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Michael Cox

Publications and source records attributed to Michael Cox.

17 recordsLinked to original sources
PubMed2006

Human lineage-specific amplification, selection, and neuronal expression of DUF1220 domains.

Extreme gene duplication is a major source of evolutionary novelty. A genome-wide survey of gene copy number variation among human and great ape lineages revealed that the most striking human lineage-specific amplification was due to an unknown gene, MGC8902, which is predicted to encode multiple copies of a protein domain of unknown function (DUF1220). Sequences encoding these domains are virtually all primate-specific, show signs of positive selection, and are increasingly amplified generally as a function of a species' evolutionary proximity to humans, where the greatest number of copies (212) is found. DUF1220 domains are highly expressed in brain regions associated with higher cognitive function, and in brain show neuron-specific expression preferentially in cell bodies and dendrites.

Amino Acid Sequence↗
PubMed2005

Current practice patterns in urologic management of upper-tract transitional-cell carcinoma.

PURPOSE: To determine the current practice patterns in the management of upper-tract transitional-cell carcinoma (TCC) among a large group of urologists. MATERIALS AND METHODS: A survey was sent to 220 practicing members of the Society of Urologic Oncology (SUO) and the Endourological Society (ES) and members of the American Urological Association who did not belong to either society. The survey consisted of 16 focused questions pertaining to the surveillance and management of upper-tract TCC. The responses were used to create a database, which was then analyzed to determine practice trends. RESULTS: Eighty-four of the urologists responded, for a response rate of 38%. Fourteen responses were excluded because of multiple answers to a given question, so 70 were included in the final analysis. Eighty percent of the respondents were in academic practice. A CT urogram was the favored initial procedure for diagnosis of upper-tract TCC and an intravenous urogram was the next commonest choice (53% and 40%, respectively). Ureterorenoscopy was the surveillance tool of choice (70%) after conservative treatment of upper- tract TCC. Laparoscopic nephroureterectomy was the preferred procedure (73%) for a high-grade, large renal-pelvic TCC. Twenty-one percent of the endourologists recommended ureteroscopic ablation for a high-grade, large distal ureteral tumor. This was in sharp contrast to 77% of the respondents who favored a distal ureterectomy for the same clinical scenario. CONCLUSIONS: This study confirms that most urologists treating upper-tract TCC follow the principles reported in the published literature regarding the management of these patients. Further, most urologists, regardless of society affiliations or years in practice, favor minimally invasive techniques for the management of upper-tract TCC. This information may be useful in formulating clear guidelines for the management of this disease.

Adult↗
PubMed2004

Androgen responsiveness of Renilla luciferase reporter vectors is promoter, transgene, and cell line dependent.

Renilla based reporters are frequently used as transfection controls for luciferase transcriptional reporter assays. However, recent evidence suggests that a commonly used reporter (HSV-thymidine kinase driven Renilla) is responsive to androgen receptor (AR) and glucocorticoid receptors in the presence of the cognate ligands, dihydrotestosterone (DHT) and dexamethasone (DEX), respectively [1]. We further validate this important technical difficulty by illustrating that in LNCaP prostate cancer cells, spurious Renilla luciferase activity is a function of (a) the promoter driving Renilla expression, (b) the presence of co-transfected transgenes, and (c) the androgen responsiveness of the cell line used. Using inhibitors of transcription and translation we showed that transcript interference or translational modulation is not a major means by which androgens affect Renilla luciferase activity. As luciferase reporter assays are a frequent means of studying transcriptional co-regulation in the highly androgen dependent LNCaP cell line, our data serves as a cautionary note that alternative normalization techniques should be employed to avoid misinterpretation of data.

Androgens↗
PubMed2004

Chest pain? Cause.

Explore the source record for details and available documents.

Bronchogenic Cyst↗
PubMed2004

Small bowel tumours: a 10 year experience in four Sydney teaching hospitals.

BACKGROUND: Small bowel tumours are uncommon and can have a long delay prior to diagnosis. The present study aims to compare the use of computed tomography (CT) and contrast small bowel series (SBS) in their diagnosis and to outline the clinical features of small bowel tumours. METHODS: A retrospective, case note study was conducted between 1990 and 2000 in four Sydney teaching hospitals. The data collected included clinical features, investigations and tumour characteristics. RESULTS: One hundred and sixty-six people with small bowel tumours were identified (91 malignant; 75 benign). Malignant tumours consisted of adenocarcinomas (31%), carcinoid tumours (12%), lymphomas (7%) and leiomyosarcomas (5%). Benign tumours consisted of adenomas (22%), hamartomas (13%), leiomyomas (4%), inflammatory polyps (4%) and hyperplastic polyps (2%) and a benign schwannoma (1%). Adenocarcinomas were mainly located in the duodenum (P < 0.001) and carcinoid tumours in the ileum (P < 0.001). Malignant tumours were associated with a higher proportion of symptoms (P < 0.01), signs (P < 0.001) and episodes of small bowel obstruction (P < 0.01). Abdominal CT scans demonstrated a greater sensitivity (87.7%) than SBS (72.9%) with a slightly improved sensitivity when both investigations were used (89.3%). Abdominal ultrasound had a lower sensitivity than both of the above investigations of 65%. Gastroduodenoscopy had a sensitivity of 90% for diagnosing duodenal tumours. Operative procedures were performed on 92 patients with a preoperative diagnosis made in 77%. Metastatic spread of malignant tumours was evident in 46%. The sites of spread were to lymph nodes (23%), liver (21%) and distant locations (2%) at diagnosis. CONCLUSIONS: Malignant small bowel tumours are more likely to produce symptoms and signs than benign tumours, particularly caused by small bowel obstruction. Abdominal CT is the best radiological investigation for small bowel tumours and has a slight complimentary effect with SBS in improving the chances of detection. Gastroduodenoscopy remains the best investigation of duodenal tumours.

Adolescent↗
PubMed2004

Myoid angioendothelioma of the spleen.

Although vascular neoplasms of the spleen are rare, they are the most common nonhemopoietic proliferation of the organ, and include hemangiomas, lymphangiomas, hamartomas, littoral cell angiomas, hemangioendotheliomas, and angiosarcomas, as well as the recently described myoid angioendothelioma (MA). MA is an uncommon, benign tumor of the spleen, which is morphologically characterized by a composite of vascular spaces and stromal cells with myoid features. In 1999, in the only report of this unusual neoplasm, Kraus and Dehner described the features of 3 cases. We present another case of MA of the spleen occurring in a 51-year-old man that demonstrated the characteristic morphologic and immunohistochemical features of this neoplasm. In addition to the features described by Kraus and Dehner, our case also displayed the previously unreported findings of focal spindling of the stromal cells and scattered S100-positive cells in the stroma. The case was further unique in having a central stellate scar. Careful attention to histology, possibly with the aid of immunohistochemistry, should distinguish other splenic neoplasms from MA. Although MA is a morphologically distinct lesion, its histologic spectrum, biological behavior, and relationship to other vascular tumors are yet to be fully discovered. It is hoped that the recognition of further cases, and the use of newer molecular technologies, will help better define the nosological position and implications of the diagnosis of this unusual tumor.

Biomarkers, Tumor↗
PubMed2003

Isolation and identification of L-dopa decarboxylase as a protein that binds to and enhances transcriptional activity of the androgen receptor using the repressed transactivator yeast two-hybrid system.

The AR (androgen receptor) is a ligand-regulated transcription factor, which belongs to the steroid receptor family and plays an essential role in growth and development of the prostate. Transcriptional activity of steroid receptors is modulated by interaction with co-regulator proteins and yeast two-hybrid analysis is commonly used to identify these steroid receptor-interacting proteins. However, a limitation of conventional two-hybrid systems for detecting AR protein partners has been that they only allow for analysis of the ligand- and DNA-binding domains of the receptor, as its NTD (N-terminal domain) possesses intrinsic transactivation activity. To identify AR N-terminus-interacting proteins, its NTD was used in the RTA (repressed transactivator) system, which is specifically designed for transactivator bait proteins and was shown to be suitable for two-hybrid analysis with the AR NTD. DDC (L-dopa decarboxylase) was detected multiple times as a novel AR-interacting protein, which was subsequently confirmed in vitro and in vivo. Furthermore, transient transfection of DDC in prostate cancer cells strongly enhanced ligand-dependent AR transcriptional activity, an effect that was antagonized using high concentrations of the anti-androgen bicalutamide. Glucocorticoid receptor activity was also strongly enhanced with DDC co-transfection, while oestrogen receptor activity was only mildly affected. Together, our data demonstrate that DDC interacts with AR to enhance steroid receptor transactivation, which may have important implications in prostate cancer progression.

Amino Acid Sequence↗
PubMed2003

Castration-induced increases in insulin-like growth factor-binding protein 2 promotes proliferation of androgen-independent human prostate LNCaP tumors.

Activation of alternative growth factor pathways after androgen withdrawal is one mechanism mediating androgen-independent (AI) progression in advanced prostate cancer. Insulin-like growth factor (IGF) I activation is modulated by a family of IGF binding proteins (IGFBPs). Although IGFBP-2 is one of the most commonly overexpressed genes in hormone refractory prostate cancer, the functional significance of changes in IGF-I signaling during AI progression remains poorly defined. In this article, we characterize changes in IGFBP-2 in the LNCaP tumor model after androgen withdrawal and evaluate its functional significance in AI progression using gain-of-function and loss-of-function analyses. IGFBP-2 mRNA and protein levels increase 2-3-fold after androgen withdrawal in LNCaP cells in vitro in LNCaP tumors during AI progression in vivo. Increased IGFBP-2 levels after castration were also identified using a human prostate tissue microarray of untreated and posthormone therapy-treated prostatectomy specimens. LNCaP cell transfectants that stably overexpressed IGFBP-2 progressed more rapidly after castration than control tumors. Antisense oligonucleotides (ASOs) targeting the translation initiation site of IGFBP-2 reduced IGFBP-2 mRNA and protein expression by >70% in a dose-dependent and sequence-specific manner. ASO-induced decreases in IGFBP-2-reduced LNCaP cell growth rates and increased apoptosis 3-fold. LNCaP tumor growth and serum prostate-specific antigen levels in mice treated with castration plus adjuvant IGFBP-2 ASOs were significantly reduced compared with mismatch control oligonucleotides. Increased IGFBP-2 levels after androgen ablation may represent an adaptive response that helps potentiate IGF-I-mediated survival and mitogenesis and promote androgen-independent tumor growth. Inhibiting IGFBP-2 expression using ASO technology may offer a treatment strategy to delay AI progression.

Androgens↗
PubMed2003

Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells.

Overexpressed epidermal growth receptor factor receptors (EGFRs) are thought to contribute to the malignant phenotype of human glioblastomas (GBMs), but the mechanism is not well understood. We found that SKMG-3 cells, a rare GBM cell line that maintains EGFR gene amplification in vitro, produced high levels of EGFR protein. The cells also expressed the related receptors HER2/neu and HER4, but not HER3. Immunoblots and tryptic phosphopeptide maps showed that the SKMG-3 EGFRs were intact and functional and that a subset of these receptors were spontaneously autophosphorylated. EGF treatment stimulated phosphorylation of the EGFRs as well as the downstream effectors Erk, AKT1, stat3 and c-Cbl. Under minimal growth conditions, the unstimulated SKMG-3 cells contained constitutively phosphorylated Erk and AKTI but no detectable stat3 DNA-binding complexes. The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1. In contrast, inhibition of phosphatidylinositol-3-kinase (PI3K) blocked the constitutive phosphorylation of Erk and AKT-1 but not the EGFR. We conclude that the SKMG-3 cells represent the subset of GBMs with amplified EGFR genes that overexpress intact receptors. The results also suggest that in some GBMs, signals from overexpressed EGFRs contribute to the constitutive phosphorylation of Erk, but these signals may not required for the constitutive activation of PI3K or AKT1.

Breast Neoplasms↗
PubMed2003

Progress on regulations for human-derived therapeutic products.

Several European work programmes are building a unified regulatory framework for therapeutic products that utilise material of human origin, that is, substances, derivatives or tissues of human origin or viable cells of human origin. This is a report on progress to date.

Artificial Organs↗
PubMed2002

Clinical performance of the Nova T380 intrauterine device in routine use by the UK Family Planning and Reproductive Health Research Network: 5-year report.

OBJECTIVES: The purpose of the study was to evaluate the pregnancy and complication rates of this new device, with its increased area of copper, in comparison with other published results, in the clinical setting of British general practice and family planning clinics. DESIGN: Doctors working in general practice and at family planning clinics throughout the UK who collaborate in the UK Family Planning and Reproductive Health Research Network were responsible for the fitting of 574 Nova T380 intrauterine contraceptive devices (IUDs). The Nova T (and formerly the identical Novagard IUDs have copper with a surface area of 200 mm(2). The Nova T380 has copper with a surface area of 380 mm(2). RESULTS: This is the first 5-year report on this device. The 5-year cumulative life-table event rates per 100 women were pregnancy 2.0, expulsion 13.0, and removal for bleeding problems and bleeding with pain 29.6. CONCLUSIONS: The increased surface area of copper was associated with a reduced pregnancy rate as compared to the Nova T though no statistical comparison is possible. Although the present study was not a direct comparative study with the Nova T, the result lends weight to the notion that increasing the copper reduces the pregnancy rate. The discontinuation rate for bleeding problems and bleeding with pain and the expulsion rates were higher than in published Nova T studies.

Adult↗
PubMed2002

Clinical performance of the levonorgestrel intrauterine system in routine use by the UK Family Planning and Reproductive Health Research Network: 5-year report.

OBJECTIVES: This study was undertaken to determine the performance of the levonorgestrel intrauterine system (LNG IUS) in British women in routine clinical use. DESIGN: Doctors working in general practice and at family planning clinics throughout the UK who collaborate in the UK Family Planning and Reproductive Health Research Network were responsible for the fitting of 678 LNG IUSs. RESULTS: Gross cumulative event rates at 5 years per 100 women were pregnancy 1.0, expulsion 5.9, removal for bleeding problems 16.7, removal for pain 4.3, and removal for pelvic inflammatory disease (PID) 1.2. Removals were also required for side effects that may be due to absorbed levonorgestrel. Positive effects include effective contraception and considerably reduced quantity of bleeding for most participants. CONCLUSIONS: A need was identified to counsel women about the early bleeding problems including the possibility of oligomenorrhoea or amenorrhoea. This is considered to be very important as it will help women to persevere so that they can enjoy the longer-term benefits.

Adult↗
PubMed2002

Investigating initial cell-seeding density and culture period of fibroblast growing on biodegradable tricalcium phosphate lysine disks.

"Tissue engineering" uses implanted cells, scaffolds, DNA, protein, and/or protein fragments to replace or repair injured or diseased tissues and organs. Recently, biocompatible materials, such as hydroxyapatite and tricalcium phosphate, have been associated with cellular migration, exposure, and an increase in inflammatory mediators. Complications are less likely after the implants have become integrated. A model was sought to study the influence of multiple cell densities on the rate of fibroblast in-growth into porous implants. Fibroblasts were seeded at three different densities (50, 100, 200 x 10(6) cells/well) onto the surface of a 24 well tissue culture plate in the presence of porous tricalcium phosphate lysine ceramic disks. Cell number, viability, and morphology were evaluated after 1, 2, and 3 days. The results show a linear 2-fold increase in cell number during the first two days in culture. By day 3, the cells initially seeded at 200 x 10(6) cells no longer exhibited linear growth. This suggests that the tissue culture wells were confluent. Interestingly, the cells growing in wells containing TCPL disks showed slightly more cell numbers than cells growing on plastic alone for each density. The results also revealed no significant differences between the groups for parameters of cell function such as protein concentration and markers of cellular damage. Evaluation of cellular morphology indicated changes in cellular appearance with time in culture. Overall, initial cell seeding is important for faster in-growth, but with time the cells seeded at lower cell numbers will also become confluent. In conclusion, this study provides a novel approach for the study of fibroblast in-growth into implants with time. This work is important for understanding functional tissue engineering and ultimately result in safer and more efficacious repairs and replacements for the surgeon and patient.

Biodegradation, Environmental↗
PubMed2002

Effect of TCP sintering temperatures on MRC-5 fibroblast proliferation and viability.

Calcium/Phosphate ceramics have recently been used as orthopaedic implants, drug delivery systems, and models for studies on bone remodeling. Although their use has been very successful, problems such as aseptic loosening, coagulation, fibrous tissue formation, and inflammation have been noted. The objective of the study was to investigate the effects of tri-calcium Phosphate (TCP) ceramics sintered at different temperatures on the proliferation of MRC-5 fibroblasts. This was accomplished by light microscopy morphologic analysis, measurements of MDA (a measure of cell damage) and total protein, and cell counts. The experimental design consisted of four experimental groups and one control group. 96 TCP ceramics were divided into 4 groups of 24, with each group being assigned a different sintering temperature of 800, 1000, 1200 or 1400 degrees celcius. Each temperature group was then further divided into 8 ceramics per phase of 24, 48 and 72 hours. All data were analyzed using Sigma Stat software. The data collected from this study provided useful information pertaining to the optimum manufacturing conditions that produce high proliferation rates with minimal cellular damage. At 72 hours (the phase simulating chronic conditions), cell counts and MDA analysis showed that the cells incubated with the TCP sintered at 1200 degrees C had the greatest proliferation and least damage when compared to the other groups. Morphological, MDA and protein analysis showed the cells incubated with the 1400 degrees C TCP capsules to have undergone lysis or other extreme cellular alterations. Overall, the data collected revealed a marked alteration in cellular function and morphology over the range of sintering temperatures that were tested.

Biocompatible Materials↗
PubMed2002

The effects of TCP fabricated with amino acid binders on the proliferation and viability of fibroblast cells.

Calcium phosphate (CaP) biomaterials were produced, by fusing individual crystals together at 1200 degrees C. This ceramic material has the ability to interact with and bond to the surrounding tissue. Therefore, ceramics can serve as scaffolds for tissue growth. The objective of this study was to determine if ceramics formulated with amino acid binders can enhance and support cell growth. A total of 147 tubes containing 1 x 10(5) MRC5 cells were divided into seven equal groups. Group I served as control, Groups II-VI were incubated with ceramics containing amino acid binders (ASP, CYS, HIS, LYS, or SER, respectively) and Group VII served as ceramic without binder control. Equal numbers of tubes were terminated from each group at 24, 48 and 72 hours. Cell numbers, morphology and markers of cell damage were determined at each time point. Results indicated: 1) Total cell numbers at 24 hours were increased in all experimental groups when compared with control. Increased levels of MDA were associated with control cells. 2). At 48 hours the total cell numbers in comparison to the control cells were increased in all groups with the exception of HIS. In addition to cell number, cellular adhesion was also increased in the experimental groups compared with the control. Significant increases in MDA levels were detected at 24 hours in the CYS treated cells. 3). Cellular adhesion in the experimental groups was increased over the control, but the total cell number was only increased in the ceramic material groups containing CYS and LYS. Cells exposed to ceramics with SER as a binder showed decreased cell numbers as well as increased MDA levels at this time point in comparison to control and other binders. Morphological evaluation of the cells showed amino acid binders with acidic side chains caused an increase in the presence of spindled shaped cells. Neutral side chains resulted in cells with elongated appearances, and basic side chains caused the cells to be less elongated. In conclusion, amino acid binders are able to induce the cells to adhere, proliferate and affect their morphological appearance as early as 24 hours.

Amino Acids↗