Michael Cox

The Incidence of Disorders of Sexual Differentiation and Chromosomal Abnormalities of Cryptorchidism and Hypospadias Stratified by Meatal Location. Commentary

The Journal of Urology, Nov 1, 2008

Routine karyotype analysis has been recommended for patients with cryptorchidism and hypospadias.... more Routine karyotype analysis has been recommended for patients with cryptorchidism and hypospadias. However, it is unclear whether karyotyping should be obtained in all patients, or tailored to the severity or degree of hypospadias. Therefore, we analyzed the incidence of chromosomal abnormalities in patients with distal or proximal hypospadias and concomitant cryptorchidism. We reviewed the records of patients with cryptorchidism and hypospadias treated at a pediatric hospital between 1994 and 2006. Data collected included karyotype analysis, gonad palpability, and meatal and testes location at time of surgery. Patients with retractile testes and congenital adrenal hyperplasia were excluded from analysis. We identified 44 patients with hypospadias and cryptorchidism (26 with proximal and 18 with distal hypospadias). Karyotype information was available in 25 patients (19 with proximal and 6 with distal hypospadias). None of the patients with distal hypospadias and cryptorchidism had an abnormality of a sex chromosome. In contrast, chromosomal abnormalities were present in 6 of 19 individuals (32%) with proximal hypospadias and cryptorchidism. The most common abnormality was mixed gonadal dysgenesis in 3 patients, followed by autosomal translocations in 2 and 48XY aneuploidy in 1. When karyotype information was stratified by meatal location with cryptorchidism we found no significant chromosomal abnormalities in distal hypospadias and cryptorchidism, whereas a third of patients with proximal hypospadias and cryptorchidism had an abnormal karyotype. Karyotype analysis appears to be important in individuals with cryptorchidism and proximal hypospadias but of little benefit in patients with distal hypospadias and palpable undescended testes.

Applying the agent paradigm to network management : Towards engineering intelligent systems

Bt Technology Journal, 1998

Network management systems are large, distributed software systems that can suffer from the scala... more Network management systems are large, distributed software systems that can suffer from the scalability and flexibility issues common in today's technology. Software agent technology offers the promise of a solution to these problems. A set of agent concepts have been adopted and used to construct an experimental system in the network management domain of ATM performance management. An evaluation of the system confirms that the software agents approach allows development of scalable network management systems that are cheaper to build, change and discard.

Download

Inhibition of the Phosphatidylinositol 3V Kinase Pathway Promotes Autocrine Fas-Induced Death of Phosphatase and Tensin Homologue-Deficient Prostate Cancer Cells

Rationally designed therapeutics that target the phosphatidy- linositol 3V -kinase (PI3K) cell su... more Rationally designed therapeutics that target the phosphatidy- linositol 3V -kinase (PI3K) cell survival pathway are currently in preclinical and clinical development for cancer therapy. Drugs targeting the PI3K pathway aim to inhibit proliferation, promote apoptosis, and enhance chemosensitivity and radio- sensitivity of cancer cells. The phosphatase and tensin homo- logue (PTEN) phosphatidylinositol 3V -phosphatase is a key negative regulator of

Download

The impact of diet and micronutrient supplements on the expression of neuroendocrine markers in murineLady transgenic prostate

Prostate, 2008

BACKGROUND. Neuroendocrine (NE) differentiation (NED) in prostate cancer (PCa) is associated with... more BACKGROUND. Neuroendocrine (NE) differentiation (NED) in prostate cancer (PCa) is associated with morbidity and death; however, the underlying cause(s) promoting NED in PCa have yet to be determined. In this study, we examined the effect of both diet and micronutrient supplementation on the expression of NE markers using the Lady (12T-10) transgenic model of PCa. Lady (12T-10) transgenic animals develop advanced adenocarcinoma with NE characteristics that exhibits metastases in approximately 80% of cases. In this model a high fat diet has been shown to increase the severity of disease, while the use of micronutrients can inhibit this progression. METHODS. In this study we used immunohistochemical analysis to determine expression of the NE markers: chromogranin A (CgA), neuron-specific enolase (NSE), bombesin, parathyroid hormone-related peptide (PTHrP), neurotensin and serotonin in prostates of PCa-bearing Lady (12T-10) mice. RESULTS. High fat diet was correlated with significantly elevated expression of CgA and serotonin in prostate tissue of Lady (12T-10) mice. Addition of micronutrients to the control and high fat diet reproducibly elevated PTHrP and bombesin expression and suppressed NSE expression, while prostate tissue from the control diet supplemented with micronutrients exhibited significantly lower numbers of calcitonin-and neurotensin-positive cells. CONCLUSIONS. These results highlight the importance of dietary control in management of disease and identify differential changes in NE marker expression, which may be diagnostically viable in monitoring the impact of therapies on disease status.

Download

A TRIP230-Retinoblastoma Protein Complex Regulates Hypoxia-Inducible Factor-1α-Mediated Transcription and Cancer Cell Invasion

Plos One, Jun 11, 2014

Localized hypoxia in solid tumors activates transcriptional programs that promote the metastatic ... more Localized hypoxia in solid tumors activates transcriptional programs that promote the metastatic transformation of cells. Like hypoxia-inducible hyper-vascularization, loss of the retinoblastoma protein (Rb) is a trait common to advanced stages of tumor progression in many metastatic cancers. However, no link between the role of Rb and hypoxia-driven metastatic processes has been established. We demonstrated that Rb is a key mediator of the hypoxic response mediated by HIF1a/b, the master regulator of the hypoxia response, and its essential co-activator, the thyroid hormone receptor/retinoblastomainteracting protein (TRIP230). Furthermore, loss of Rb unmasks the full co-activation potential of TRIP230. Using small inhibitory RNA approaches in vivo, we established that Rb attenuates the normal physiological response to hypoxia by HIF1a. Notably, loss of Rb results in hypoxia-dependent biochemical changes that promote acquisition of an invasive phenotype in MCF7 breast cancer cells. In addition, Rb is present in HIF1a-ARNT/HIF1b transcriptional complexes associated with TRIP230 as determined by co-immuno-precipitation, GST-pull-down and ChIP assays. These results demonstrate that Rb is a negative modulator of hypoxia-regulated transcription by virtue of its direct effects on the HIF1 complex. This work represents the first link between the functional ablation of Rb in tumor cells and HIF1a-dependent transcriptional activation and invasion.

Download

Fujimura et al 2010 JACI dust asthma

Download

Regulation of Mutagenic DNA Polymerase V Activation in Space and Time

PLOS Genetics, 2015

Spatial regulation is often encountered as a component of multi-tiered regulatory systems in euka... more Spatial regulation is often encountered as a component of multi-tiered regulatory systems in eukaryotes, where processes are readily segregated by organelle boundaries. Well-characterized examples of spatial regulation are less common in bacteria. Low-fidelity DNA polymerase V (UmuD&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;2C) is produced in Escherichia coli as part of the bacterial SOS response to DNA damage. Due to the mutagenic potential of this enzyme, pol V activity is controlled by means of an elaborate regulatory system at transcriptional and posttranslational levels. Using single-molecule fluorescence microscopy to visualize UmuC inside living cells in space and time, we now show that pol V is also subject to a novel form of spatial regulation. After an initial delay (~ 45 min) post UV irradiation, UmuC is synthesized, but is not immediately activated. Instead, it is sequestered at the inner cell membrane. The release of UmuC into the cytosol requires the RecA* nucleoprotein filament-mediated cleavage of UmuD→UmuD&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;. Classic SOS damage response mutants either block [umuD(K97A)] or constitutively stimulate [recA(E38K)] UmuC release from the membrane. Foci of mutagenically active pol V Mut (UmuD&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;2C-RecA-ATP) formed in the cytosol after UV irradiation do not co-localize with pol III replisomes, suggesting a capacity to promote translesion DNA synthesis at lesions skipped over by DNA polymerase III. In effect, at least three molecular mechanisms limit the amount of time that pol V has to access DNA: (1) transcriptional and posttranslational regulation that initially keep the intracellular levels of pol V to a minimum; (2) spatial regulation via transient sequestration of UmuC at the membrane, which further delays pol V activation; and (3) the hydrolytic activity of a recently discovered pol V Mut ATPase function that limits active polymerase time on the chromosomal template.

Integrin-Linked Kinase Regulates Senescence in an Rb-Dependent Manner in Cancer Cell Lines

Cell cycle (Georgetown, Tex.), Jan 15, 2015

Anti-integrin-linked kinase (ILK) therapies result in aberrant mitosis including altered mitotic ... more Anti-integrin-linked kinase (ILK) therapies result in aberrant mitosis including altered mitotic spindle organization, centrosome declustering and mitotic arrest. In contrast to cells that expressed the retinoblastoma tumour suppressor protein Rb, we have shown that in retinoblastoma cell lines that do not express Rb, anti-ILK therapies induced aberrant mitosis that led to the accumulation of temporarily viable multinucleated cells. The present work was undertaken to: 1) determine the ultimate fate of cells that had survived anti-ILK therapies and 2) determine whether or not Rb expression altered the outcome of these cells. Our data indicate that ILK, a chemotherapy drug target is expressed in both well-differentiated, Rb-positive, and relatively undifferentiated, Rb-negative retinoblastoma tissue. We show that small molecule targeting of ILK in Rb-positive and Rb-deficient cancer cells results in increased centrosomal declustering, aberrant mitotic spindle formation and multinuclea...

Increasing line rate by combining ETDM and OTDM in a semiconductor Mach-Zehnder modulator

Optical Fiber Communication, 2001

Line rate is doubled by combining electrical time division multiplexing (ETDM) and OTDM technique... more

A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice

The Journal of steroid biochemistry and molecular biology, Jan 19, 2015

Dietary factors continue to preside as dominant influences in prostate cancer prevalence and prog... more Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P=0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P=0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in th...

Download

p,p'-Dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) repress prostate specific antigen levels in human prostate cancer cell lines

Chemico-biological interactions, Jan 25, 2015

Despite stringent restrictions on their use by many countries since the 1970s, the endocrine disr... more Despite stringent restrictions on their use by many countries since the 1970s, the endocrine disrupting chemicals, DDT and DDE are still ubiquitous in the environment. However, little attention has been directed to p,p'-DDT and the anti-androgen, p,p'-DDE on androgen receptor (AR) target gene transcription in human cells. Inhibitors of androgenic activity may have a deleterious clinical outcome in prostate cancer screens and progression, therefore we determined whether environmentally relevant concentrations of p,p'-DDT and p,p'-DDE negatively impact AR-regulated expression of prostate-specific antigen (PSA), and other AR target genes in human LNCaP and VCaP prostate cancer cells. Quantitative real-time PCR and immuno-blotting techniques were used to measure intracellular PSA, PSMA and AR mRNA and protein levels. We have shown for the first time that p,p'-DDT and p,p'-DDE repressed R1881-inducible PSA mRNA and protein levels in a dose-dependent manner. Additi...

The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer

by Michael Cox and Naokazu Ibuki

Molecular cancer therapeutics, 2014

Insulin-like growth factor (IGF) signaling is associated with castrate-resistant prostate cancer ... more Insulin-like growth factor (IGF) signaling is associated with castrate-resistant prostate cancer (CRPC) progression. Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from IGF1 receptor (IGF1R), insulin receptor, and other oncoproteins. This study demonstrates that IRS1/2 expression is increased in prostate cancer, and persists in CRPC. Furthermore, this study assesses the anticancer activity of NT157, a small molecule tyrphostin targeting IRS proteins, using androgen-responsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. NT157 treatment resulted in dose-dependent inhibition of IGF1R activation, suppression of IRS protein expression, inhibition of IGF1-induced AKT activation, but increased ERK activation in NT157-treated cells in vitro. These effects were correlated with decreased proliferation and increasing apoptosis of LNCaP cells and increasing G2-M arrest in PC3 cells. NT157 also suppressed androgen-respons...

Download

Species-specific antagonism of Ah receptor action by 2,2',5,5'-tetrachloro- and 2,2',3,3'4,4'-hexachlorobiphenyl

European journal of pharmacology, Jan 7, 1995

Using recombinant cell lines showing Ah receptor-controlled expression of a luciferase reporter g... more Using recombinant cell lines showing Ah receptor-controlled expression of a luciferase reporter gene, the interaction of di-ortho-substitute polychlorinated biphenyls (PCBs) with Ah receptor agonists was studied. In the recombinant Hepa1c1c7 mouse hepatoma (H1L1.1c7) cells strong antagonistic interaction of 2,2',5,5'-tetrachlorobiphenyl (PCB52) with luciferase expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3',4,4'-tetrachlorobiphenyl (PCB77) was observed, and similarly, between 2,2',3,3',4,4'-hexachlorobiphenyl (PCB128) and PCB77. Accordingly, PCB52 was found to inhibit ethoxyresorufin-O-deethylase (EROD) induction by PCB77 in wild-type Hepa1c1c7 cells. In contrast, the antagonistic effect of PCB52 on TCDD-induced luciferase expression was only minor in recombinant guinea pig GPC16 colon adenocarcinoma (G16L1.1c8) and human HepG2 hepatoma (HG2L1.1c3) cells, and intermediate in recombinant H4IIE rat hepatoma (H4L1.1c4) cells. Gel ret...

Wavelength conversion based on cross-phase modulation in a semiconductor Mach-Zehnder modulator

OFC 2001. Optical Fiber Communication Conference and Exhibit. Technical Digest Postconference Edition (IEEE Cat. 01CH37171), 2001

Wavelength converters are key components for future advanced optical networks, and several techno... more

440 Effects of bispecific antisense oligonucleotide targeting both insulin-like growth factor binding proteins 2 and 5 on cell survival and apoptosis in prostate cancer model

EJC Supplements

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

Cancer research, 2003

Activation of alternative growth factor pathways after androgen withdrawal is one mechanism media... more 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 pro...

Download

Emergence of Collective Action in a Groundwater Commons: Irrigators in the San Luis Valley of Colorado

Society & Natural Resources, 2015

Under what conditions are irrigators able to develop adaptive governance arrangements? This paper... more Under what conditions are irrigators able to develop adaptive governance arrangements? This paper addresses this question by developing an empirically-grounded theory of self-governance of a snowmelt commons in Southern Colorado. Drawing on previous work in collective action and institutional theory, we argue that self-regulation of the hydro-commons is driven by changes in shared user perceptions with regards to the salience and scarcity of the resource, as well as the perceived probability of salvaging the resource system. We further posit that several conditioning factors affect the likelihood of effective local responses, including the existing institutional arrangements for self-governance, techno-institutional complementarities, and vested interests. We test and refine our theoretical argument by conducting a historical analysis of regional responses to hydrologic, social, and institutional disturbances in Colorado's San Luis Valley.

Download

Results from the MAST spherical tokamak

Proceedings of the 19th IEEE/IPSS Symposium on Fusion Engineering. 19th SOFE (Cat. No.02CH37231), 2002

... P. G. Carolan, D. Ciric, NJ Conway, M.Cox,GF Counsell, G. Cunningham, AC Darke, J. Dowling, M... more

A TRIP230-Retinoblastoma Protein Complex Regulates Hypoxia-Inducible Factor-1α-Mediated Transcription and Cancer Cell Invasion

PLoS ONE, 2014

Localized hypoxia in solid tumors activates transcriptional programs that promote the metastatic ... more Localized hypoxia in solid tumors activates transcriptional programs that promote the metastatic transformation of cells. Like hypoxia-inducible hyper-vascularization, loss of the retinoblastoma protein (Rb) is a trait common to advanced stages of tumor progression in many metastatic cancers. However, no link between the role of Rb and hypoxia-driven metastatic processes has been established. We demonstrated that Rb is a key mediator of the hypoxic response mediated by HIF1a/b, the master regulator of the hypoxia response, and its essential co-activator, the thyroid hormone receptor/retinoblastomainteracting protein (TRIP230). Furthermore, loss of Rb unmasks the full co-activation potential of TRIP230. Using small inhibitory RNA approaches in vivo, we established that Rb attenuates the normal physiological response to hypoxia by HIF1a. Notably, loss of Rb results in hypoxia-dependent biochemical changes that promote acquisition of an invasive phenotype in MCF7 breast cancer cells. In addition, Rb is present in HIF1a-ARNT/HIF1b transcriptional complexes associated with TRIP230 as determined by co-immuno-precipitation, GST-pull-down and ChIP assays. These results demonstrate that Rb is a negative modulator of hypoxia-regulated transcription by virtue of its direct effects on the HIF1 complex. This work represents the first link between the functional ablation of Rb in tumor cells and HIF1a-dependent transcriptional activation and invasion.

Download

Comprehensive expression analysis of l-dopa decarboxylase and established neuroendocrine markers in neoadjuvant hormone-treated versus varying Gleason grade prostate tumors

Human Pathology, 2007

Current hormone withdrawal therapies used for treatment of advanced prostate cancer lead to andro... more Current hormone withdrawal therapies used for treatment of advanced prostate cancer lead to androgen-independent tumor growth. Increased prostatic neuroendocrine (NE) cell density has been implicated in promoting progression of prostate cancer, but the process by which this occurs remains unclear. The aim of this study was to determine whether there is an association of increased NE differentiation with neoadjuvant hormone therapy and Gleason grade. Using adjacently sectioned tissue microarrays, the expression profile of novel and known NE markers were monitored. l-Dopa decarboxylase (DDC), a catecholamine synthesis enzyme and androgen receptor (AR) coregulator protein, was identified as an additional NE marker of prostate cancer. Immunohistochemical analysis of DDC with the established NE markers, chromogranin A and bombesin, revealed a significant increase in NE differentiation after 6 months of hormone therapy and after progression to androgen independence but no apparent correlation with Gleason grade. In addition, dual immunofluorescence analysis revealed that approximately 55% of the mixed population of DDC-and chromogranin A-expressing NE cells continue to express AR. Taken together, these results suggest that the increase of NE differentiation in prostate cancers depends specifically on duration of hormone therapy. This increase may be due to the transdifferentiation of AR-expressing epithelial-derived adenocarcinoma cells into an NE cell phenotype. D

Download

Uploads

Papers by Michael Cox

Log In