the cytotoxic effect of &gamma, T3 through activation of AMP-activated protein kinase (AMPK) and subsequent interruption of autophagy. Our results highlighted the therapeutic potential of using &gamma, T3 in combination with a Tie-2 inhibitor to treat advanced prostate cancer.
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- 2019
19. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality
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Elizabeth D. Williams, K McGowan, Miriam S. Butler, Jennifer H. Gunter, Ellca Ratther, Pamela J. Russell, N. Erho, Mohammed Alshalafa, Melanie Lehman, Mannan Nouri, Edward M. Schaeffer, Ladan Fazli, Robert Jeffrey Karnes, P S Rennie, Ashley E. Ross, Brett G. Hollier, Stephen McPherson, Nataly Stylianou, Rajdeep Das, Ralph Buttyan, Philip A. Gregory, Jacqui A. McGovern, Josselin Caradec, Luke A. Selth, E. Davicioni, Brian W.C. Tse, Marianna Volpert, Robert B. Jenkins, Robert B. Den, Martin E. Gleave, Colleen C. Nelson, Mani Roshan-Moniri, M. Takhar, Cheryl Y. Gregory-Evans, Tse, BWC, Volpert, M, Ratther, E, Stylianou, N, Gregory, PA, and Hollier, B. G.
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Male ,0301 basic medicine ,Biochemical recurrence ,PCA3 ,Cancer Research ,Epithelial-Mesenchymal Transition ,medicine.medical_treatment ,Biology ,androgen-targeted ,Metastasis ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Neoplasm Metastasis ,Molecular Biology ,Tissue microarray ,Prostatic Neoplasms ,metastatic progression ,Cancer ,Androgen Antagonists ,medicine.disease ,Survival Analysis ,prostate tumors ,Neuropilin-1 ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Radiation therapy ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Tumor progression ,030220 oncology & carcinogenesis ,Immunology ,Disease Progression ,Cancer research ,Original Article ,Neoplasm Grading ,patient mortality - Abstract
Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa. Refereed/Peer-reviewed
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- 2017
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20. Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer
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Pamela J. Russell, Lidija Jovanovic, Carolina Soekmadji, Irina Oleinikova, Guido Jenster, Colleen C. Nelson, Niall M. Corcoran, Grant A. Ramm, and Urology
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Pathology ,Urology ,Exosome ,Decision Support Techniques ,03 medical and health sciences ,Prostate cancer ,Extracellular Vesicles ,0302 clinical medicine ,Circulating tumor cell ,Breast cancer ,SDG 3 - Good Health and Well-being ,Internal medicine ,Biomarkers, Tumor ,Medicine ,Humans ,Precision Medicine ,Neoplasm Staging ,business.industry ,Patient Selection ,Cancer ,Bone metastasis ,Prostatic Neoplasms ,Extracellular vesicle ,Precision medicine ,medicine.disease ,Neoplastic Cells, Circulating ,030104 developmental biology ,030220 oncology & carcinogenesis ,business - Abstract
The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation.
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- 2017
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21. Using prostate specific membrane antigen (PSMA) expression in clear cell renal cell carcinoma for imaging advanced disease
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Simon Wood, Keng Lim Ng, Glenda C. Gobe, Mei-Chun Yeh, Colleen C. Nelson, Handoo Rhee, Ian Vela, Hemamali Samaratunga, Brian W.C. Tse, Pamela J. Russell, and Paul Thomas
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.disease ,030218 nuclear medicine & medical imaging ,Pathology and Forensic Medicine ,03 medical and health sciences ,Clear cell renal cell carcinoma ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Cancer research ,Glutamate carboxypeptidase II ,Advanced disease ,medicine ,Neoplasm staging ,business ,Positron Emission Tomography-Computed Tomography - Published
- 2016
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22. Modulation of paracrine signaling by CD9 positive small extracellular vesicles mediates cellular growth of androgen deprived prostate cancer
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Stephen McPherson, Michelle M. Hill, Niall M. Corcoran, Carolina Soekmadji, James D. Riches, Chenwei Wang, Christopher M. Hovens, Pamela J. Russell, Colleen C. Nelson, and Jayde E. Ruelcke
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0301 basic medicine ,medicine.medical_specialty ,medicine.drug_class ,exosomes ,urologic and male genital diseases ,03 medical and health sciences ,Paracrine signalling ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,androgen receptor ,LNCaP ,medicine ,Extracellular ,business.industry ,CD9 ,Androgen ,medicine.disease ,prostate cancer ,Androgen receptor ,Prostate-specific antigen ,030104 developmental biology ,Endocrinology ,Oncology ,030220 oncology & carcinogenesis ,Dihydrotestosterone ,embryonic structures ,Cancer research ,business ,extracellular vesicles ,medicine.drug ,Research Paper - Abstract
Proliferation and maintenance of both normal and prostate cancer (PCa) cells is highly regulated by steroid hormones, particularly androgens, and the extracellular environment. Herein, we identify the secretion of CD9 positive extracellular vesicles (EV) by LNCaP and DUCaP PCa cells in response to dihydrotestosterone (DHT) and use nano-LC-MS/MS to identify the proteins present in these EV. Subsequent bioinformatic and pathway analyses of the mass spectrometry data identified pathologically relevant pathways that may be altered by EV contents. Western blot and CD9 EV TR-FIA assay confirmed a specific increase in the amount of CD9 positive EV in DHT-treated LNCaP and DUCaP cells and treatment of cells with EV enriched with CD9 after DHT exposure can induce proliferation in androgen-deprived conditions. siRNA knockdown of endogenous CD9 in LNCaPs reduced cellular proliferation and expression of AR and prostate specific antigen (PSA) however knockdown of AR did not alter CD9 expression, also implicating CD9 as an upstream regulator of AR. Moreover CD9 positive EV were also found to be significantly higher in plasma from prostate cancer patients in comparison with benign prostatic hyperplasia patients. We conclude that CD9 positive EV are involved in mediating paracrine signalling and contributing toward prostate cancer progression.
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- 2016
23. Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone
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Ferdinand Wagner, Christoph A. Lahr, Jacqui A. McGovern, Daniela Loessner, Pamela J. Russell, Boris Michael Holzapfel, Judith A. Clements, Elizabeth D. Williams, Marietta Landgraf, Abbas Shafiee, Gail P. Risbridger, Dietmar W. Hutmacher, and Christoph Meinert
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0301 basic medicine ,Cancer Research ,Cancer-associated fibroblast ,urologic and male genital diseases ,lcsh:RC254-282 ,Article ,Metastasis ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Prostate ,Medicine ,tumor microenvironment ,bone metastasis ,Tumor microenvironment ,orthotopic model ,humanized bone ,business.industry ,Bone metastasis ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,prostate cancer ,Primary tumor ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,tissue engineering ,Cancer cell ,Cancer research ,business ,cancer-associated fibroblasts ,Homing (hematopoietic) - Abstract
The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVECs), to humanized tissue-engineered bone constructs (hTEBCs) in NOD-SCID IL2Rγnull (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized PCa model developed via convergence of cancer research and tissue engineering concepts provides a platform to dissect mechanisms of species-specific PCa bone metastasis and to develop precision medicine strategies.
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- 2018
24. Tie-2 regulates the stemness and metastatic properties of prostate cancer cells
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Dietmar W. Hutmacher, Kai Dun Tang, Terence Kin Wah Lee, Jiyuan An, Stephanie Ma, Lidija Jovanovic, Boris Michael Holzapfel, Pamela J. Russell, Judith A. Clements, Ji Liu, and Ming-Tat Ling
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cancer stem cells ,Male ,0301 basic medicine ,Oncology ,Apoptosis ,Mice, SCID ,Metastasis ,Immunoenzyme Techniques ,Mice ,Prostate cancer ,0302 clinical medicine ,Mice, Inbred NOD ,Prostate ,Tumor Cells, Cultured ,RNA, Small Interfering ,education.field_of_study ,Reverse Transcriptase Polymerase Chain Reaction ,prostate cancer ,Receptor, TIE-2 ,3. Good health ,medicine.anatomical_structure ,Cabazitaxel ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Research Paper ,medicine.drug ,medicine.medical_specialty ,Stromal cell ,Population ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Tie-2 ,Cancer stem cell ,Internal medicine ,Cell Adhesion ,medicine ,metastasis ,Animals ,Humans ,RNA, Messenger ,education ,Cell Proliferation ,Osteoblasts ,business.industry ,Prostatic Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Cancer cell ,Endothelium, Vascular ,Stromal Cells ,business - Abstract
Ample evidence supports that prostate tumor metastasis originates from a rare population of cancer cells, known as cancer stem cells (CSCs). Unfortunately, little is known about the identity of these cells, making it difficult to target the metastatic prostate tumor. Here, for the first time, we report the identification of a rare population of prostate cancer cells that express the Tie-2 protein. We found that this Tie-2High population exists mainly in prostate cancer cell lines that are capable of metastasizing to the bone. These cells not only express a higher level of CSC markers but also demonstrate enhanced resistance to the chemotherapeutic drug Cabazitaxel. In addition, knockdown of the expression of the Tie-2 ligand angiopoietin (Ang-1) led to suppression of CSC markers, suggesting that the Ang-1/Tie-2 signaling pathway functions as an autocrine loop for the maintenance of prostate CSCs. More importantly, we found that Tie-2High prostate cancer cells are more adhesive than the Tie-2Low population to both osteoblasts and endothelial cells. Moreover, only the Tie-2High, but not the Tie-2Low cells developed tumor metastasis in vivo when injected at a low number. Taken together, our data suggest that Tie-2 may play an important role during the development of prostate tumor metastasis.
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- 2015
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25. Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1
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Michelle M. Hill, Kerry L. Inder, Hyeongsun Moon, Pamela J. Russell, Andrew J. Brown, Zeyad D. Nassar, Anup Shah, Laura J. Sharpe, Marie-Odile Parat, Helle Bielefeldt-Ohmann, Jayde E. Ruelcke, Eunju Choi, Robert G. Parton, and Mathias Francois
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Male ,Oncology ,caveolin-1 ,medicine.medical_specialty ,medicine.drug_class ,Caveolin 1 ,Cell ,Mice, SCID ,Metastasis ,Mice ,Prostate cancer ,IQGAP1 ,Mice, Inbred NOD ,In vivo ,Cell Line, Tumor ,Internal medicine ,medicine ,metastasis ,Animals ,Humans ,Neoplasm Metastasis ,hypercholesterolemia ,business.industry ,medicine.disease ,Androgen ,3. Good health ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,ras GTPase-Activating Proteins ,Disease Progression ,Heterografts ,Signal transduction ,business ,Research Paper ,Signal Transduction - Abstract
Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgen-independent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.
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- 2015
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26. Establishing Prostate Cancer Patient Derived Xenografts: Lessons Learned From Older Studies
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Brian W.C. Tse, Peter Russell, Derek Raghavan, Elizabeth D. Williams, Pamela J. Russell, and Christina Rudduck
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PCA3 ,Male ,Pathology ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,Transplantation, Heterologous ,Mice, Nude ,cancer model ,Prostate cancer ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Testosterone ,xenograft ,Transurethral resection of the prostate ,Mice, Inbred BALB C ,business.industry ,animal model ,Cancer ,Prostatic Neoplasms ,Original Articles ,medicine.disease ,prostate cancer ,Prostate-specific antigen ,Neuroendocrine Tumors ,Oncology ,Prostatic acid phosphatase ,Adenocarcinoma ,Female ,business ,Neoplasm Transplantation - Abstract
Background Understanding the progression of prostate cancer to androgen-independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling. Methods We subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 patients. Successful xenografts were passaged into new host mice. They were characterized using histology, immunohistochemistry for marker expression, flow cytometry for ploidy status, and in some cases by electron microscopy and response to testosterone. Two xenografts were karyotyped by G-banding. Results Tissues from 3/29 donors (10%) gave rise to xenografts that were successfully serially passaged in vivo. Two, (UCRU-PR-1, which subsequently was replaced by a mouse fibrosarcoma, and UCRU-PR-2, which combined epithelial and neuroendocrine features) have been described. UCRU-PR-4 line was a poorly differentiated prostatic adenocarcinoma derived from a patient who had undergone estrogen therapy and bilateral castration after his cancer relapsed. Histologically, this comprised diffusely infiltrating small acinar cell carcinoma with more solid aggregates of poorly differentiated adenocarcinoma. The xenografted line showed histology consistent with a poorly differentiated adenocarcinoma and stained positively for prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA) and the cytokeratin cocktail, CAM5.2, with weak staining for prostate specific antigen (PSA). The line failed to grow in female nude mice. Castration of three male nude mice after xenograft establishment resulted in cessation of growth in one, growth regression in another and transient growth in another, suggesting that some cells had retained androgen sensitivity. The karyotype (from passage 1) was 43–46, XY, dic(1;12)(p11;p11), der(3)t(3:?5)(q13;q13), -5, inv(7)(p15q35) x2, +add(7)(p13), add(8)(p22), add(11)(p14), add(13)(p11), add(20)(p12), -22, +r4[cp8]. Conclusions Xenografts provide a clinically relevant model of prostate cancer, although establishing serially transplantable prostate cancer patient derived xenografts is challenging and requires rigorous characterization and high quality starting material. Xenografting from advanced prostate cancer is more likely to succeed, as xenografting from well differentiated, localized disease has not been achieved in our experience. Strong translational correlations can be demonstrated between the clinical disease state and the xenograft model. Prostate 75: 628–636, 2015. © The Authors. The Prostate published by Wiley Periodicals, Inc.
- Published
- 2015
27. Extracellular Vesicles in the Adaptive Process of Prostate Cancer during Inhibition of Androgen Receptor Signaling by Enzalutamide
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Carolina Soekmadji, Pamela J. Russell, Anja Rockstroh, Colleen C. Nelson, and Grant A. Ramm
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0301 basic medicine ,Male ,medicine.drug_class ,Cell Survival ,Pharmacology ,Biology ,Adenocarcinoma ,Biochemistry ,Metastasis ,Androgen deprivation therapy ,Thrombospondin 1 ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,Extracellular Vesicles ,Plasma Membrane Calcium-Transporting ATPases ,Nitriles ,Phenylthiohydantoin ,medicine ,Tumor Cells, Cultured ,Enzalutamide ,Humans ,Secretion ,Molecular Biology ,Gelsolin ,Cell Proliferation ,Integrin beta1 ,Cancer ,Prostatic Neoplasms ,medicine.disease ,Androgen ,Androgen receptor ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,chemistry ,Receptors, Androgen ,Benzamides ,Cancer research ,Signal Transduction - Abstract
Current treatments for advanced prostate cancer focus on inhibition of the androgen receptor (AR) by androgen deprivation therapy (ADT). However, complex interactions mediated by tumor suppressors, oncogenes, aberrations of AR expression, or de novo androgen production have been shown to induce the adaptive response of prostate cancer, leading to the development of castration resistant prostate cancer. In this study, we report the effects of AR antagonist, enzalutamide on the protein contents of extracellular vesicles (EVs). EVs mediate cell-to-cell communication and increasing evidence shows the role of EVs in promoting cancer survival and metastasis. We found that treatment with enzalutamide alters the secretion of EVs, one of which is a plasma membrane calcium pump, ATP2B1/PMCA ATPase, as an AR-regulated EV protein. We highlight the networks of interactions between AR, Ca2+ , and ATP2B1, where the extracellular proteins thrombospondin-1, gelsolin, and integrins1 were previously reported as regulators for cancer progression and metastasis, indicating the potential role of EV-derived proteins in mediating calcium homoeostasis under AR inhibition by enzalutamide. Our data further highlight the cross-talk between AR signaling and EV pathways in mediating resistance toward ADT.
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- 2017
28. Improved quality of risk-reducing salpingo-oophorectomy in Australasian women at high risk of pelvic serous cancer
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Sandra Picken, Pamela J. Russell, Kelly-Anne Phillips, Mathias Bressel, Belinda E Kiely, Charmaine Smith, M. Friedlander, Martha Hickey, John L. Hopper, Yeh Chen Lee, Sue-Anne McLachlan, S. Camm, Roger L. Milne, and Peter Grant
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Cancer Research ,Pelvic serous cancer ,medicine.medical_treatment ,Genes, BRCA2 ,Genes, BRCA1 ,0302 clinical medicine ,Risk Factors ,Epidemiology ,Genetics(clinical) ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Genetics (clinical) ,Oncologists ,Ovarian Neoplasms ,Obstetrics ,Prophylactic Surgical Procedures ,Middle Aged ,Risk-reducing salpingo-oophorectomy ,Serous fluid ,Oncology ,030220 oncology & carcinogenesis ,Ovarian cancer prevention ,Cohort ,Female ,Original Article ,Adult ,medicine.medical_specialty ,Heterozygote ,Salpingo-oophorectomy ,BRCA2 mutation carrier ,03 medical and health sciences ,medicine ,Carcinoma ,Genetics ,Fallopian Tube Neoplasms ,Humans ,Aged ,Quality of Health Care ,BRCA1 mutation carrier ,Gynecology ,Hysterectomy ,business.industry ,Australia ,medicine.disease ,Cystadenocarcinoma, Serous ,Clinical research ,business ,Ovarian cancer ,New Zealand - Abstract
Objectives The quality of risk-reducing salpingo-oophorectomy (RRSO) performed in Australasian women was previously reported to be suboptimal. Here we describe the quality of RRSO performed since 2008 in women enrolled in the same cohort and determine whether it has improved. Design Prospective cohort study of women at high risk of pelvic serous cancer (PSC) in kConFab. Eligible women had RRSO between 2008 and 2014 and their RRSO surgical and pathology reports were reviewed. “Adequate” surgery and pathology were defined as complete removal and paraffin embedding of all ovarian and extra-uterine fallopian tube tissue, respectively. Associations between clinical factors and “adequate” pathology were assessed using logistic regression. Data were compared with published cohort data on RRSO performed prior to 2008 using Chi square test. Results Of 164 contemporary RRSOs performed in 78 centres, 158/159 (99%) had “adequate” surgery and 108/164 (66%) had “adequate” pathology. Surgery performed by a gynaecologic oncologist rather than a general gynaecologist [OR 8.2, 95%CI (3.6–20.4), p
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- 2017
29. Development of a polymer theranostic for prostate cancer
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Andrew K. Whittaker, Barbara E. Rolfe, Kristofer J. Thurecht, Adrian V. Fuchs, Amanda K. Pearce, Pamela J. Russell, and Brian W.C. Tse
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Polymers and Plastics ,Ethylene glycol dimethacrylate ,Organic Chemistry ,Bioengineering ,Chain transfer ,Polyethylene glycol ,Methacrylate ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,Prostate cancer ,Monomer ,chemistry ,Drug delivery ,Biophysics ,medicine ,Organic chemistry ,Linker - Abstract
Theranostics offers an improved treatment strategy for prostate cancer by facilitating simultaneous targeting of tumour cells with subsequent drug delivery and imaging. In this report we describe the synthesis of hyperbranched polymers that are biocompatible, can specifically target and be internalised by prostate cancer cells (through targeting of prostate-specific membrane antigen – PSMA) and ultimately facilitate controlled delivery of a model drug. The theranostic also incorporates a far-red fluorescent dye that allows tracking of the polymer via optical imaging. Controlled synthesis of the polymer is achieved via reversible addition fragmentation chain transfer polymerisation of polyethylene glycol monomethyl methacrylate, with ethylene glycol dimethacrylate as the branching agent. Incorporation of 20 mol% of an hydrazide-methacrylate monomer allows post-ligation of a model drug, fluorene-2-carboxaldehyde, through a hydrolytically-degradable hydrazone linkage. The rate of degradation of this particular linker was enhanced at endosomal pH (pH = 5.5) where [similar]95% of the model drug was released in 4 hours compared to less than 5% released over the same period at physiological pH. The theranostic showed high uptake into prostate cancer cells expressing prostate-specific membrane antigen, while minimal uptake was observed in PC3 cells negative for PSMA, highlighting the enhanced efficacy of the targeting ligand.
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- 2014
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30. PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer
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Michelle M. Hill, Clay Winterford, Kim-Anh Lê Cao, Robert G. Parton, David J. Craik, Hyeongsun Moon, Jermaine Coward, Ming-Tat Ling, Pamela J. Russell, Eunju Choi, Kerry L. Inder, Cheok Soon Lee, Sowmya Sharma, and Debra Black
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Male ,Cancer Research ,Caveolin 1 ,Biology ,Metastasis ,Mice ,Prostate cancer ,Membrane Microdomains ,PTRF ,Prostate ,Cell Line, Tumor ,Caveolae ,LNCaP ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Phosphorylation ,Molecular Biology ,Aged ,Cell Proliferation ,Interleukin-6 ,Prostatic Neoplasms ,RNA-Binding Proteins ,Middle Aged ,medicine.disease ,Actins ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Receptors, Androgen ,Cancer cell ,Disease Progression ,Cancer research ,Proto-Oncogene Proteins c-akt - Abstract
Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF; polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of α-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co-expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets.
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- 2013
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31. Humanised xenograft models of bone metastasis revisited: novel insights into species-specific mechanisms of cancer cell osteotropism
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Anna Taubenberger, Dietmar W. Hutmacher, Laure Thibaudeau, Boris Michael Holzapfel, Carl Power, Parisa Hesami, Nina Pauline Holzapfel, Pamela J. Russell, Susanne Mayer-Wagner, and Judith A. Clements
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Metastatic cascade ,Cancer Research ,Xenotransplantation ,medicine.medical_treatment ,Bone metastasis ,Human bone ,Bone Neoplasms ,Biology ,medicine.disease ,Disease Models, Animal ,Mice ,Haematopoiesis ,Species Specificity ,Oncology ,Immunity ,Cancer cell ,Immunology ,Cancer research ,medicine ,Animals ,Heterografts ,Humans ,Human cancer - Abstract
The determinants and key mechanisms of cancer cell osteotropism have not been identified, mainly due to the lack of reproducible animal models representing the biological, genetic and clinical features seen in humans. An ideal model should be capable of recapitulating as many steps of the metastatic cascade as possible, thus facilitating the development of prognostic markers and novel therapeutic strategies. Most animal models of bone metastasis still have to be derived experimentally as most syngeneic and transgeneic approaches do not provide a robust skeletal phenotype and do not recapitulate the biological processes seen in humans. The xenotransplantation of human cancer cells or tumour tissue into immunocompromised murine hosts provides the possibility to simulate early and late stages of the human disease. Human bone or tissue-engineered human bone constructs can be implanted into the animal to recapitulate more subtle, species-specific aspects of the mutual interaction between human cancer cells and the human bone microenvironment. Moreover, the replication of the entire "organ" bone makes it possible to analyse the interaction between cancer cells and the haematopoietic niche and to confer at least a partial human immunity to the murine host. This process of humanisation is facilitated by novel immunocompromised mouse strains that allow a high engraftment rate of human cells or tissue. These humanised xenograft models provide an important research tool to study human biological processes of bone metastasis.
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- 2013
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32. Patient-Derived Xenograft Models of Prostate Tumors
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Renea A. Taylor, Pamela J. Russell, Gail P. Risbridger, Elizabeth D. Williams, and Mitchell G. Lawrence
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Oncology ,medicine.medical_specialty ,Tumor biology ,business.industry ,Tissue Recombination ,medicine.disease ,Prostate cancer ,Preclinical research ,medicine.anatomical_structure ,Prostate ,Internal medicine ,medicine ,Prostate tumors ,Solid tumor ,business ,Tumor xenograft - Abstract
In contrast to many other solid tumor types, the potential of using patient-derived xenografts (PDXs) from prostate cancer for preclinical research has yet to be fully realized. Prostate cancer PDXs are notoriously difficult to establish and this section provides a state-of-the-art summary including the effect of implantation site on revealing metastatic potential and the role of the microenvironment in supporting take rate and model fidelity. Tissue recombination is described as a technique that can improve the take rate of prostate xenografts that span the stages of prostate cancer progression. Comparisons of the pathology and molecular profiles of short- and long-term transplantable xenografts are made to describe their potential for studies of tumor biology and for preclinical applications involving patient-directed/targeted therapies.
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- 2017
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33. Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer
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Pamela J. Russell, Sonja Gustafson, Ian Vela, Greg Malone, Colleen C. Nelson, Simon Wood, Peter Heathcote, Glen Wood, Benjamin Shepherd, Eric Chung, Paul Thomas, and Handoo Rhee
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Male ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Prostate ,Glutamate carboxypeptidase II ,Medicine ,Humans ,Prospective Studies ,Multiparametric Magnetic Resonance Imaging ,medicine.diagnostic_test ,business.industry ,Prostatectomy ,Prostatic Neoplasms ,Reproducibility of Results ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Prostate-specific antigen ,medicine.anatomical_structure ,Positron emission tomography ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Radiology ,business ,Nuclear medicine - Abstract
Positron emission tomography using ligands targeting prostate specific membrane antigen has recently been introduced. Positron emission tomography imaging with (68)Ga-PSMA-HBED-CC has been shown to detect metastatic prostate cancer lesions at a high rate. In this study we compare multiparametric magnetic resonance imaging and prostate specific membrane antigen positron emission tomography of the prostate with whole mount ex vivo prostate histopathology to determine the true sensitivity and specificity of these imaging modalities for detecting and locating tumor foci within the prostate.In a prospective clinical trial setting 20 patients with localized prostate cancer and a planned radical prostatectomy were recruited. All patients underwent multiparametric magnetic resonance imaging and positron emission tomography before surgery, and whole mount histopathology slides were directly compared to the images. European Society of Urogenital Radiology guidelines for reporting magnetic resonance imaging were used as a template for regional units of analysis. The uropathologist and radiologists were blinded to individual components of the study, and the final correlation was performed by visual and deformable registration analysis.A total of 50 clinically significant lesions were identified from the whole mount histopathological analysis. Based on regional analysis the sensitivity, specificity, positive predictive value and negative predictive value for multiparametric magnetic resonance imaging were 44%, 94%, 81% and 76%, respectively. With prostate specific membrane antigen positron emission tomography the sensitivity, specificity, positive predictive value and negative predictive value were 49%, 95%, 85% and 88%, respectively. Prostate specific membrane antigen positron emission tomography yielded a higher specificity and positive predictive value.A significant proportion of cancers are potentially missed and underestimated by both imaging modalities. Prostate specific membrane antigen positron emission tomography may be used in addition to multiparametric magnetic resonance imaging to help improve local staging in those patients undergoing retropubic radical prostatectomy.
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- 2016
34. Targeting Aurora Kinases: A Novel Approach to Curb the Growth & Chemoresistance of Androgen Refractory Prostate Cancer
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Nirupama D. Verma, Aparajita Khatri, Pamela J. Russell, and Varinder Jeet
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Male ,Oncology ,endocrine system ,Cancer Research ,medicine.medical_specialty ,Mice, Transgenic ,Docetaxel ,Protein Serine-Threonine Kinases ,Real-Time Polymerase Chain Reaction ,Piperazines ,Mice ,Prostate cancer ,Aurora kinase ,Aurora Kinases ,Internal medicine ,Drug Discovery ,Survivin ,medicine ,Animals ,Neoplasm Metastasis ,Protein Kinase Inhibitors ,Pharmacology ,business.industry ,Cell growth ,Gene Expression Profiling ,Prostatic Neoplasms ,Cancer ,Drug Synergism ,medicine.disease ,Drug Resistance, Neoplasm ,Androgens ,Cancer research ,Adenocarcinoma ,RNA Interference ,Taxoids ,business ,medicine.drug ,Tramp - Abstract
Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.
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- 2012
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35. Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer
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Pamela J. Russell, Swapna Joshi, Aparajita Khatri, Xiaochun Wang, Nirupama D. Verma, and Preetinder Pal Singh
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Male ,Cancer Research ,Lung Neoplasms ,medicine.medical_treatment ,Genetic Vectors ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Docetaxel ,Pharmacology ,urologic and male genital diseases ,Adenoviridae ,Mice ,Prostate cancer ,Th2 Cells ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Neoplasm Staging ,Mice, Inbred BALB C ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Cell growth ,Prostatic Neoplasms ,Cancer ,Interleukin ,Drug Synergism ,medicine.disease ,Xenograft Model Antitumor Assays ,Tumor Burden ,Mice, Inbred C57BL ,Cell killing ,Purine-Nucleoside Phosphorylase ,Oncology ,Cancer research ,Cytokines ,Taxoids ,business ,medicine.drug - Abstract
Purpose: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase–mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments. Methods: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment. Results: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in “local and distant” tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy. Conclusion: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients. Clin Cancer Res; 17(12); 4006–18. ©2011 AACR.
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- 2011
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36. Adequacy of risk-reducing gynaecologic surgery in BRCA1 or BRCA2 mutation carriers and other women at high risk of pelvic serous cancer
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John L. Hopper, kConFab Investigators, Belinda E Kiely, Peter Grant, Michael Friedlander, Roger L. Milne, Sue-Anne McLachlan, Pamela J. Russell, Mark A. Jenkins, Kelly-Anne Phillips, P. Weideman, and L. Stanhope
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Cancer Research ,medicine.medical_treatment ,Cancer prevention ,Gynecologic Surgical Procedures ,0302 clinical medicine ,Prophylactic salpingo-oophorectomy ,Risk Factors ,Epidemiology ,Odds Ratio ,Genetics(clinical) ,Genetics (clinical) ,Pelvic Neoplasms ,Ovarian Neoplasms ,0303 health sciences ,BRCA1 Protein ,Obstetrics ,Middle Aged ,3. Good health ,Serous fluid ,Oncology ,030220 oncology & carcinogenesis ,Female ,Adult ,Heterozygote ,medicine.medical_specialty ,Breast Neoplasms ,Article ,03 medical and health sciences ,Breast cancer ,Ovarian cancer ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Risk-reducing surgery ,030304 developmental biology ,BRCA2 Protein ,Gynecology ,Hysterectomy ,business.industry ,Endometrial cancer ,Australia ,Odds ratio ,medicine.disease ,Cystadenocarcinoma, Serous ,BRCA1/BRCA2 mutations ,Mutation ,business - Abstract
The aim of this study was to describe the type of risk-reducing gynaecologic surgery (RRGS) and the extent of pathological evaluation being undertaken for Australasian women at high familial risk of pelvic serous cancer. Surgical and pathology reports were reviewed for women with BRCA1/BRCA2 mutations, or a family history of breast and ovarian cancer, who underwent RRGS between 1998 and 2008. “Adequate” surgery was defined as complete removal of all ovarian and extra-uterine fallopian tube tissue. “Adequate” pathology was defined as paraffin embedding of all removed ovarian and tubal tissue. Predictors of adequacy were assessed using logistic regression. There were 201 women, including 173 mutation carriers, who underwent RRGS. Of these, 91% had adequate surgery and 23% had adequate pathology. Independent predictors of adequate surgery were surgeon type (OR = 20; 95% CI 2–167; P = 0.005 for gynaecologic oncologists versus general gynaecologists), more recent surgery (OR = 1.33/year; 95% CI 1.07–1.67; P = 0.012) and younger patient age (OR = 0.93/year of age; 95% CI 0.87–0.99; P = 0.028). Independent predictors of adequate pathology were more recent surgery (OR = 1.26/year; 95% CI 1.06–1.49; P = 0.008) and surgeon type (OR = 3.1; 95% CI 1.4–6.7; P = 0.004 for gynaecologic oncologists versus general gynaecologists). Four serous ovarian cancers and one endometrioid endometrial cancer were detected during surgery or pathological examination. In conclusion Australasian women attending a specialist gynaecologic oncologist for RRGS are most likely to have adequate surgery and pathological examination. Additional education of clinicians and consumers is needed to ensure optimal surgery and pathology in these women.
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- 2011
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37. Clinical pharmacology of isoflavones and its relevance for potential prevention of prostate cancer
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John H. Kearsley, Paul de Souza, Pamela J. Russell, and Laurence G. Howes
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Oncology ,medicine.medical_specialty ,Nutrition and Dietetics ,Clinical pharmacology ,business.industry ,Daidzein ,Phenoxodiol ,Medicine (miscellaneous) ,Cancer ,Genistein ,Isoflavones ,medicine.disease ,law.invention ,chemistry.chemical_compound ,Prostate cancer ,Endocrinology ,chemistry ,law ,Internal medicine ,Medicine ,Phytoestrogens ,business - Abstract
Isoflavones are phytoestrogens that have pleiotropic effects in a wide variety of cancer cell lines. Many of these biological effects involve key components of signal transduction pathways within cancer cells, including prostate cancer cells. Epidemiological studies have raised the hypothesis that isoflavones may play an important role in the prevention and modulation of prostate cancer growth. Since randomized phase III trials of isoflavones in prostate cancer prevention are currently lacking, the best evidence for this concept is presently provided by case control studies. However, in vitro data are much more convincing in regard to the activity of a number of isoflavones, and have led to the development of genistein and phenoxodiol in the clinic as potential treatments for cancer. In addition, the potential activity of isoflavones in combination with cytotoxics or radiotherapy warrants further investigation. This review focuses on the clinical pharmacology of isoflavones and its relevance to their development for use in the prevention of prostate cancer, and it evaluates some of the conflicting data in the literature.
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- 2010
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38. Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression
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Warick Delprado, Michele C. Madigan, Hongmin Chen, Paul J. Cozzi, Weiwei Xiao, Jingli Hao, Pamela J. Russell, Yong Li, and Julia Beretov
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Male ,Cancer Research ,CD44v3-10 ,ATP-binding cassette transporter ,Docetaxel ,Drug resistance ,physiological processes ,Metastasis ,Prostate cancer ,polycyclic compounds ,Medicine ,Neoplasm Metastasis ,monocarboxylate transporters ,P-glycoprotein ,biology ,Middle Aged ,prostate cancer ,Up-Regulation ,Hyaluronan Receptors ,Oncology ,CD147 ,Disease Progression ,Taxoids ,Adult ,Monocarboxylic Acid Transporters ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,multidrug resistance ,Cell Line, Tumor ,Internal medicine ,Biomarkers, Tumor ,metastasis ,Animals ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Molecular Diagnostics ,neoplasms ,Aged ,business.industry ,Prostatic Neoplasms ,Cancer ,medicine.disease ,Endocrinology ,Drug Resistance, Neoplasm ,Tumor progression ,Basigin ,biology.protein ,Cancer research ,business - Abstract
Background: The aim of this study is to seek an association between markers of metastatic potential, drug resistance-related protein and monocarboxylate transporters in prostate cancer (CaP). Methods: We evaluated the expression of invasive markers (CD147, CD44v3-10), drug-resistance protein (MDR1) and monocarboxylate transporters (MCT1 and MCT4) in CaP metastatic cell lines and CaP tissue microarrays (n=140) by immunostaining. The co-expression of CD147 and CD44v3-10 with that of MDR1, MCT1 and MCT4 in CaP cell lines was evaluated using confocal microscopy. The relationship between the expression of CD147 and CD44v3-10 and the sensitivity (IC50) to docetaxel in CaP cell lines was assessed using MTT assay. The relationship between expression of CD44v3-10, MDR1 and MCT4 and various clinicopathological CaP progression parameters was examined. Results: CD147 and CD44v3-10 were co-expressed with MDR1, MCT1 and MCT4 in primary and metastatic CaP cells. Both CD147 and CD44v3-10 expression levels were inversely related to docetaxel sensitivity (IC50) in metastatic CaP cell lines. Overexpression of CD44v3-10, MDR1 and MCT4 was found in most primary CaP tissues, and was significantly associated with CaP progression. Conclusions: Our results suggest that the overexpression of CD147, CD44v3-10, MDR1 and MCT4 is associated with CaP progression. Expression of both CD147 and CD44v3-10 is correlated with drug resistance during CaP metastasis and could be a useful potential therapeutic target in advanced disease.
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- 2010
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39. Concise review: Nanoparticles and cellular carriers-allies in cancer imaging and cellular gene therapy?
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Rosetta Martiniello-Wilks, Aparajita Khatri, Catherine Tang, John E.J. Rasko, and Pamela J. Russell
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Genetic enhancement ,Immunology ,Translational and Clinical Research ,Contrast Media ,Cancer imaging ,Biology ,Mesenchymal Stem Cell Transplantation ,Gene therapy ,Stem cell tracking and imaging ,Predictive Value of Tests ,Neoplasms ,medicine ,Nanotechnology ,Animals ,Humans ,Magnetite Nanoparticles ,Cancer ,medicine.diagnostic_test ,Mesenchymal stem cell ,SPION ,Gene Transfer Techniques ,Dextrans ,Magnetic resonance imaging ,Genetic Therapy ,Cell Biology ,medicine.disease ,Magnetic Resonance Imaging ,Ferrosoferric Oxide ,Treatment efficacy ,Molecular Imaging ,Treatment Outcome ,Magnetic nanoparticles ,Cancer research ,Mesenchymal stem cells ,Nanoparticles ,Molecular Medicine ,Stem cell ,Molecular imaging ,Developmental Biology - Abstract
Ineffective treatment and poor patient management continue to plague the arena of clinical oncology. The crucial issues include inadequate treatment efficacy due to ineffective targeting of cancer deposits, systemic toxicities, suboptimal cancer detection and disease monitoring. This has led to the quest for clinically relevant, innovative multifaceted solutions such as development of targeted and traceable therapies. Mesenchymal stem cells (MSCs) have the intrinsic ability to “home” to growing tumors and are hypoimmunogenic. Therefore, these can be used as (a) “Trojan Horses” to deliver gene therapy directly into the tumors and (b) carriers of nanoparticles to allow cell tracking and simultaneous cancer detection. The camouflage of MSC carriers can potentially tackle the issues of safety, vector, and/or transgene immunogenicity as well as nanoparticle clearance and toxicity. The versatility of the nanotechnology platform could allow cellular tracking using single or multimodal imaging modalities. Toward that end, noninvasive magnetic resonance imaging (MRI) is fast becoming a clinical favorite, though there is scope for improvement in its accuracy and sensitivity. In that, use of superparamagnetic iron-oxide nanoparticles (SPION) as MRI contrast enhancers may be the best option for tracking therapeutic MSC. The prospects and consequences of synergistic approaches using MSC carriers, gene therapy, and SPION in developing cancer diagnostics and therapeutics are discussed.
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- 2010
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40. Molecular and traditional chemotherapy: A united front against prostate cancer
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Aparajita Khatri, Pamela J. Russell, M. Yam, and Preetinder Pal Singh
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Castrate-resistant prostate cancer ,Antineoplastic Agents ,Docetaxel ,Genetic therapy ,Prostate cancer ,Internal medicine ,medicine ,Humans ,Dosing ,Chemotherapy ,business.industry ,Prostatic Neoplasms ,Genetic Therapy ,medicine.disease ,Oncolytic virus ,Survival benefit ,Chemotherapy, Adjuvant ,Taxoids ,business ,medicine.drug - Abstract
Castrate resistant prostate cancer (CRPC) is essentially incurable. Recently though, chemotherapy demonstrated a survival benefit ( approximately 2months) in the treatment of CRPC. While this was a landmark finding, suboptimal efficacy and systemic toxicities at the therapeutic doses warranted further development. Smart combination therapies, acting through multiple mechanisms to target the heterogeneous cell populations of PC and with potential for reduction in individual dosing, need to be developed. In that, targeted molecular chemotherapy has generated significant interest with the potential for localized treatment to generate systemic efficacy. This can be further enhanced through the use of oncolytic conditionally replicative adenoviruses (CRAds) to deliver molecular chemotherapy. The prospects of chemotherapy and molecular-chemotherapy as single and as components of combination therapies are discussed.
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- 2010
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41. Post-translation modification of proteins in tears
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Valerie C. Wasinger, Peter Graham, Pamela J. Russell, Anna Fitzgerald, Yong Li, Paul J. Cozzi, Bradley J. Walsh, Ling Zhong, Mark D. P. Willcox, Zhenjun Zhao, and Jingjing You
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chemistry.chemical_classification ,Glycosylation ,Clinical Biochemistry ,Biochemistry ,eye diseases ,Analytical Chemistry ,Nucleobindin 2 ,chemistry.chemical_compound ,chemistry ,Phosphoprotein ,Phosphorylation ,Tears ,Cystatin ,Glycoprotein ,Lipocalin 1 - Abstract
This is the first 2-DE study using sequential dyes to analyse phospho-, glyco- and total tear protein profiles (Pro-Q Diamond for phosphoprotein, Pro-Q Emerald for glycoprotein and Sypro Ruby for total protein). This method minimised the gel-gel variations, allowing better comparisons among the three profiles and generated a whole map of PTM profiles of tear protein. A novel tear protein, dermcidin, was identified for the first time in this study. The identification of this antimicrobial protein suggests a new model of defence in tears. In addition, we are able to present the first experimental evidence of the presence of glycosylated lipocalin 1 and cystatin S. Nucleobindin 2 was only detected using phospho staining, suggesting it is only phosphorylated in tears. This study provides the groundwork for understanding the PTM of tear proteins and consequently these methods could be useful in the search for biomarkers in tears.
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- 2010
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42. Effects of Gastrocnemius, Hamstring, and Combined Stretching Programs on Knee Extensibility
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Darcie Enea, Pamela J. Russell, and Laura C. Decoster
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medicine.medical_specialty ,Physical medicine and rehabilitation ,business.industry ,Medicine ,General Medicine ,business ,Extensibility ,Hamstring ,Stretching exercises - Published
- 2010
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43. Innovative biomarkers for prostate cancer early diagnosis and progression
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Yong Li, John H. Kearsley, Bradley J. Walsh, Jingjing You, Pamela J. Russell, Mark D. P. Willcox, and Paul J. Cozzi
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Male ,Proteomics ,Oncology ,medicine.medical_specialty ,Pathology ,business.industry ,Negative information ,Prostatic Neoplasms ,Early detection ,Cancer ,Hematology ,medicine.disease ,Protein markers ,Prostate cancer ,Tumor progression ,Internal medicine ,Biomarkers, Tumor ,Disease Progression ,medicine ,Humans ,business ,Benign prostate - Abstract
The marker currently used for prostate cancer (CaP) detection is an increase in serum prostate-specific antigen (PSA). However, the PSA test which may give false positive or negative information, is not reliable and does not allow the differentiation of benign prostate hyperplasia (BPH), non-aggressive CaP and aggressive CaP. There is thus an urgent need to search for novel CaP biomarkers to improve the early detection and accuracy of diagnosis, determine the aggressiveness of CaP and to monitor the efficacy of treatment. Proteomic techniques allow for a high-throughput analysis of bio-fluids with the visualization and quantification of thousands of potential protein markers and represent very promising tools in the search for new, improved molecular markers of CaP. In this review, we will summarize conventional CaP biomarkers and focus on novel identified biomarkers for CaP early diagnosis and progression that might be used in the future.
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- 2010
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44. Radiotherapy is not associated with an increased rate of Second Primary Tumours in Oral Squamous Carcinoma: A study of 370 patients
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Pamela J. Russell, Ross Darius Farhadieh, Petr Otahal, Arash Salardini, Robert Smee, and Charles Geoffrey Gordon Rees
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasms, Radiation-Induced ,medicine.medical_treatment ,Disease-Free Survival ,Risk Factors ,Internal medicine ,medicine ,Carcinoma ,Humans ,Aged ,Retrospective Studies ,Mouth neoplasm ,business.industry ,Incidence (epidemiology) ,Cancer ,Neoplasms, Second Primary ,Retrospective cohort study ,Middle Aged ,Prognosis ,medicine.disease ,Surgery ,Squamous carcinoma ,Radiation therapy ,stomatognathic diseases ,Epidermoid carcinoma ,Carcinoma, Squamous Cell ,Radiation Oncology ,Female ,Mouth Neoplasms ,New South Wales ,Oral Surgery ,business - Abstract
Oral Squamous Cell Carcinoma (OSCC) remains a public health scourge. Radiotherapy (RT) is a major treatment modality and has been implicated in possible formation of Second Primary Tumours (SPT). In a single centre retrospective study of 370 patients with OSCCs (1967-2004) associations between RT, diagnosis of SPTs, median SPT diagnostic time lag, Disease Free Survival (DFS) and overall survival (OS) were analysed. Sixty-eight (18.4%) patients developed metachronous SPTs. Two hundred and twenty patients (59.3%) underwent some form of RT whilst 151 (40.7%) patients were not exposed to RT. No significant increased incidence of SPTs was demonstrated in the RT group. No significant difference in SPT diagnostic time lag was noted amongst the groups. This study suggests that RT is neither a risk for SPT induction nor increases the relative diagnostic time delay of upper aero-digestive tract SPTs.
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- 2009
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45. Diagnosis of second head and neck tumors in primary laryngeal SCC is an indicator of overall survival and not associated with poorer overall survival: A single centre study in 987 patients
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Pamela J. Russell, Jia-Lin Yang, Arash Salardini, Ross Darius Farhadieh, and Robert Smee
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Larynx ,medicine.medical_specialty ,Lung ,business.industry ,Incidence (epidemiology) ,General Medicine ,Gastroenterology ,Surgery ,Single centre ,medicine.anatomical_structure ,Oncology ,Internal medicine ,medicine ,Overall survival ,Field cancerization ,Esophagus ,business ,Survival analysis - Abstract
Objectives: Second primary tumors (SPTs) have been implicated in poor overall survival (OS) of head and neck squamous cell carcinomas (HNSCCs). Confusion remains regarding their actual incidence and prognostic impact. This study assessed the incidence of SPTs; the SPT diagnostic time lag; the impact on OS; and the mean annual risk. Methods: Nine hundred eighty seven consecutive patients treated for primary larynx SCC (1967-2004) were analyzed in this study. 96.3% and 91.4% of patients reached a minimum follow-up period of 3 and 5 years. Results: Two hundred eight (21.1%) patients were diagnosed with SPTs. One hundred forty three (14.5%) patients developed upper aerodigestive tract (UAD)-SPTs, 83 (8.4%) were HNSCCs, 56 (5.7%) were lung, and 4 (0.41%) were esophageal-SPTs. Survival analysis demonstrated clear superior OS rates for the UAD-SPT (P
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- 2009
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46. Stacked Search For Gravitational Waves From The 2006 Sgr 1900+14 Storm
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Antonio Lucianetti, J. Ulmen, P. G. Murray, Keisuke Goda, J. H. Hough, N. A. Robertson, S. Kandhasamy, Jolien D. E. Creighton, D. Ugolini, Douglas R. Cook, Erik Katsavounidis, S. Caride, Michele Zanolin, And J. Zweizig, D. Hammer, F. Seifert, Lindy Blackburn, K. Holt, V. Sandberg, M. Lormand, Giuseppe Castaldi, M. J. Lubinski, Kirk McKenzie, Jonah Kanner, J. C. Dumas, Albert Lazzarini, Tom Fricke, G. McIntyre, John G. Dwyer, Rajesh Kumar, Vladimir B. Braginsky, S. Mrka, G. D. Hammond, K. Kokeyama, N. Fotopoulos, D. J. Hosken, J. G. Rollins, Leo C. Stein, B. Lantz, V. V. Frolov, V. Parameshwaraiah, H. Vahlbruch, K. Riles, C. Veltkamp, H. Overmier, D. Barker, A. Bullington, Rahul Biswas, D. S. Rabeling, K. Haughian, E. Espinoza, M. Weinert, L. Bogue, D. Sellers, V. Kondrashov, R. DeSalvo, S. R. P. Mohapatra, Peter Kalmus, S. Roddy, Supriyo Sinha, B. Moe, Alberto Vecchio, B. Sorazu, A. Thüring, R. L. Ward, L. Prokhorov, Kazuhiro Hayama, K. Mors, B. Behnke, John D. Scott, R. A. Mercer, M. A. Arain, A. C. Melissinos, T. Morioka, Ravi Kumar Kopparapu, A. M. Cruise, Simon Chelkowski, M. Guenther, Gregory M. Harry, H. Lin, R. M. S. Schofield, K. A. Hodge, Roberto Conte, Evan Ochsner, Chad Forrest, Vuk Mandic, J. A. Giaime, D. F. Menéndez, E. E. Doomes, Stanislav Babak, Duncan A. Brown, D. Talukder, C. Pankow, I. W. Harry, M. Lei, C. Aulbert, A. M. Sintes, P. Aufmuth, L. Sancho De La Jordana, Matthew P. Edgar, A. J. Weinstein, T. Z. Summerscales, I. Gholami, W. Wu, Matthew Benacquista, Scott Koranda, L. Matone, A. F. Brooks, E. Chalkley, R. L. Savage, P. Armor, Kevin M. Ryan, Benjamin J. Owen, T. Isogai, Lee Samuel Finn, Tyson Littenberg, R. M. Culter, J. Dueck, Jesper Munch, Cheng Li, N. D. Smith, Jordan Camp, S. Wen, G. S. Allen, H. Yamamoto, P. J. Sutton, C. C. Wipf, Patrick Brady, K. V. Tokmakov, Badri Krishnan, Benno Willke, H. Rehbein, I. W. Martin, P. Shawhan, Virginio Sannibale, J. Betzwieser, A. Franzen, David E. McClelland, Seiji Kawamura, C. Torres, F. Y. Khalili, A. Sibley, C. M. Mow-Lowry, K. Flasch, M. V. Van Der Sluys, Shantanu Desai, P. Charlton, Kip S. Thorne, T. Chalermsongsak, John S. Markowitz, A. Grant, S. B. Anderson, Ruslan Vaulin, David B. Tanner, Chunnong Zhao, David H. Shoemaker, Reinhard Prix, A. Effler, Elizabeth Harstad, V. Raymond, J. H. Romie, Martin Hewitson, Junwei Cao, L. Cunningham, P. Ehrens, F. J. Raab, C. N. Colacino, L. Zhang, T. Reed, Z. Frei, C. Echols, K. Mailand, Rana X. Adhikari, A. Stroeer, Peter Fritschel, P. Lu, O. Burmeister, Gareth Jones, I. Wilmut, I. A. Bilenko, V. Dergachev, B. Machenschalk, M. Sung, Karel E. Urbanek, D. O. Bridges, Maurizio Longo, Walter Winkler, N. A. Lockerbie, A. Ivanov, David J. Ottaway, Osamu Miyakawa, David H. Reitze, E. Hirose, J. E. Brau, Matthew Evans, R. Mittleman, B. F. Whiting, S. H. Huttner, Roman Schnabel, D. Muhammad, A. Stochino, V. P. Mitrofanov, M. C. Araya, Nelson Christensen, F. Donovan, A. S. Markosyan, A. A. van Veggel, Andrew Melatos, Harald Lück, A. Cumming, S. Foley, Efim A. Khazanov, Moritz Mehmet, Kenneth A. Strain, M. Pedraza, G. P. Newton, M. Fyffe, L. Cardenas, Gabriela Gonzalez, Maria Alessandra Papa, H. Mukhopadhyay, B. Johnson, M. Bastarrika, H. Radkins, K. Wette, J. S. Kissel, Timothy Evans, S. Saraf, S. P. Vyachanin, B. Schulz, J. M. Hallam, S. C. McGuire, D. J. A. McKechan, A. Dietz, D. Kasprzyk, B. O'Reilly, S. Klimenko, H. Müller-Ebhardt, D. Sigg, C. Van Den Broeck, C. T. Y. Chung, Michael E Zucker, Roger Jones, Boris Hage, T. Etzel, R. Taylor, P. T. Baker, B. Hughey, S. Giampanis, Ilya Mandel, A. C. Searle, P. Sarin, I. Leonor, John K. Cannizzo, D. Hoyland, P. Savov, Alessandra Buonanno, David Coward, Christian Röver, Hansheng Lei, S. W. Ballmer, Michael Landry, H. R. Williams, R. Gustafson, Yi Pan, T. P. Bodiya, C. M. Reed, James Whelan, P. Ajith, I. Duke, A. L. Stuver, David Jones, G. Moreno, Jon M. Miller, J. Slutsky, Imre Bartos, D. Hoak, Richard A. Matzner, G. Billingsley, V. Quetschke, M. S. Meyer, Bangalore Suryanarayana Sathyaprakash, E. Black, Michael L. Gorodetsky, Marco Cavaglia, E. J. Daw, K. D. Giardina, J. Minelli, C. Barker, Helena Armandula, H. J. Pletsch, Kipp Cannon, G. Traylor, Thomas Corbitt, R. J. S. Greenhalgh, Gavin Davies, R. S. Ottens, J. R. Smith, T. Nash, Sanichiro Yoshida, J. O'Dell, Ke-Xun Sun, K. Kawabe, Rainer Weiss, C. Gray, S. M. Aston, R. W. P. Drever, E. Myers, A. W. Heptonstall, Peter R. Saulson, B. Sears, Mark A. Satterthwaite, Graham Woan, D. B. Kozak, S. Penn, A. Nishizawa, G. H. Ogin, N. Rainer, C. Vorvick, Pamela J. Russell, Yoichi Aso, B. Rivera, Pablo Barriga, A. M. Gretarsson, W. W. Johnson, M. V. Plissi, M. Mageswaran, Kentaro Somiya, M. Ito, L. Wallace, Vicky Kalogera, Robert L. Byer, Stuart Reid, H. Fehrmann, L. Tang, M. Brinkmann, Andreas Freise, Vincenzo Pierro, Matthew Pitkin, Kenji Numata, David Blair, S. E. Strigin, Robert Stone, R. Frey, C. Messenger, C. Robinson, Laura Cadonati, S. Goler, Stefan Hild, Benjamin William Allen, P. T. Beyersdorf, Hartmut Grote, Malcolm B. Gray, M. A. Barton, G. Mendell, R. Wooley, P. J. King, B. Shapiro, J. K. Blackburn, Yaohui Fan, Bernard F. Schutz, Li Ju, Karsten Danzmann, Yasushi Mino, Carlos Cepeda, Robert J. McCarthy, Linqing Wen, P. Raffai, D.B. DeBra, A. G. Wiseman, M. R. Smith, A. S. Sengupta, J. Hanson, Susan M. Scott, Guido Mueller, Teviet Creighton, Slawomir Gras, Nick Leindecker, O. Punken, M. Frei, Sheila Rowan, Neil J. Cornish, Maik Frede, A. Weidner, Ping Koy Lam, Marco Aurelio Diaz, Chad Hanna, D. C. Coyne, C. Wilkinson, Shuichi Sato, P. E. Lindquist, Martin P McHugh, B. J. J. Slagmolen, Fabio Postiglione, P. Kwee, D. Lodhia, K. A. Thorne, A. J. Stein, Fumiko Kawazoe, Riccardo Bassiri, F. Matichard, P. Schwinberg, J. R. Taylor, J. N. Marx, C. I. Torrie, J. Thacker, A. Perreca, E. Maros, P. J. Veitch, D. R. Ingram, Phil Willems, A. Brummit, Soma Mukherjee, Guenakh Mitselmakher, A. M. Sergeev, V. Boschi, Joseph D. Romano, H. Zur Mühlen, W. G. Anderson, Drew Keppel, Zewu Yan, J. H. Clayton, Vincenzo Galdi, Sarah Caudill, Lisa M. Goggin, R. Gouaty, B. Daudert, B. P. Abbott, E. K. Gustafson, R. Bork, Innocenzo M. Pinto, F. Grimaldi, Z. Mrka, D. E. Clark, Thomas Cokelaer, Kasem Mossavi, S. Vass, Jian Zhang, W. Kells, Lucía Santamaría, Soumya D. Mohanty, Maria Ilaria Del Principe, G. P. Szokoly, S. Grunewald, N. Zotov, K. Mason, Sanjeev Dhurandhar, R. M. Martin, S. L. Danilishin, K. L. Dooley, M. Scanlan, Xavier Siemens, Lisa Barsotti, J. Garofoli, Yi Chen, Jan Harms, Lutz Winkelmann, Evan Goetz, Paul Roberts, S. Meshkov, John Veitch, M. MacInnis, R. S. Amin, A. E. Villar, Nergis Mavalvala, Jerome Degallaix, J. Heefner, R. Grosso, John A. Clark, S. J. Waldman, J. Myers, Shourov Chatterji, D. Fazi, Suvadeep Bose, Michele Vallisneri, Ik Siong Heng, S. Steplewski, Emma L. Robinson, S. P. Tarabrin, John Nelson, I. Yakushin, S. E. Whitcomb, S. Sakata, Rubab Khan, Miquel Trias, A. Mullavey, Richard O'Shaughnessy, B. Barr, P. Patel, Malik Rakhmanov, J. Worden, L. Williams, A. Rüdiger, R. Riesen, Roland Schilling, Y. Faltas, Richard J. Abbott, Alexander Khalaidovski, B. Bland, G. Brunet, Z. Raics, and Stephen Fairhurst
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Physics ,High Energy Astrophysical Phenomena (astro-ph.HE) ,Gravitational wave ,gamma rays: bursts ,Astrophysics::High Energy Astrophysical Phenomena ,MAGNETIZED NEUTRON-STARS ,Gamma ray ,Soft gamma repeater ,Astronomy ,FOS: Physical sciences ,Astronomy and Astrophysics ,Astrophysics ,pulsars: individual (SGR 1900+14) ,LIGO ,Neutron star ,Stars ,stars: neutron ,SOFT GAMMA-REPEATERS ,Pulsar ,gravitational waves ,Space and Planetary Science ,Astrophysics - High Energy Astrophysical Phenomena ,Gamma-ray burst ,QC - Abstract
We present the results of a LIGO search for short-duration gravitational waves (GWs) associated with the 2006 March 29 SGR 1900+14 storm. A new search method is used, "stacking'' the GW data around the times of individual soft-gamma bursts in the storm to enhance sensitivity for models in which multiple bursts are accompanied by GW emission. We assume that variation in the time difference between burst electromagnetic emission and potential burst GW emission is small relative to the GW signal duration, and we time-align GW excess power time-frequency tilings containing individual burst triggers to their corresponding electromagnetic emissions. We use two GW emission models in our search: a fluence-weighted model and a flat (unweighted) model for the most electromagnetically energetic bursts. We find no evidence of GWs associated with either model. Model-dependent GW strain, isotropic GW emission energy E_GW, and \gamma = E_GW / E_EM upper limits are estimated using a variety of assumed waveforms. The stacking method allows us to set the most stringent model-dependent limits on transient GW strain published to date. We find E_GW upper limit estimates (at a nominal distance of 10 kpc) of between 2x10^45 erg and 6x10^50 erg depending on waveform type. These limits are an order of magnitude lower than upper limits published previously for this storm and overlap with the range of electromagnetic energies emitted in SGR giant flares., Comment: 7 pages, 3 figures
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- 2009
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47. A novel model of bone-metastatic prostate cancer in immunocompetent Mice
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Yan Yu, Jae Cho, Carl Power, Pamela J. Russell, Jeffrey Chan, William R. Walsh, and Hnin Pwint
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Pathology ,medicine.medical_specialty ,Osteolysis ,Bone cancer ,business.industry ,Urology ,Bone metastasis ,Cancer ,Osteoblast ,medicine.disease ,Metastasis ,Prostate cancer ,medicine.anatomical_structure ,Oncology ,Cancer stem cell ,medicine ,business - Abstract
BACKGROUND. Bone metastasis is a frequent and catastrophic consequence of prostate cancer for which only palliative treatment is available. Animal models of bone metastatic prostate cancer are necessary for understanding disease mechanisms but few models exist. METHODS. We have used the murine prostate carcinoma cell line RM1 to generate a bone metastatic model of prostate cancer. Repeated intracardiac injection of RM1 cells followed by isolation of cells from bone tumors has yielded a cell line with strong bone-metastatic potential, RM1 bone metastatic (BM). RESULTS. This cell line metastasizes to multiple bony sites in over 95% of injected C57BL/6 mice and is far less tropic to soft tissues. Bone tumors produced by the RM1(BM) cell line show no preference for particular skeletal sites as most bones are affected. Histology, and microcomputed tomography show that RM1(BM) cells form osteolytic tumors, but with evidence of osteoblastic changes. In vitro the RM1 cells express E-cadherin but not vimentin, do not form colonies in soft agar, are non-invasive but are more motile than the parent cell line. CONCLUSIONS. This model provides a novel means for identifying cellular and molecular mechanisms that contribute to bone metastasis and allow for preclinical testing of therapies to prevent and treat tumor metastasis to bone. Finally as the syngeneic tumor cells are injected into immunocompetent mice, this model will provide a means to study interactions between the immune system, tumors and bone, and therapies that target such interactions.
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- 2009
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48. Mutant p53 and cyclin A1 protein expression in primary laryngeal squamous cell carcinomas do not correlate to second primary tumours of the head and neck*
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Pamela J. Russell, Ross Darius Farhadieh, Arash Salardini, Sarah A. Eggleton, Robert Smee, Charles Geoffrey Gordon Rees, and Jia-Lin Yang
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Male ,Oncology ,medicine.medical_specialty ,Cell ,Mutant ,Cyclin A ,Disease-Free Survival ,Neoplasms, Multiple Primary ,Internal medicine ,Humans ,Medicine ,Laryngeal Neoplasms ,Predictive marker ,business.industry ,General Medicine ,Second primary cancer ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Head and neck squamous-cell carcinoma ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Female ,Surgery ,Field cancerization ,Cyclin A1 ,Neoplasm Recurrence, Local ,Tumor Suppressor Protein p53 ,business - Abstract
Background: Field cancerization is a feature of head and neck squamous cell carcinoma. No biological marker in the index tumour has been correlated to the development of second primary tumours (SPT). Cyclin A1 is a cell cycle regulator and a downstream target of p53. This study assessed predictive correlation of cyclin A1 and mut-p53 with clinicopathological parameters and occurrence of (SPT) 7in the head and neck. Methods: Using immunohistochemistry 106 patients treated for primary laryngeal squamous cell carcinoma were investigated for expression of cyclin A1 and mut-p53. Results: Expression of cyclin A1 and mut-p53 were noted in 83 of 106 (78.3%) and 25 of 106 (23.6%) patients. There was a weak but significant correlation between mut-p53 and cyclin A1 (r = 0.301, P = 0.002) expression. During the follow-up period (median 41.0 months (range 1-205 months)), 21 of 106 (19.8%) patients developed an SPT. There was no statistically significant correlation between the markers investigated and disease recurrence, SPT diagnosis or clinicopathological parameters. Conclusion: Second primary tumours are an intriguing problem in treatment of HNSCC and a predictive marker identifying those greatest at risk would be a leap forward.
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- 2009
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49. Cytosolic Phospholipase A2-α: A Potential Therapeutic Target for Prostate Cancer
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Kieran F. Scott, Mu Yao, Michael H. Gelb, Fiona Maclean, Manish I. Patel, Marzieh Niknami, Qihan Dong, Sasa Lu, Jaskirat Singh, Caroline Kurek, Pamela J. Russell, John Boulas, and Nicholas J. C. King
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Male ,Cancer Research ,medicine.medical_specialty ,Small interfering RNA ,Apoptosis ,Biology ,Article ,chemistry.chemical_compound ,Prostate cancer ,Cytosol ,Cyclin D1 ,Phospholipase A2 ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Enzyme Inhibitors ,Phosphorylation ,Protein kinase B ,Cell Proliferation ,Cell growth ,Group IV Phospholipases A2 ,Prostatic Neoplasms ,medicine.disease ,Endocrinology ,Oncology ,chemistry ,Cell culture ,Cancer research ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Growth inhibition ,Proto-Oncogene Proteins c-akt - Abstract
Purpose: Cytosolic phospholipase A2-α (cPLA2-α) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-α in prostate cancer cell lines and tissue and the effect of targeting cPLA2-α in vitro and in vivo. Experimental Design: The expression of cPLA2-α was determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-α activity were determined after inhibition with cPLA2-α small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-α inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-α was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens. Results: cPLA2-α is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1 results in significant reductions in prostate cancer cell numbers, as a result of reduced proliferation as well as increased apoptosis, and this was also associated with a reduction in cPLA2-α activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by ∼33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA2-α is increased when hormone refractory is reached. Conclusions: Expression and activation of cPLA2-α are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA2-α results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.
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- 2008
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50. Preparation and testing of bevacizumab radioimmunoconjugates with Bismuth-213 and Bismuth-205 / Bismuth-206
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Chand Raja, Pamela J. Russell, Alfred Morgenstern, Christos Apostolidis, Julia Beretov, Syed M. Abbas Rizvi, Kamel Abbas, John H. Kearsley, Emma Song, and Barry J. Allen
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Quality Control ,Vascular Endothelial Growth Factor A ,Cancer Research ,Immunoconjugates ,Time Factors ,Bevacizumab ,medicine.drug_class ,chemistry.chemical_element ,Angiogenesis Inhibitors ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Monoclonal antibody ,Bismuth ,Pharmacokinetics ,In vivo ,Cell Line, Tumor ,Humans ,Medicine ,Chelation ,Chelating Agents ,Radioisotopes ,Clinical Trials as Topic ,business.industry ,Antibodies, Monoclonal ,Pentetic Acid ,In vitro ,Treatment Outcome ,Oncology ,chemistry ,Bismuth isotope ,Molecular Medicine ,business ,medicine.drug - Abstract
Bevacizumab, a humanized anti-VEGF monoclonal antibody has shown promise in various clinical trials. We report the development and testing of Bi-213 (an alpha-emitting radionuclide) labeled bevacizumab for in vitro and in vivo studies using two different chelators viz cDTPA and CHX-A''. The developed labeling method showed high labeling yields of 93.6% and 89.7% for cDTPA and CHX-A'' respectively and the results were reproducible. The in vitro and in vivo stability tests were carried out using Bi-213 and long half-life Bismuth isotope (Bi-205/Bi-206) for pharmacokinetics. The in vitro results showed remarkable stability of the radiolabeled bevacizumab regardless of the chelator. The in vivo pharmacokinetics studies however, showed that the uptake and retention of cDTPA-bevacizumab was significantly higher in kidneys (p-value 0.02) and lower in liver and spleen (p-value0.0001 and 0.0009 respectively). The values for the two conjugates compared well in blood but the longer term data for CHX-A'' conjugate showed slow clearance resulting in a significantly longer blood half-life of the product (211 hours compared to 4 hours for cDTPA-bevacizumab). Preliminary in vivo results showed increased efficacy of the combination therapy compared to bevacizumab only. The tumor area (mm(2)) decreased from 24.8 +/- 3.6 and 12.8 +/- 1.7 for 1 and 3 mg/kg cold bevacizumab only to 6.5 +/- 0.7 and 7.5 +/- 4.8 when single dose of 333 MBq/kg of (213)Bi-bevacizumab was administered as combination therapy. In conclusion it can be said that stable radiolabeled bevacizumab conjugates can be prepared with Bi-213 with either chelators used. The shorter blood half-life with cDTPA-bevacizumab may not be a major concern with Bi-213 as its own half-life is 46 minutes only. The combination therapy proved superior to bevacizumab alone therapy, a phenomenon that can be particularly useful in cancers where bevacizumab alone has shown limited success like prostate cancer.
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- 2008
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