Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between June 1982 and July 1990, 55 patients (41 with bladder cancers and 14 with renal pelvic or ureteral cancers) who had undergone radical extirpative surgery and/or node dissection for pathological stage pT2-4 and/or nodal disease received adjuvant chemotherapy consisting of cisplatin alone or in combination with other agents. In all, 26 of the bladder-cancer patients also received preoperative chemotherapy consisting of arterial infusion of cisplatin, mitomycin C, and Adriamycin. Adjuvant chemotherapy was performed according to the following protocol. Between June 1982 and July 1987, 30-50 mg/m2 cisplatin either alone or in combination with Adriamycin and 5-fluorouracil (CAF) was given to 35 patients in an induction and maintenance setting for 1 year. After July 1987, short-course cisplatin (70 mg/m2) or cisplatin, etoposide, and Adriamycin combination chemotherapy (CVA) was given to 20 patients. Of the 55 patients, 38 are alive and show no evidence of disease, three are alive with disease, 13 have died of their disease, and 1 has died of an unrelated cause. The 5-year survival of all patients was 65.1%. The survival of the 20 patients who were treated after July 1987 was better than that of the 35 patients who were treated before June 1987. Local recurrence and/or distant dissemination occurred in 16 patients, 13 of whom died of cancer progression. Nausea and vomiting and anorexia occurred in most patients during the administration of cisplatin. Mild to moderate myelosuppression developed in patients who received CAF or CVA combination chemotherapy. Although adjuvant chemotherapy combined with radical surgery seemed to be effective in cases with a pathological stage of pT3a or less, more intensive pre- or postoperative chemotherapy is needed to improve the poor prognosis of patients with deeply invasive uroepithelial cancer.
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PMID:Results of adjuvant chemotherapy for invasive uroepithelial cancer. 139 19

The ileal neobladder produces a completely detubularized, low pressure, high capacity reservoir constructed from ileum without any valves. Since April 1986, 161 patients underwent this type of surgery at our institution. Of these patients 141 underwent simultaneous radical cystectomy for bladder cancer, and 20 received a bladder augmentation. The mean postoperative follow-up is 23.8 months with a range of 3-52 months. Perioperative mortality was 0.5 percent, 9.5 percent of the patients died later than 2 months postoperatively, 7.5 percent due to tumor progression, 2 percent because of pneumonia, severe metabolic acidosis, myocardial infarction and apoplexy. Day and night continence was preserved in 78% of all patients; severe stress incontinence was found in 4.2 percent of the patients and night time incontinence needing some external device in 7.7%. 10 percent with mild stress incontinence do not require further treatment. Our experience with this relatively simple procedure is excellent: the need for reoperation is low and the high reservoir capacity results in early continence in most cases. This concept offers a genuine alternative to any form of cutaneous urinary diversion with an incidence of complications not higher than after standard supravesical urinary diversion.
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PMID:The ileal neobladder. 205 41

Hypoxia occurs to a variable extent in a vast majority of rodent and human solid tumors. It results from an inadequate and disorganized tumor vasculature, and hence an impaired oxygen delivery. A probe for the non-invasive detection of tumor hypoxia could find important utility in the selection of patients for therapy with bioreductive agents, anti-angiogenic/anti-vascular therapies and hypoxia-targeted gene therapy. In addition, tumor hypoxia has been shown to predict for treatment outcome following radio- or chemotherapy in human cancers, the underlying mechanism for which may involve hypoxia driving genetic instability and resulting tumor progression. Beyond oncology, utility can also be envisaged in stroke, ischemic heart disease, peripheral vascular disease, arthritis and other disorders. Design, validation, preclinical development and current status of a fluorinated 2-nitroimidazole, N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-l-imidazolyl) acetamide (SR 4554, CRC 94/17), which has been rationally designed for the measurement of tumor hypoxia by magnetic resonance spectroscopy (MRS) and imaging (MRI), are reviewed. Application in positron emission tomography (PET) detection is also proposed. Design goals were: (i) a nitro group with appropriate redox potential for selective reduction and binding in hypoxic tumor cells; (ii) hydrophilic/hydrogen bonding character in the side chain to limit nervous tissue penetration and prevent neurotoxicity; and (iii) three equivalent fluorine atoms to enhance MRS/MRI detection, located in a metabolically stable position. Reduction of SR 4554 by mouse liver microsomes was dependent on oxygen content, with a half-maximal inhibition at 0.48 +/- 0.06%. SR 4554 underwent nitroreduction by hypoxic but not oxic tumor cells in vitro and electron energy loss spectroscopic analysis showed selective retention in the hypoxic regions of multicellular tumor spheroids. Pharmacokinetic design goals were met. In particular, low brain tissue concentrations were seen in contrast to excellent tumor levels, as measured by high performance liquid chromatography. The extent of this restricted entry to brain tumor was surprising given the overall octanol/water partition coefficient and was attributed to the hydrophilic/hydrogen bonding character of the side chain. Quantitative MRS was used to assess the retention of 19F signal in murine tumors and human tumor xenografts. The 19F retention index (FRI; ratio of 19F signal levels at 6 h relative to that at 45 min) ranged from 0.5 to 1.0 and 0.2 to 0.9 for murine tumors and human xenografts respectively. The correlation between SR 4554 retention and pO2 was not a linear one, but when FRI was > 0.5, the % pO2 < or = 5 mmHg was always > 60%, indicating that high FRI was associated with low levels of oxygenation. Finally, whole body 19F-MRI in mice demonstrated that SR 4554 and related metabolites localized mainly in tumor, liver and bladder regions. A selective MRS signal was readily detectable in tumors at doses at least 7-fold lower than those likely to cause toxicity in mice. We conclude that proof of principle is established for the use of SR 4554 as a non-invasive MRS/MRI probe for the detection of tumor hypoxia. Based on these promising studies, SR 4554 has been selected for clinical development.
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PMID:Preclinical development and current status of the fluorinated 2-nitroimidazole hypoxia probe N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR 4554, CRC 94/17): a non-invasive diagnostic probe for the measurement of tumor hypoxia by magnetic resonance spectroscopy and imaging, and by positron emission tomography. 975 26

Intraoperative radiotherapy (IORT) is a new concept in the treatment of recurrent and primary advanced colorectal tumors. Between October 1994 and December 1997 27 patients (primary tumor: 8, first recurrent tumor: 12, second recurrent tumor: 7) received IORT (32 applications). Chemotherapy and percutaneous radiotherapy had already been given to all patients with advanced and recurrent colorectal tumors. The intraoperative irradiation was performed through HDR iridium afterloading. A flexible flab--individually adapted to the "tumor bed"--was used as applicator. The contact dose ranged from 10 to 15 Gy. The mean operation time (rectum resection: 5, rectum amputation: 14, debulking: 8) increased by 30 min on average. Eight patients had postoperative complications: perianal wound infections (3), sacrovesical fistulas (3), leakage of anastomosis (1) and neural ureter dysfunction (1). To date--on average 17.1 months (range: 3-33) after operation--13 patients are free of tumor recurrence or show stable disease. Ten patients--all of them had macroscopic residual tumor--have local tumor progression combined with good quality of life. Only 4 patients died (acute kidney failure, stroke, marasmus, systemic progression). The afterloading flab technique represents a technically simple, minimally harmful procedure in the therapy of colorectal tumor. Even when IORT with electrons is not feasible or the patients have already been irradiated, a higher radiation dose is possible. Given the demonstrated rate of local tumor recurrence, the afterloading flab technique seems to be a valuable treatment alternative to extended, high-risk resections. Long-term follow-ups will be necessary.
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PMID:[In Process Citation] 1006 22

Chemokines are a family of proteins associated with the trafficking of leukocytes in physiological immune surveillance and inflammatory cell recruitment in host defence. They are classified into four classes based on the positions of key cystiene residues: C, CC, CXC, and CX3C. Chemokines act through both specific and shared receptors that all belong to the superfamily of G-protein-coupled receptors. Besides their well-established role in the immune system, several recent reports have demonstrated that these proteins also play a role in the central nervous system (CNS). In the CNS, chemokines are constitutively expressed by microglial cells, astrocytes, and neurons, and their expression can be increased after induction with inflammatory mediators. Constitutive expression of chemokines and chemokine receptors has been observed in both developing and adult brains, and the role played by these proteins in the normal brain is the object of intense study by many research groups. Chemokines are involved in brain development and in the maintenance of normal brain homeostasis; these proteins play a role in the migration, differentiation, and proliferation of glial and neuronal cells. The chemokine stromal cell-derived factor 1 and its receptor, CXCR4, are essential for life during development, and this ligand-receptor pair has been shown to have a fundamental role in neuron migration during cerebellar formation. Chemokine and chemokine receptor expression can be increased by inflammatory mediators, and this has in turn been associated with several acute and chronic inflammatory conditions. In the CNS, chemokines play an essential role in neuroinflammation as mediators of leukocyte infiltration. Their overexpression has been implicated in different neurological disorders, such as multiple sclerosis, trauma, stroke, Alzheimer's disease, tumor progression, and acquired immunodeficiency syndrome-associated dementia. An emerging area of interest for chemokine action is represented by the communication between the neuroendocrine and the immune system. Chemokines have hormone-like actions, specifically regulating the key host physiopathological responses of fever and appetite. It is now evident that chemokines and their receptors represent a plurifunctional family of proteins whose actions on the CNS are not restricted to neuroinflammation. These molecules constitute crucial regulators of cellular communication in physiological and developmental processes.
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PMID:Chemokines and their receptors in the central nervous system. 1145 67

The serine/threonine protein kinase PKB (also known as Akt) is thought to be a key mediator of signal transduction processes. The identification of PKB substrates and the role PKB phosphorylation plays in regulating these molecules have been a major focus of research in recent years. A recently developed motif-profile scoring algorithm that can be used to scan the genome for potential PKB substrates is therefore a useful tool, although additional considerations, such as the evolutionary conservation of the phosphorylation site, must also be taken into account. Recent evidence indicates that PKB plays a key role in cancer progression by stimulating cell proliferation and inhibiting apoptosis and is also probably a key mediator of insulin signalling. These findings indicate that PKB is likely to be a hot drug target for the treatment of cancer, diabetes and stroke. There are, however, a number of pitfalls of methodologies currently employed to study PKB function, and therefore caution should be used in interpretation of such experiments.
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PMID:PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? 1168 94

We present an unusual case of rapid onset of vitiligo heralding blindness due to pituitary apoplexy secondary to a non-secreting pituitary adenoma in a 49-year-old man. Deterioration in vision and skin condition coincided with tumor progression over 3 years. He subsequently died of acute lymphoblastic leukemia after pituitary radiation. The possible pathological associations between the 2 malignancies and vitiligo are discussed.
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PMID:Vitiligo as a paraneoplastic syndrome preceding pituitary adenoma and subsequent acute lymphoblastic leukemia. 1537 Feb 25

The immunoglobulin superfamily member CD147 plays an important role in fetal, neuronal, lymphocyte and extracellular matrix development. Here we review the current understanding of CD147 expression and protein interactions with regard to CD147 function and its role in pathologic conditions including heart disease, Alzheimer's disease, stroke and cancer. A model linking hypoxic conditions found within the tumor microenvironment to upregulation of CD147 expression and tumor progression is introduced.
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PMID:CD147 immunoglobulin superfamily receptor function and role in pathology. 1794 11

G protein-coupled receptors (GPCRs) are important targets for medicinal agents. Four different G protein families, G(s), G(i), G(q), and G(12), engage in their linkage to activation of receptor-specific signal transduction pathways. G(12) proteins were more recently studied, and upon activation by GPCRs they mediate activation of RhoGTPase guanine nucleotide exchange factors (RhoGEFs), which in turn activate the small GTPase RhoA. RhoA is involved in many cellular and physiological aspects, and a dysfunction of the G(12/13)-Rho pathway can lead to hypertension, cardiovascular diseases, stroke, impaired wound healing and immune cell functions, cancer progression and metastasis, or asthma. In this study, regulator of G protein signaling (RGS) domain-containing RhoGEFs were tagged with enhanced green fluorescent protein (EGFP) to detect their subcellular localization and translocation upon receptor activation. Constitutively active Galpha(12) and Galpha(13) mutants induced redistribution of these RhoGEFs from the cytosol to the plasma membrane. Furthermore, a pronounced and rapid translocation of p115-RhoGEF from the cytosol to the plasma membrane was observed upon activation of several G(12/13)-coupled GPCRs in a cell type-independent fashion. Plasma membrane translocation of p115-RhoGEF stimulated by a GPCR agonist could be completely and rapidly reversed by subsequent application of an antagonist for the respective GPCR, that is, p115-RhoGEF relocated back to the cytosol. The translocation of RhoGEF by G(12/13)-linked GPCRs can be quantified and therefore used for pharmacological studies of the pathway, and to discover active compounds in a G(12/13)-related disease context.
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PMID:Reversible translocation of p115-RhoGEF by G(12/13)-coupled receptors. 1832 May 79

Hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxia-inducible genes involved in the mediation of survival and adaptive responses to insufficient oxygen availability, such as genes involved in hematopoesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumor progression. The stability of the HIFalpha subunit is regulated by oxygen-dependent prolyl 4-hydroxylation catalyzed by the HIF prolyl 4-hydroxylases (P4Hs). The 4-hydroxyproline residues generated in normoxic conditions facilitate binding of HIFalpha to the von Hippel-Lindau E3 ubiquitin ligase complex resulting in the attachment of ubiquitin molecules and subsequent rapid proteasomal degradation of HIFalpha. In hypoxia this oxygen-requiring hydroxylation event is inhibited, HIFalpha escapes degradation and can translocate to the nucleus and form a functional dimer with HIFbeta that triggers the hypoxic response. HIF-P4Hs are considered as promising drug development targets in the treatment of diseases such as myocardial infarction, stroke, peripheral vascular disease, inflammation, diabetes and severe anemias. Studies with HIF-P4H inhibitors in various animal models and ongoing clinical trials support this hypothesis by demonstrating efficacy in many applications.
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PMID:HIF prolyl 4-hydroxylases and their potential as drug targets. 1967 Oct 43


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