Search PubMed⌕ Search

Biomedical subjects

D Robinson

Publications and source records attributed to D Robinson.

At least 163 records · Page 9Linked to original sources
PubMed1998

Altered expression of RET proto-oncogene product in prostatic intraepithelial neoplasia and prostate cancer.

BACKGROUND: The RET proto-oncogene encodes a protein that belongs to the tyrosine kinase growth factor receptor family. Germline point mutations in RET are found in individuals with multiple endocrine neoplasia (MEN) syndromes, and gene rearrangements have been reported in papillary thyroid cancers. We recently identified transcripts of the RET proto-oncogene in human prostate cancer xenografts and prostate cancer cell lines by means of reverse transcription-polymerase chain reaction analyses. The purpose of this study was to investigate Ret protein expression in human prostate tissue. METHODS: Ret protein expression was evaluated immunohistochemically in formalin-fixed, paraffin-embedded whole-prostate sections. The prostate specimens were obtained from 30 patients with prostate cancer after radical prostatectomies. Ret protein expression was compared in tumor foci and benign prostatic tissue. Medullary thyroid carcinoma tissue associated with an MEN syndrome and papillary thyroid cancer tissue served as positive controls. RESULTS: Ret appeared to be overexpressed in high-grade (histopathologically advanced) prostatic intraepithelial neoplasia (PIN) and prostate cancer when compared with its expression level in benign prostatic secretory epithelium. In addition, there was an apparent increase in Ret protein expression with decreased cellular differentiation, i.e., increasing Gleason pattern. CONCLUSION: Expression of the RET proto-oncogene in benign prostatic epithelium, high-grade PIN, and histopathologically advanced prostate cancer suggests that RET may play a role in the growth of both benign and neoplastic prostate epithelial cells.

Drosophila Proteins↗
PubMed1998

Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells.

Etk/Bmx is the newest member of Btk tyrosine kinase family that contains a pleckstrin homology domain, an src homology 3 domain, an src homology 2 domain, and a catalytic domain. Unlike other members of the Btk family kinases, which are mostly hemopoietic cell-specific, Etk/Bmx is preferentially expressed in epithelial and endothelial cells. We first identified this kinase in prostate cancer [Robinson, D., He, F., Pretlow, T. & Kung, H. J. (1996) Proc. Natl. Acad. Sci. USA 93, 5958-5962). Here we report that Etk is engaged in phosphatidylinositol 3-kinase (PI3-kinase) pathway and plays a pivotal role in interleukin 6 (IL-6) signaling in a prostate cancer cell line, LNCaP. Our evidence that PI3-kinase is involved in Etk activation includes: (i) Wortmannin, a specific inhibitor of PI3-kinase, abolished the activation of Etk by IL-6; (ii) a constitutively active p110 subunit of PI3-kinase was able to activate Etk in the absence of IL-6; and (iii) a dominant negative p85 subunit of PI3-kinase mutant blocked the activation of Etk by IL-6. Interestingly, IL-6 treatment of LNCaP induced a remarkable neuroendocrine-like differentiation phenotype, with neurite extension and enhanced expression of neuronal markers. This phenotype could be abrogated by the overexpression of a dominant-negative Etk, indicating Etk is required for this differentiation process.

Amino Acid Sequence↗
PubMed1998

IL-1 alpha and TNF-alpha are required for IL-12-induced development of Th1 cells producing high levels of IFN-gamma in BALB/c but not C57BL/6 mice.

The development of Th1- or Th2-type responses determines the type of immune response that is elicited in response to Ag. Responsiveness to IL-12 is critical for the development of Th1-type CD4+ T cells required for cell-mediated immune responses. Addition of IL-12 to primary cultures of CD4+ T cells stimulated with OVA and splenocytes or dendritic cells resulted in the development of a Th1 phenotype with the capacity to secrete high levels of IFN-gamma upon restimulation with splenic APC. The present study shows that using dendritic cells to present Ag upon restimulation reveals a requirement for additional cofactors, including IL-1 alpha and TNF-alpha, which were provided by spleen cells but not dendritic cells. Furthermore, these cofactors are required for optimal IL-12-induced Th1 development in BALB/c but not C57BL/6 mice. This differential requirement for such cofactors in IL-12-driven Th1 development may play a role in genetic predisposition to Th1 or Th2 responses to infectious agents.

Adjuvants, Immunologic↗
PubMed1998

The effects of delayed hormone replacement therapy on estrogen receptors of the cynomolgus monkey bladder and vagina.

The aim of this study was to determine cytosolic estrogen receptor content of the cynomolgus monkey bladder and vagina after hormone replacement therapy. Animals maintained without hormone therapy for 2 years after surgical menopause were randomized to receive either no hormones (OVX), conjugated equine estrogens (CEE), or estrogen/medroxyprogesterone acetate (CEE + MPA) treatment for 30 months. Estrogen receptor content of bladder and vagina cytosolic extracts was determined using a commercial enzyme-linked immunosorbent assay. Estrogen receptors were uniformly present, although the vaginal concentration was 100-fold greater than in the bladder. Estrogen and combination therapy significantly decreased cytosolic receptor content in both sites compared with controls. The cynomolgus urogenital tract remains estrogen sensitive 2 years after surgical menopause. Prolonged exposure to estrogens decreases cytosolic estrogen receptor content in a manner similar to that described for short-term estrogen therapy. These results suggest that the effects of hormone replacement on the urinary tract can be identified even if initiated years after menopause.

Animals↗
PubMed1998

Molecular profiling of tyrosine kinases in normal and cancer cells.

As the post-genome era is approaching, with vast amount of sequence information available and new technology developed, scientists are presented with opportunities to explore in simple analysis the structure and expression pattern of not just a single gene, but of an entire family of genes, if not the entire genome. The concept of 'molecular profiling' or 'expression array' has thus emerged. The need to simultaneously 'see' all genes in the same family is obvious under the precept of the combinatorial process being an underlying principle of complex biological systems: no gene exists in isolation, for virtually every molecule participates in intermolecular interactions. The activation of receptor tyrosine kinases through homo or hetero-dimerization is the prototypic example. In this review, a tyrosine kinase profile technique and its application to studying the expression of tyrosine kinases and the identification of novel kinases will be discussed. This serves as an introduction to the several interesting papers published in this special 'kinase' issue of the Journal of Biomedical Sciences, using this technique. A new simplified approach, kinase display, which is an extension of the profiling method and requires only restriction digestion and gel analysis will also be introduced.

Gene Expression↗
PubMed1998

Digital cloning: identification of human cDNAs homologous to novel kinases through expressed sequence tag database searching.

Identification of novel kinases based on their sequence conservation within kinase catalytic domain has relied so far on two major approaches, low-stringency hybridization of cDNA libraries, and PCR method using degenerate primers. Both of these approaches at times are technically difficult and time-consuming. We have developed a procedure that can significantly reduce the time and effort involved in searching for novel kinases and increase the sensitivity of the analysis. This procedure exploits the computer analysis of a vast resource of human cDNA sequences represented in the expressed sequence tag (EST) database. Seventeen novel human cDNA clones showing significant homology to serine/threonine kinases, including STE-20, CDK- and YAK-related family kinases, were identified by searching EST database. Further sequence analysis of these novel kinases obtained either directly from EST clones or from PCR-RACE products confirmed their identity as protein kinases. Given the rapid accumulation of the EST database and the advent of powerful computer analysis software, this approach provides a fast, sensitive, and economical way to identify novel kinases as well as other genes from EST database.

Amino Acid Sequence↗
PubMed1998

Tyrosine kinase expression profiles of chicken erythro-progenitor cells and oncogene-transformed erythroblasts.

Tyrosine kinases are implicated in the growth and differentiation of erythroid cells. Aberrant expression and structural alterations of certain tyrosine kinases, such as erbB and sea, are known to trigger erythroleukemia development. To facilitate our understanding of the signal transduction pathways involved in erythroid differentiation and leukemic transformation, we have applied a recently developed tyrosine kinase profile technique to identify the tyrosine kinases and some novel serine/threonine kinases expressed in normal chicken erythroid progenitor cells that respond to TGFalpha (TGFalpha-EB), and erythroblasts transformed by viruses encoding v-erbB (v-erbB-EB) and v-sea (v-sea-EB). Our results reveal that the non-receptor tyrosine kinases, Abl, Fyn, Lyn, Btk and Csk, are expressed in all three cell types. The expression level of Btk, a tyrosine kinase implicated in Bruton's syndrome, is exceptionally high in the erythroblastoid cell line 6C2, transformed by the v-erbB carrying avian erythroblastosis virus, AEV-ES4. We have also uncovered a new STE-20-related serine/threonine kinase, KFC, which is abundantly expressed in both the TGFalpha-stimulated erythroid progenitor cells and v-sea-transformed erythroblasts. Based on sequence homology of the kinase domain, KFC appears to be the first member of a new subfamily of STE-20-like kinases.

Amino Acid Sequence↗
PubMed1998

Protein-tyrosine kinase and protein-serine/threonine kinase expression in human gastric cancer cell lines.

Protein kinases play key roles in cellular functions. They are involved in many cellular functions including; signal transduction, cell cycle regulation, cell division, and cell differentiation. Alterations of protein kinase by gene amplification, mutation or viral factors often induce tumor formation and tumor progression toward malignancy. The identification and cloning of kinase genes can provide a better understanding of the mechanisms of tumorigenesis as well as diagnostic tools for tumor staging. In this study, we have used degenerated polymerase-chain-reaction primers according to the consensus catalytic domain motifs to amplify protein kinase genes (protein-tyrosine kinase, PTK, and protein-serine/threonine kinase, PSK) from human stomach cancer cells. Following amplification, the protein kinase molecules expressed in the gastric cancer cells were cloned into plasmid vectors for cloning and sequencing. Sequence analysis of polymerase-chain-reaction products resulted in the identification of 25 protein kinases, including two novel ones. Expression of several relevant PTK/PSK genes in gastric cancer cells and tissues was further substantiated by RT-PCR using gene-specific primers. The identification of protein kinases expressed or activated in the gastric cancer cells provide the framework to understand the oncogenic process of stomach cancer.

Amino Acid Sequence↗
PubMed1998

Relationship between patient reports of urinary incontinence symptoms and quality of life measures.

OBJECTIVE: To determine if patient reports of urinary incontinence symptoms can predict quality of life as measured by the short forms of the Incontinence Impact Questionnaire and the Urogenital Distress Inventory, two standardized, disease-specific instruments. METHODS: Telephone surveys were conducted of 384 community dwelling incontinent women, aged 60 years and older, who admitted to at least one episode of incontinence per week during the previous 3 months. Subjects were asked if they considered the incontinence a problem, as well as questions regarding volume and frequency of voids and urine loss. Each subject completed both standardized quality of life questionnaires. Responses to incontinence symptom questions were correlated with the standardized measures. RESULTS: The question, "Do you consider this accidental loss of urine a problem that interferes with your day-to-day activities or bothers you in other ways?" was the best predictor of the subject's responses to both quality-of-life measures, with a correlation coefficient of 0.69 for the Incontinence Impact Questionnaire and 0.67 for the Urogenital Distress Inventory. The patients' symptoms that best correlated with both quality of life measures and the report of bothersome incontinence were frequent episodes of incontinence (0.40-0.58), greater amounts of urine loss (0.26-0.54), and more frequent voids (0.24-0.41). CONCLUSION: Primary care practitioners may screen for problematic incontinence by asking if patients' incontinence is bothersome to them and by obtaining simple historic information on voiding and leaking patterns. These questions may provide an efficient tool to detect bothersome incontinence in older women.

Aged↗
PubMed1998

Pathophysiology of female lower urinary tract dysfunction.

Urinary incontinence is a disorder with widely varying severity, patient symptoms, and etiologies. Urine loss can be because of reversible or irreversible systemic disease, abnormalities of urine storage, or voiding phase disorders. The optimal work up of an individual incontinence may include evaluation of neurologic, muscular, and urogenital systems, as well as medical, pharmaceutical, environmental, and psychosocial issues.

Female↗
PubMed1998

Primary angiosarcomas of the chest wall and pleura.

Primary angiosarcomas of the chest wall and pleura are extremely rare and carry a dismal prognosis. Two cases are reported. One patient (case 1), presented with massive recurrent haemothorax, was found to have multifocal angiosarcoma of the pleura, treated with surgical de-bulking, chemical pleurodesis and chemotherapy, achieving control of the bleeding. She died 10 months later from complications related to chemotherapy. A full post-mortem examination confirmed this was a primary pleural angiosarcoma with no evidence of disease elsewhere. Another patient (case 2) with a large solitary angiosarcoma of the chest wall, discovered incidentally on a routine physical examination, was successfully treated with surgical excision and subsequent radical radiotherapy, remaining well 15 years post-operatively.

Adult↗
PubMed1998

In vivo properties of an in situ forming gel for parenteral delivery of macromolecular drugs.

PURPOSE: This study characterizes the in vivo properties of an in situ forming gel, comprising of IPC of water-soluble polymers, PMA and PEG, for sustained release of macromolecular drugs. METHODS: 40, 50, or 60% w/v formulations were injected subcutaneously in a rat model either alone, or containing model macromolecules, 3A2-ATG-psODN or REV-psODN, to (i) determine the approximate gelling and residence time of the gel at the site of injection (ii) assess the biological efficacy of the formulation using a MZ sleep time model and (iii) demonstrate specificity of the sequence and selectivity of the psODNs by measuring changes in microsomal enzyme levels and urine volumes. RESULTS: A sol to gel transition requires 15 min in vivo, and the 60% w/v IPC gel remains at the site of injection for up to 72 hr. The MZ sleep times and CYP3A2 expression due to 3A2-ATG-psODNs released from the gel are significantly different compared to that of REV-psODNs. CONCLUSIONS: The IPC solutions exhibit phase transformation in vivo. and demonstrate no evidence of toxicity. The pharmacological effects observed from the of release of 3A2-ATG-psODNs suggest that the formulation can entrap, protect, and sustain the delivery of macromolecules. .

Animals↗
PubMed1998

The quality of life of older adults with urinary incontinence: determining generic and condition-specific predictors.

Urinary incontinence (UI) is an unpleasant problem for many adults. This study determined the importance of demographic, health and incontinence variables for the generic and incontinence-specific quality of life (QoL) of older adults (age > or = 60 years). Telephone surveys of adults reporting at least weekly episodes of UI (n = 435) were conducted as part of a randomized, controlled trial. Logistic regression analyses showed that the predictors of generic and incontinence-specific QoL differed. Life satisfaction, a generic outcome, was predicted by education, the number of days in bed due to health problems, the number of days not feeling well and the amount of urine lost. Generic health was related to education, the number of days sick in the previous 30 days and the number of days health issues restricted activities. The incontinence-specific QoL outcomes were predicted by age, mobility difficulties, the amount of urine lost, the frequency of UI, and the number of daytime and night-time voids. The specific QoL measures provide a different profile of those most affected in this sample than that obtained by the generic measures. The most affected are younger persons with severe urine loss. Older persons may have other conditions impinging on QoL and may have adapted behaviourally and psychologically to urine loss.

Aged↗
PubMed1998

Treatment of infected tunneled venous access hemodialysis catheters with guidewire exchange.

Cuffed venous access catheters have become commonplace for hemodialysis access. The major complications of these catheters are catheter thrombosis, catheter fibrin sheathing and infection. When catheter associated bacteremia occurs treatment with antimicrobial therapy alone has been unsuccessful in providing acceptable cure rates. Failed antimicrobial therapy exposes the patient to the risks of prolonged bacteremia, while the alternative, catheter replacement at a new site can lead to central venous stenosis and compromise future long-term upper extremity access. Catheter guidewire exchange when the tunnel tract is clinically not infected theoretically allows the preservation of future access sites and yields a higher treatment success rate while avoiding temporary non-cuffed access placement. We report a series of 23 cases of hemodialysis patients with tunneled cuffed catheters and bacteremia related to the catheter who were treated with the exchange of a new catheter over a guidewire combined with three weeks of systemic antibiotics. Patients eligible for the study required no evidence of tunnel tract infection and defervescence within 48 hours of antimicrobial therapy. Technique failure was defined as repeat infection from any organism within 90 days of catheter exchange. Four patients (18%) redeveloped bacteremia within 90 days of the exchange. The bacteremias developed at 4, 19, 63 and at 74 days days after the exchange. Guidewire exchange in combination with intravenous antibiotics in cases of catheter related bacteremia has an acceptable rate of treatment success and is a viable treatment option in a carefully selected patient population.

Bacteremia↗
PubMed1998

The development of treatment resistance in patients with schizophrenia: a clinical and pathophysiologic perspective.

The pathophysiologic process and clinical factors that contribute to the development of treatment resistance in schizophrenia are not well defined. This article describes data indicating that treatment resistance may evolve over the course of the patients' illness and maturational development. Data from multiepisode patients suggest that early effective intervention with clozapine can prevent treatment resistance. Early identification of patients with signs of treatment resistance is vital. Treatments must be effective and prevent relapse. At the first indication that a patient may be developing resistance (e.g., the emergence of extrapyramidal symptoms or increases in negative symptomatology) or may not be complying with treatment, clozapine therapy should be considered.

Animals↗
PubMed1998

Neutrophils stimulated with a variety of chemoattractants exhibit rapid activation of p21-activated kinases (Paks): separate signals are required for activation and inactivation of paks.

Activation of the p21-activated protein kinases (Paks) was compared in neutrophils stimulated with a wide variety of agonists that bind to receptors coupled to heterotrimeric G proteins. Neutrophils stimulated with sulfatide, a ligand for the L-selectin receptor, or the chemoattractant fMet-Leu-Phe (fMLP), platelet-activating factor, leukotriene B4, interleukin-8, or the chemokine RANTES exhibited a rapid and transient activation of the 63- and 69-kDa Paks. These kinases exhibited maximal activation with each of these agonists within 15 s followed by significant inactivation at 3 min. In contrast, neutrophils treated with the chemoattractant and anaphylatoxin C5a exhibited a prolonged activation (>15 min) of these Paks even though the receptor for this ligand may activate the same overall population of complex G proteins as the fMLP receptor. Addition of fMLP to neutrophils already stimulated with C5a resulted in the inactivation of the 63- and 69-kDa Paks. Optimal activation of Paks could be observed at concentrations of these agonists that elicited only shape changes and chemotaxis in neutrophils. While all of the agonists listed above triggered quantitatively similar activation of the 63- and 69-kDa Paks, fMLP was far superior to the other stimuli in triggering activation of the c-Jun N-terminal kinase (JNK) and the p38 mitogen-activated protein kinase (MAPK). These data indicate that separate signals are required for activation and inactivation of Paks and that, in contrast to other cell types, activated Pak does not trigger activation of JNK or p38-MAPK in neutrophils. These results are consistent with the recent hypothesis that G-protein-coupled receptors may initiate signals independent of those transmitted by the alpha and betagamma subunits of complex G proteins.

Animals↗
PubMed1998

Treatment of staphylococcal septic arthritis in rabbits by systemic antibiotics and intra-articular corticosteroids.

OBJECTIVE: To assess the effect of intra-articular corticosteroids added to systemic antibiotics in experimental septic arthritis. METHODS: Rabbits were injected intra-articularly by Staphylococcus epidermidis. Rabbits received no additional treatment and served as control (group 1), were treated with systemic antibiotics (group 2), or treated with systemic antibiotics and intra-articular corticosteroids (group 3). After 15 days animals were killed and joint histopathological-histochemical parameters were assessed. RESULTS: All rabbits survived the experiment. The treated groups (2-3) had lower histological-histochemical scores in comparison with the untreated group (1). Group 3 had significantly lower scores in joint sections in comparison with group 2: (mean (SD) 6.5 (1.4) v 4.0 (1.0), p = 0.001 and 7.4 (2.6) v 4.2 (2.2), p = 0.01), because of lower damage expressed in clustering of chondrocytes, pannus formation, proteoglycan depletion, and synovitis. CONCLUSION: Addition of local corticosteroids to systemic antibiotics in septic arthritis seems to be harmless, and improves joint histological-histochemical parameters in this experimental setting.

Administration, Topical↗