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Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. | ate insulin secretion via anaplerosis; evidence is just emerging about the possible extramitochondrial roles of exported citric acid cycle intermediates. This article speculates on their potential roles as signaling molecules themselves and as exporters of equivalents of NADPH; acetyl-CoA and malonyl-CoA; as well as alpha-ketoglutarate as a substrate for hydroxylases. We also discuss the "succinate mechanism;" which hypothesizes that insulin secretagogues produce both NADPH and mevalonate. Finally; we discu | 15585595 | [
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Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. | ss the role of mitochondria in causing oscillations in beta-cell citrate levels. These parallel oscillations in ATP and NAD(P)H. Oscillations in beta-cell plasma membrane electrical potential; ATP/ADP and NAD(P)/NAD(P)H ratios; and glycolytic flux are known to correlate with pulsatile insulin release. Citrate oscillations might synchronize oscillations of individual mitochondria with one another and mitochondrial oscillations with oscillations in glycolysis and; therefore; with flux of pyruvate into mitocho | 15585595 | [
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Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. | ndria. Thus citrate oscillations may synchronize mitochondrial ATP production and anaplerosis with other cellular oscillations. | 15585595 | [
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Beta-cell CaV channel regulation in physiology and pathophysiology. | The beta-cell is equipped with at least six voltage-gated Ca2+ (CaV) channel alpha1-subunits designated CaV1.2; CaV1.3; CaV2.1; CaV2.2; CaV2.3; and CaV3.1. These principal subunits; together with certain auxiliary subunits; assemble into different types of CaV channels conducting L-; P/Q-; N-; R-; and T-type Ca2+ currents; respectively. The beta-cell shares customary mechanisms of CaV channel regulation with other excitable cells; such as protein phosphorylation; Ca2+-dependent inactivation; and G protein m | 15585596 | [
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Beta-cell CaV channel regulation in physiology and pathophysiology. | odulation. However; the beta-cell displays some characteristic features to bring these mechanisms into play. In islet beta-cells; CaV channels can be highly phosphorylated under basal conditions and thus marginally respond to further phosphorylation. In beta-cell lines; CaV channels can be surrounded by tonically activated protein phosphatases dominating over protein kinases; thus their activity is dramatically enhanced by inhibition of protein phosphatases. During the last 10 years; we have revealed some n | 15585596 | [
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Beta-cell CaV channel regulation in physiology and pathophysiology. | ovel mechanisms of beta-cell CaV channel regulation under physiological and pathophysiological conditions; including the involvement of exocytotic proteins; inositol hexakisphosphate; and type 1 diabetic serum. This minireview highlights characteristic features of customary mechanisms of CaV channel regulation in beta-cells and also reviews our studies on newly identified mechanisms of beta-cell CaV channel regulation. | 15585596 | [
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Maternal smoking is associated with mitochondrial DNA depletion and respiratory chain complex III deficiency in placenta. | Maternal smoking during pregnancy is often associated with a decrease in placental function; which might lead to intrauterine growth retardation. Because tobacco is known to alter the mitochondrial respiratory function in cardiomyocytes and lung tissue; we hypothesized that placental mitochondrial function could be altered by maternal smoking. Placental mitochondria from 9 smoking and 19 nonsmoking mothers were isolated by differential centrifugation. Mitochondrial oxygen consumption was measured by polarog | 15585597 | [
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Maternal smoking is associated with mitochondrial DNA depletion and respiratory chain complex III deficiency in placenta. | raphy; and the enzymatic activity of each complex of the electron transport chain was assessed by spectrophotometry. In addition; the relative content in mitochondrial DNA (mtDNA) was determined by real-time quantitative PCR in placentas from seven smoking and seven nonsmoking mothers. We observed a 29% reduction in the enzymatic activity of complex III in the placental mitochondria from smokers compared with nonsmokers (P = 0.03). The relative content of mtDNA (with respect to the beta-globin gene) was red | 15585597 | [
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Maternal smoking is associated with mitochondrial DNA depletion and respiratory chain complex III deficiency in placenta. | uced by 37% in the placental tissue from smokers compared with nonsmokers (P < 0.02). Both the enzymatic activity of complex III and mtDNA content were inversely related with the daily consumption of cigarettes; and mtDNA content was correlated with cord blood insulin-like growth factor-binding protein-3 (r = 0.74; P < 0.01); a marker of fetal growth. These results show that maternal smoking is associated with placental mitochondrial dysfunction; which might contribute to restricted fetal growth by limiting | 15585597 | [
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Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans. | Acute increases of the key counterregulatory hormone epinephrine can be modified by a number of physiological and pathological conditions in type 1 diabetic patients (T1DM). However; it is undecided whether the physiological effects of epinephrine are also reduced in T1DM. Therefore; the aim of this study was to determine whether target organ (liver; muscle; adipose tissue; pancreas; cardiovascular) responses to epinephrine differ between healthy subjects and T1DM patients. Thirty-four age- and weight-match | 15585598 | [
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Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans. | ed T1DM (n = 17) and healthy subjects (n = 17) underwent two randomized; single-blind; 2-h hyperinsulinemic euglycemic clamp studies with (Epi) and without epinephrine infusion. Muscle biopsy was performed at the end of each study. Epinephrine levels during Epi were similar in all groups (4;039 +/- 384 pmol/l). Glucose (5.3 +/- 0.06 mmol/l) and insulin levels (462 +/- 18 pmol/l) were also similar in all groups during the glucose clamps. Glucagon responses to Epi were absent in T1DM and significantly reduced | 15585598 | [
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Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans. | compared with healthy subjects. Endogenous glucose production during the final 30 min was significantly greater during Epi in healthy subjects compared with T1DM (8.4 +/- 1.3 vs. 4.4 +/- 0.6 micromol.kg(-1).min(-1); P = 0.041). Glucose uptake showed almost a twofold greater decrease with Epi in healthy subjects vs. T1DM (Delta31 +/- 2 vs. Delta17 +/- 2 nmol.kg(-1).min(-1); respectively; P = 0.026). Glycerol; beta-hydroxybutyrate; and nonesterified fatty acid (NEFA) all increased significantly more in T1DM | 15585598 | [
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Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans. | compared with healthy subjects. Increases in systolic blood pressure were greater in healthy subjects; but reductions of diastolic blood pressure were greater in T1DM patients with Epi. Reduction of glycogen synthase was significantly greater during epinephrine infusion in T1DM vs. healthy subjects. In summary; despite equivalent epinephrine; insulin; and glucose levels; changes in glucose flux; glucagon; and cardiovascular responses were greater in healthy subjects compared with T1DM. However; T1DM patient | 15585598 | [
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Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans. | s had greater lipolytic responses (glycerol and NEFA) during Epi. Thus we conclude that there is a spectrum of significant in vivo physiological differences of epinephrine action at the liver; muscle; adipose tissue; pancreas; and cardiovascular system between T1DM and healthy subjects. | 15585598 | [
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Regulation of regional expression in rat brain PC2 by thyroid hormone/characterization of novel negative thyroid hormone response elements in the PC2 promoter. | The prohormone convertases (PCs) PC1 and PC2 are involved in the tissue-specific endoproteolytic processing of neuropeptide precursors within the secretory pathway. We previously showed that changes in thyroid status altered pituitary PC2 mRNA and that this regulation was due to triiodothyronine-dependent interaction of the thyroid hormone receptor (TR) with negative thyroid hormone response elements (nTREs) contained in a large proximal region of the human PC2 promoter. In the current study; we examined th | 15585599 | [
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Regulation of regional expression in rat brain PC2 by thyroid hormone/characterization of novel negative thyroid hormone response elements in the PC2 promoter. | e in vivo regulation of brain PC2 mRNA by thyroid status and found that 6-n-propyl-2-thiouracil-induced hypothyroidism stimulated; whereas thyroxine-induced hyperthyroidism suppressed; PC2 mRNA levels in the rat hypothalamus and cerebral cortex. To address the mechanism of T3 regulation of the PC2 gene; we used human PC2 (hPC2) promoter constructs transiently transfected into GH3 cells and found that triiodothyronine negatively and 9-cis-retinoic acid positively regulated hPC2 promoter activity. EMSAs; usin | 15585599 | [
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Regulation of regional expression in rat brain PC2 by thyroid hormone/characterization of novel negative thyroid hormone response elements in the PC2 promoter. | g purified TRalpha1 and retinoid X receptor-beta (RXRbeta) proteins demonstrated that TRalpha bound the distal putative nTRE-containing oligonucleotide in the PC2 promoter; and RXR bound to both nTRE-containing oligonucleotides. EMSAs with oligonucleotides containing deletion mutations of the nTREs demonstrated that the binding to TR and RXR separately is reduced; but specific binding to TR and RXR together persists even with deletion of each putative nTRE. We conclude that there are two novel TRE-like sequ | 15585599 | [
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Regulation of regional expression in rat brain PC2 by thyroid hormone/characterization of novel negative thyroid hormone response elements in the PC2 promoter. | ences in the hPC2 promoter and that these regions act in concert in a unique manner to facilitate the effects of thyroid hormone and 9-cis-retinoic acid on PC2. | 15585599 | [
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Taurine replacement attenuates hyperalgesia and abnormal calcium signaling in sensory neurons of STZ-D rats. | The etiology of painful diabetic neuropathy is poorly understood; but may result from neuronal hyperexcitability secondary to alterations of Ca2+ signaling in sensory neurons. The naturally occurring amino acid taurine functions as an osmolyte; antioxidant; Ca2+ modulator; inhibitory neurotransmitter; and analgesic such that its depletion in diabetes may predispose one to neuronal hyperexcitability and pain. This study reports the effects of taurine replacement on hyperalgesia and sensory neuron Ca2+ homeos | 15585600 | [
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Taurine replacement attenuates hyperalgesia and abnormal calcium signaling in sensory neurons of STZ-D rats. | tasis in streptozotocin-diabetic (STZ-D) rats. Nondiabetic and STZ-D rats were treated with a 2% taurine-supplemented diet for 6-12 wk. Thermal hyperalgesia and mechanical allodynia were determined by measuring hindpaw withdrawal latency to radiant heat and the withdrawal threshold to the von Frey anesthesiometer. Intracellular Ca2+ signaling was explored in neurons from L4-L6 dorsal root ganglia (DRG); using fura 2 fluorescence. Taurine replacement of diabetic rats attenuated deficits of nerve conduction a | 15585600 | [
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Taurine replacement attenuates hyperalgesia and abnormal calcium signaling in sensory neurons of STZ-D rats. | nd prevented reductions of mechanical and thermal withdrawal threshold and latency; respectively. In small DRG sensory neurons from diabetic rats; recovery of intracellular Ca2+ concentration ([Ca2+]i) in response to KCl was slowed and 73% corrected by taurine. The amplitudes of caffeine and ATP-induced [Ca2+]i transients were decreased by 47 and 27% (P < 0.05); respectively; in diabetic rat DRG sensory neurons and corrected by 74 and 93% (P < 0.05); respectively; by taurine replacement. These data indicate | 15585600 | [
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Taurine replacement attenuates hyperalgesia and abnormal calcium signaling in sensory neurons of STZ-D rats. | that taurine is important in the regulation of neuronal Ca2+ signaling and that taurine deficiency may predispose one to nerve hyperexcitability and pain; complicating diabetes. | 15585600 | [
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Making sense: a scientific approach to intravenous iron therapy. | nan | 15585602 | [
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Structure, chemistry, and pharmacokinetics of intravenous iron agents. | nan | 15585603 | [
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Toll-like receptors in innate immunity. | Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways; which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors; such as MyD88; TIRAP/Mal; T | 15585605 | [
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Toll-like receptors in innate immunity. | RIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways; and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus; TLR-mediated activation of innate immunity controls not only host defense against | 15585605 | [
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Toll-like receptors in innate immunity. | pathogens but also immune disorders. | 15585605 | [
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Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart. | We have used mouse 27k cDNA arrays to compare gene expression patterns in four sets of three hearts each of neonatal wild types and four sets of three hearts each of littermates lacking the major cardiac gap junction protein; connexin43 (Cx43). Each individual set of hearts was hybridized against aliquots of an RNA standard prepared from selected mouse tissues; allowing calculation of variability and coordination of gene expression among the samples from both genotypes. Overall variance of gene expression w | 15585606 | [
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Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart. | as found to be markedly higher in wild-type hearts than in those from Cx43 null littermates. Expression levels of 586 of 5;613 adequately quantifiable distinct genes with known protein products were statistically altered in the Cx43 null hearts; 38 upregulated and 548 downregulated compared with wild types. Downregulation was confirmed for seven tested genes by quantitative RT-PCR. Functions of proteins encoded by the altered genes encompassed all functional categories; with largest percent changes in genes | 15585606 | [
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Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart. | involved in intracellular transport and transcription factors. Among the downregulated genes in the Cx43 null hearts were those related to neuronal and glial function; suggesting that cardiac innervation might be compromised as a consequence of Cx43 deletion. This was supported by immunodetection of sympathetic innervation; using antibodies to the synaptic vesicle protein synaptophysin and to the adrenergic nerve terminal marker tyrosine hydroxylase. These findings reinforce the proposal that the cardiac a | 15585606 | [
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Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart. | bnormality in Cx43 null animals may be contributed by altered innervation and indicate that Cx43 deletion has consequences in addition to reduced intercellular communication. | 15585606 | [
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Lifelong genetic minipumps. | Most physiologists working with animals are familiar with osmotic minipumps. These surgically implanted devices can; for a limited period; administer a reagent at a constant predetermined rate that is unaffected by concurrent procedures. The investigator can then test the physiological effects of other treatments knowing that the animals' homeostatic responses will not be able to alter the dose of the pumped reagent. To develop the genetic equivalent of a lifelong minipump; simply inherited as an autosomal | 15585607 | [
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Lifelong genetic minipumps. | dominant; we here combine three of our previously described strategies; genetic clamping; single-copy chosen-site integration; and modification of untranslated regions (UTRs). As a test of the procedure; we have generated a series of intrinsically useful animals having genetic minipumps secreting renin ectopically from the liver at levels controlled by the investigator but not subject to homeostatic changes. To achieve the different dosage levels of these genetic minipumps; we altered the UTRs of a renin tr | 15585607 | [
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Lifelong genetic minipumps. | ansgene driven by an albumin promoter and inserted it into the genome as a single copy at the ApoA1/ApoC3 locus; a locus that is strongly expressed in the liver. The resulting mice express plasma renin over ranges from near physiological to eightfold wild type and develop graded cardiovascular and kidney disease consequent to their different levels of ectopically secreted renin. The procedure and DNA constructs we describe can be used to generate genetic minipumps for controlling plasma levels of a wide var | 15585607 | [
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New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as P-glycoprotein inhibitors. | Efflux of cytotoxic agents mediated by P-glycoprotein is believed to be an important mechanism of multidrug resistance; which remains a serious limitation to successful chemotherapy in cancers such as metastatic breast cancer. A series of 4-aryl-1;4-dihydropyridines and corresponding aromatized 4-arylpyridines have been synthesized based on structure modifications of niguldipine to enhance multidrug resistance reversal activity; while minimizing calcium channel binding. Thirty new compounds were characteriz | 15585608 | [
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New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as P-glycoprotein inhibitors. | ed. [(3)H]Vinblastine accumulation studies indicated that at a concentration level of 3 muM; 15 of 18 4-aryl-1;4-dihydropyridines and all 4-arylpyridines can successfully restore intracellular accumulation of vinblastine in a resistant human breast adenocarcinoma cell line; MCF-7/adr; which overexpresses P-glycoprotein. The most potent compounds led to an approximately 15-fold increase of vinblastine accumulation. All of the test compounds that significantly increased vinblastine accumulation in MCF/adr cel | 15585608 | [
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New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as P-glycoprotein inhibitors. | ls were able to substantially reduce IC(50) values of daunomycin and increase its cytotoxicity in MCF-7/adr-resistant cells; confirming the results of the vinblastine accumulation studies. Calcium channel binding assays for these newly synthesized compounds were conducted using rat cerebral cortex membrane. All but eight compounds demonstrated negligible calcium channel binding over the concentration range from 15 to 2500 nM. The results demonstrate that the newly synthesized series of 1;4-dihydropyridines | 15585608 | [
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New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as P-glycoprotein inhibitors. | and pyridines represent P-glycoprotein modulators with negligible calcium channel blocking activity. | 15585608 | [
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Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: toxicity, clinical response, and immunological response to minor histocompatibility antigens. | This phase I trial assessed the safety; efficacy; and immunologic responses to minor histocompatibility antigens following nonmyeloablative allogeneic hematopoietic cell transplantation as treatment for metastatic renal cell carcinoma.Eight patients received conditioning with fludarabine and low-dose total body irradiation followed by hematopoietic cell transplantation from an HLA-matched sibling donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients we | 15585611 | [
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Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: toxicity, clinical response, and immunological response to minor histocompatibility antigens. | re monitored for donor engraftment of myeloid and lymphoid cells; for clinical response by serial imaging; and for immunologic response by in vitro isolation of donor-derived CD8(+) CTLs recognizing recipient minor histocompatibility (H) antigens.All patients achieved initial mixed hematopoietic chimerism with two patients rejecting their graft and recovering host hematopoiesis. Four patients developed acute; grade 2 to 3; graft-versus-host disease and four patients developed extensive chronic graft-versus- | 15585611 | [
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Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: toxicity, clinical response, and immunological response to minor histocompatibility antigens. | host disease. Five patients had progressive disease; two patients had stable disease; and one patient experienced a partial response after receiving donor lymphocyte infusions and IFN-alpha. CD8(+) CTL clones recognizing minor H antigens were isolated from five patients studied. Clones from three patients with a partial response or stable disease recognized antigens expressed on renal cell carcinoma tumor cells.Treatment of metastatic renal cell carcinoma with allogeneic hematopoietic cell transplantation a | 15585611 | [
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Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: toxicity, clinical response, and immunological response to minor histocompatibility antigens. | fter nonmyeloablative conditioning with fludarabine/total body irradiation is feasible and may induce tumor regression or stabilization in some patients. CD8(+) CTL-recognizing minor H antigens on tumor cells can be isolated posttransplant and could contribute to the graft-versus-tumor effect. Such antigens may represent therapeutic targets for posttransplant vaccination or adoptive T-cell therapy to augment the antitumor effects of allogeneic hematopoietic cell transplantation. | 15585611 | [
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The radioisotope contributes significantly to the activity of radioimmunotherapy. | A multicenter; randomized study was undertaken to estimate the single agent activity of Tositumomab and to determine the contribution of radioisotope-labeling with (131)I to activity and toxicity by comparing treatment outcomes for Tositumomab and Iodine I 131 Tositumomab (BEXXAR) to an equivalent total dose of unlabeled Tositumomab.Seventy-eight patients with refractory/relapsed non-Hodgkin's lymphoma were randomized to either unlabeled Tositumomab or Iodine I 131 Tositumomab. Patients progressing after un | 15585610 | [
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The radioisotope contributes significantly to the activity of radioimmunotherapy. | labeled Tositumomab could cross over to receive Iodine I 131 Tositumomab. The median follow-up at analysis was 42.6 months (range 1.9 to 71.5 months).Responses in the Iodine I 131 Tositumomab versus unlabeled Tositumomab groups: overall response 55% versus 19% (P = 0.002); complete response 33% versus 8% (P = 0.012); median duration of overall response not reached versus 28.1 months (95% confidence interval: 7.6; not reached); median duration of complete response not reached in either arm; and median TTP 6. | 15585610 | [
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The radioisotope contributes significantly to the activity of radioimmunotherapy. | 3 versus 5.5 months (P = 0.031); respectively. Of the patients who had a complete response after initial Iodine I 131 Tositumomab therapy; 71% (10 of 14) continued in complete response at 29.8 to 71.1 months. Two patients who achieved a complete response after unlabeled Tositumomab had ongoing responses at 48.1 to 56.9 months. Nineteen patients received Iodine I 131 Tositumomab crossover therapy. Responses after crossover versus prior response to unlabeled Tositumomab were as follows: complete response rate | 15585610 | [
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The radioisotope contributes significantly to the activity of radioimmunotherapy. | s of 42% versus 0% (P = 0.008); overall response 68% versus 16% (P = 0.002); median durations of overall response 12.6 versus 7.6 months (P = 0.001); and median TTP 12.4 versus 5.5 months (P = 0.01); respectively. Hematologic toxicity was more severe and nonhematologic adverse events were more frequent after Iodine I 131 Tositumomab than after Tositumomab alone. Elevated thyrotropin occurred in 5% of patients. Seroconversion to human antimurine antibody after Iodine I 131 Tositumomab; unlabeled Tositumomab; | 15585610 | [
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The radioisotope contributes significantly to the activity of radioimmunotherapy. | and Iodine I 131 Tositumomab-crossover was 27%; 19%; and 0%; respectively.Unlabeled Tositumomab showed single agent activity; but in this direct comparison; all of the therapeutic outcome measures were significantly enhanced by the conjugation of (131)I to Tositumomab. | 15585610 | [
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A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. | The epidermal growth factor receptor (EGFR) is overexpressed in 75 to 90% of renal cell carcinomas and may play a role in tumor initiation and progression. Gefitinib (Iressa; ZD1839) is a potent; selective EGFR-tyrosine kinase inhibitor. This trial was undertaken to assess the efficacy and toxicity of gefitinib in advanced renal cell carcinoma.Oral gefitinib; 500 mg once daily; was given continuously. A single-dose reduction to 250 mg daily was allowed for toxicity. The primary end point was response rate ( | 15585612 | [
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A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. | defined as complete remission + partial remission + stable disease). Secondary end points were progression-free survival; overall survival; toxicity; and correlation of response with EGFR status.Twenty-one patients were enrolled on this study; and all are evaluable for response and toxicity. Patient characteristics were median age 61 (range; 35-78 years); 17 males; 4 females; median performance status 0 (range 0-2); median number of prior systemic therapies 1 (range; 0-3). The median and mean number of cycl | 15585612 | [
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A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. | es of therapy received was 3 and 4.7 (range; 1-14+). The best response was stable disease in eight patients (38%). Median progression-free survival was 2.7 months. Median overall survival was 8.3 months. The difference in overall survival was significantly different between patients with progressive disease versus stable disease (6.1 months versus 16+ months; Log-Rank test P value < 0.0001). Three patients required a dose reduction; all for grade 3 diarrhea. There was no apparent correlation between EGFR st | 15585612 | [
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A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. | atus and stability of disease or progression of disease.Gefitinib is without significant conventional activity in renal cell carcinoma. The relation of "stable disease" to treatment or to disease-related prognostic heterogeneity remains to be defined. | 15585612 | [
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Molecular stratification of diagnostically challenging high-grade gliomas composed of small cells: the utility of fluorescence in situ hybridization. | There is considerable morphologic overlap between various entities of high-grade gliomas; and; therefore; a further planning of their optimal treatment is a controversial issue. The aim of this study was molecular stratification of morphologically ambiguous high-grade gliomas composed from small cells. Fluorescence in situ hybridization (FISH) with commercially available probes was used for this purpose.We analyzed a set of 114 high-grade small-cell gliomas that were difficult to interpret diagnostically be | 15585613 | [
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Molecular stratification of diagnostically challenging high-grade gliomas composed of small cells: the utility of fluorescence in situ hybridization. | cause of their distinct cytological origin. FISH assay with locus probes for EGFR; p16; PTEN; and 1p and 19q was done.Morphologically uniform high-grade gliomas composed of small cells varied greatly in terms of molecular features and clinical outcome. Four clinically relevant subsets of patients whose tumors showed distinctly different molecular profiles were identified as follows: (a) 13 patients whose tumors exhibited no discernable molecular alterations (5-year survival rate; 83%); (b) 20 patients whose | 15585613 | [
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Molecular stratification of diagnostically challenging high-grade gliomas composed of small cells: the utility of fluorescence in situ hybridization. | tumors harbored either 1p/19q codeletion or isolated deletion of 19q unaccompanied by other molecular abnormalities (5-year survival rate; 59%); (c) 35 patients whose tumors showed p16 and/or PTEN deletions unaccompanied by EGFR amplification (5-year survival rate; 8%); and (d) 46 patients whose tumors harbored EGFR amplification (5-year survival rate; 0).The FISH method provides clinically useful information in the molecular analysis of morphologically ambiguous malignant small-cell gliomas that could pot | 15585613 | [
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Targeting of HER2 antigen for the treatment of disseminated peritoneal disease. | The studies reported herein demonstrate the efficacy of alpha-particle-targeted radiation therapy of peritoneal disease with Herceptin as the targeting vehicle. Using the CHX-A-DTPA linker; Herceptin was radiolabeled with indium-111 and bismuth-213 with high efficiency without compromising immunoreactivity. A pilot radioimmunotherapy study treating mice bearing 5-day LS-174T (i.p.) xenografts; a low but uniform HER2 expressing; human colon carcinoma; with a single dose of (213)Bi-CHX-A"-Herceptin; proved di | 15585615 | [
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Targeting of HER2 antigen for the treatment of disseminated peritoneal disease. | sappointing. This defined the effect of tumor burden/size on tumor response to radioimmunotherapy with alpha-radiation. A more successful experiment with a lower tumor burden (3 days) in mice followed. A specific dose-response (P = 0.009) was observed; and although a maximum-tolerated dose was not determined; a dose of 500 to 750 muCi was selected as the operating dose for future experiments based on changes in animal weight. Median survival was increased from 20.5 days for the mock-treated mice to 43 and 5 | 15585615 | [
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Targeting of HER2 antigen for the treatment of disseminated peritoneal disease. | 9 days with 500 and 750 muCi; respectively. The therapeutic effectiveness of (213)Bi-CHX-A"-Herceptin was also evaluated in a second animal model for peritoneal disease with a human pancreatic carcinoma (Shaw). The results of this study were not as dramatic as with the former model; and higher doses were required to obtain an increase in survival of the mice (P = 0.001). | 15585615 | [
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Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients. | Despite improvements in locoregional treatment of head and neck squamous cell carcinoma (HNSCC); local and distant failure rates remain high. The strongest prognostic indicator of HNSCC is the presence of lymph node metastases in the neck; but the value of this indicator has limitations when using for the individual patient. The presence of micrometastatic cells in bone marrow has been shown to be a putative prognostic indicator in HNSCC and other epithelial malignancies; which might allow more accurate sta | 15585614 | [
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Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients. | ging and selection of patients for whom adjuvant or experimental therapy is recommended. The gene encoding the E48 antigen is selectively expressed by HNSCC; and the detection of E48 transcripts in bone marrow by reverse transcription-polymerase chain reaction (RT-PCR) presumably represents the presence of micrometastatic cells. The purpose of this study was to determine the association between the presence of micrometastatic cells in bone marrow of HNSCC patients and clinical outcome.A total of 162 patient | 15585614 | [
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Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients. | s treated surgically for primary HNSCC underwent a single bone marrow aspiration from the upper iliac crest for detection of micrometastatic cells using E48 RT-PCR. In total; 139 patients were evaluable. The primary statistical endpoints were disease-free survival and distant metastasis-free survival. In addition; bone marrow samples of 30 noncancer controls were evaluated.E48 RT-PCR indicated the presence of micrometastatic cells in the bone marrow in 56 of 139 (40%) of the HNSCC patients and 0 of 30 of th | 15585614 | [
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Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients. | e noncancer controls (P < 0.0001). The presence of micrometastatic cells had no significant influence on disease-free survival or distant metastasis-free survival for the whole group of HNSCC patients (P = 0.1460 and P = 0.2912; respectively). For patients with >or=2 lymph node metastases; however; the presence of micrometastatic cells was associated with a poor distant metastasis-free survival (P = 0.0210).The presence of micrometastatic cells in bone marrow of HNSCC patients with >or=2 lymph node metastas | 15585614 | [
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Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients. | es is correlated with a poor distant metastasis-free survival. In this subgroup of HNSCC patients; E48 RT-PCR seems to be a valuable tool to identify patients who are at increased risk for development of distant metastases and therefore might benefit from experimental adjuvant systemic therapy. | 15585614 | [
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Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as an early surrogate marker. | To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model; tumors were treated with direct intratumoral administration of DTI-015; a solution of 1;3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats; and three treatment groups were established: DTI-015; EtOH; and sham. Two groups of rats received intratumoral injecti | 15585617 | [
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] |
Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as an early surrogate marker. | on of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 mul under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1; 24; 48; and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals | 15585617 | [
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Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as an early surrogate marker. | (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast; rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours; which further increased over time; followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage; development of a cystic region; and enhanced animal survival. Finally; not only were ADC measurements | 15585617 | [
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Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as an early surrogate marker. | predictive of differences between treatment groups; but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy. | 15585617 | [
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Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. | The anti-CD20 antibody rituximab is useful in the treatment of certain B-cell malignancies; most notably non-Hodgkin's lymphoma. Its efficacy has been increased when used in combination with chemotherapy; yet anti-CD20 monoclonal antibodies (mAbs) directly conjugated with drugs such as doxorubicin (Dox) have failed to deliver drug or to demonstrate antitumor activity. We have produced anti-CD20 antibody-drug conjugates that possess potent antitumor activity by using the anti-mitotic agent; monomethyl aurist | 15585616 | [
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Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. | atin E (MMAE); linked via the lysosomally cleavable dipeptide; valine-citrulline (vc). Two anti-CD20 conjugates; rituximab-vcMMAE and 1F5-vcMMAE; were selectively cytotoxic against CD20(+) B-lymphoma cell lines; with IC(50) values ranging from 50 ng/mL to 1 microg/mL. Unlike rituximab; which showed diffuse surface localization; rituximab-vcMMAE capped and was internalized within 4 hours after binding to CD20(+) B cells. Internalization of rituximab-vcMMAE was followed by rapid G(2)-M phase arrest and onset | 15585616 | [
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Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. | of apoptosis. Anti-CD20 antibody-drug conjugates prepared with Dox were internalized and localized as with rituximab-vcMMAE; yet these were not effective for drug delivery (IC(50) > 50 microg/mL). Consistent with in vitro activity; rituximab-vcMMAE showed antitumor efficacy in xenograft models of CD20-positive lymphoma at doses where rituximab or rituximab-Dox conjugates were ineffective. These data indicate that anti-CD20-based antibody-drug conjugates are effective antitumor agents when prepared with a st | 15585616 | [
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Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. | able; enzyme-cleavable peptide linkage to highly potent cytotoxic agents such as MMAE. | 15585616 | [
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Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy. | As molecularly targeted agents reach the clinic; there is a need for assays to detect their presence and effectiveness against target molecules in vivo. Proteinase inhibitors are one example of a class of therapeutic agent for which satisfactory methods of identifying successful target modulation in vivo are lacking. This is of particular importance while these drugs are in clinical trials because standard maximum-tolerated dose-finding studies often are not suitable due to lack of toxicity. Saliva represen | 15585619 | [
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Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy. | ts a readily accessible bodily fluid that can be repeatedly sampled and used for assaying in vivo effects of systemic drugs. Here we show the development of a simple assay that can be used to measure proteinase activity in saliva and proteinase inhibition after systemic treatment with three different proteinase inhibitors. A variety of gelatinolytic activities present in human and murine saliva have been assayed with a fluorescent dye-labeled substrate and assigned to different proteinase categories by incl | 15585619 | [
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Proteinase activity in human and murine saliva as a biomarker for proteinase inhibitor efficacy. | usion of specific classes of inhibitors. Treatment of mice with either matrix metalloproteinase inhibitors or a urokinase inhibitor for a period as short as 48 hours results in levels of the drugs that can be detected in saliva by mass spectrometry and concomitant decreases in salivary proteinase activity; thus demonstrating that these inhibitors successfully modulate their targets in vivo. | 15585619 | [
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S-1 plus cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer: a multi-institutional phase II trial. | To evaluate the efficacy and toxicity of a novel combination chemotherapeutic regimen including cisplatin with an oral anticancer agent; S-1 that consisted of tegafur; 5-chloro-2; 4-dihydroxypyridine; and potassium oxonate; for non-small-cell lung cancer (NSCLC) patients.In this phase II trial; patients with locally advanced and metastatic NSCLC were treated with the oral administration of S-1 at 40 mg/m(2) twice a day for 21 consecutive days while cisplatin (60 mg/m(2)) was administered intravenously on da | 15585618 | [
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S-1 plus cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer: a multi-institutional phase II trial. | y 8. This schedule was repeated every 5 weeks.Of 56 patients enrolled in the study; 55 patients were eligible and analyzed. The median number of cycles administered was 3 (range; 1-12 cycles). Among these 55 patients; one complete response and 25 partial responses were observed with an overall response rate of 47% (95% confidence interval; 34-61%). The median survival time was 11 months and the 1-year survival rate was 45%. Hematologic toxicities of grades 3 and 4 included neutropenia (29%) and anemia (22%) | 15585618 | [
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S-1 plus cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer: a multi-institutional phase II trial. | . No grade 4 nonhematologic toxicity was observed. Grade 3 toxicity included anorexia (13%); vomiting (7%); or diarrhea (7%).S-1 plus cisplatin combination chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigations of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC. | 15585618 | [
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Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy. | Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair enzyme that cleaves DNA at cytotoxic abasic sites caused by alkylating agents and radiation. We have observed that human glioma cells deficient in Ap endo activity are hypersensitive to clinically used alkylators (Silber et al.; Clin Cancer Res 2002;8:3008.). Here we examine the association of glioma Ap endo activity with clinical response after alkylating agent-based chemotherapy or after radiotherapy.Cox proportional hazards regression model | 15585620 | [
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Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy. | s were used to analyze the relationship of Ap endo activity with time to tumor progression (TTP).In a univariate model with Ap endo activity entered as a continuous variable; the hazard ratio (HR) for progression after alkylator therapy in 30 grade III gliomas increased by a factor of 1.061 for every 0.01 increase in activity (P = 0.013). Adjusting for age; gender; extent of resection; and prior treatment strengthened slightly the association (HR = 1.094; P = 0.003). Similarly; the HR for progression after | 15585620 | [
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Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy. | radiotherapy in 44 grade II and III tumors increased by a factor of 1.069 (P = 0.008). Adjusting for the aforementioned variables had little effect on the association. In contrast; we observed no association between activity and TTP in grade IV gliomas after either alkylator therapy in 34 tumors or radiotherapy in 26 tumors.Our data suggest that Ap endo activity mediates resistance to alkylating agents and radiation and may be a useful predictor of progression after adjuvant therapy in a subset of gliomas. | 15585620 | [
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Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. | Recently; a new ABC protein; breast cancer resistance protein (BCRP); was described. But its prognosis is not known in acute myeloid leukemia (AML). In addition; the prognosis of P-glycoprotein (Pgp) and BCRP in patients treated homogeneously by the same anthracycline (daunorubicin; idarubicin; or mitoxantrone) during all of the treatment with aracytine is not known. Therefore; we have evaluated the relationship between drug resistance phenotype; in vitro anthracene sensitivity; and the relation to treatmen | 15585622 | [
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] |
Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. | t outcome.We have analyzed 149 AML treated according to protocol of the European Organization for Research and Treatment of Cancer group. The prognostic value of BCRP and Pgp were analyzed in the whole population and according to intercalating agent.BCRP was a prognostic factor; for achievement of complete remission (43% in positive patients and 69% in negative patients; P = 0.005); the 4-year disease-free survival (12% versus 33%; P = 0.03); and the 4-year overall survival (19% versus 38%; P = 0.003). When | 15585622 | [
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Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. | BCRP expression and Pgp function were categorized in three groups; +/+; +/- or -/+; and -/-; the achievement of complete remission was 45%; 66%; and 90% (P = 0.0003); the 4-year disease-free survival was 8%; 26%; and 40% (P = 0.01); and the 4-year overall survival was 16%; 37%; and 48% (P = 0.001); respectively. Pgp function was a prognostic factor in patients treated by daunorubicin and idarubicin but not by mitoxantrone. In contrast; BCRP expression was a prognostic factor in patients treated by daunorub | 15585622 | [
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Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. | icin and mitoxantrone but not by idarubicin.BCRP would be implicated in the resistance to chemotherapies in AML. But these are the patients expressing both BCRP and Pgp who have the poorest prognosis. | 15585622 | [
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Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-alpha/5-fluorouracil against Hepatocellular Carcinoma. | Our purpose was to explore the contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of IFNalpha and 5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC).Susceptibility of HCC cell lines to TRAIL and/or 5-FU was examined by 3-(4;5-dimethylthiazol-2-yl)-2;5-diphenyltetrazolium bromide assay. The effects of 5-FU; IFNalpha; or both on the expression of TRAIL receptors (R1; R2; R3; and R4) on HCC cells or TRAIL in peri | 15585621 | [
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Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-alpha/5-fluorouracil against Hepatocellular Carcinoma. | pheral blood mononuclear cells (PBMC) were examined by flow cytometry. IFNalpha-induced cytotoxic effects of PBMC on HCC cell lines were examined by (51)Cr release assay. TRAIL expression in peripheral blood mononuclear cells and liver tissue from patients was examined by real-time reverse transcription-PCR or immunohistochemistry.HLE and HepG2 were sensitive to TRAIL; but HuH7; PLC/PRF/5; and HLF were resistant. 5-FU had synergistic effect on TRAIL in HLF and additive effect in four other HCC cell lines. T | 15585621 | [
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Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-alpha/5-fluorouracil against Hepatocellular Carcinoma. | RAIL receptors on HCC cells were up-regulated by 5-FU; and IFNalpha induced TRAIL on CD4(+) T cells; CD14(+) monocytes; and CD56(+) NK cells. Treatment of effector cells by IFNalpha and target HCC cells by 5-FU enhanced the cytotoxicity of CD14(+) monocytes and CD56(+) NK cells against HCC cells via a TRAIL-mediated pathway. TRAIL mRNA overexpression was noted in PBMC of HCC patients who clinically responded to IFNalpha/5-FU combination therapy; and TRAIL(+) mononuclear cells were found in cancer tissue of | 15585621 | [
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Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-alpha/5-fluorouracil against Hepatocellular Carcinoma. | a responder.Our results suggest that modulation of TRAIL/TRAIL receptor-mediated cytotoxic pathway might partially contribute to the anti-HCC effect of IFNalpha and 5-FU combination therapy. | 15585621 | [
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Thymidylate synthase 5'- and 3'-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. | Folate deficiency and reduced DNA repair capacity are established risk factors for squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of the thymidylate synthase (TYMS) gene; which regulates a key enzyme in folate metabolism required for DNA synthesis and repair; are associated with SCCHN risk.In a hospital-based case-control study of 704 SCCHN cases and 1;085 controls; frequency matched by age; sex; and ethnicity; we genotyped the TSER (thymidylate synthase in the 5'-u | 15585623 | [
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Thymidylate synthase 5'- and 3'-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. | ntranslated enhanced region) and TS3'UTR (thymidylate synthase in the 3'-untranslated region) polymorphisms.The TS3'UTR 0bp/0bp genotype was associated with a significantly decreased risk of SCCHN [adjusted odd ratio (OR) = 0.67; 95% confidence interval (CI) = 0.47-0.94] compared with the 6bp/6bp genotype; but the TSER polymorphism had no main effect on risk of SCCHN. When we evaluated the two polymorphisms together by the number of protective alleles (the TSER 3R and TS3'UTR 0bp alleles); we found that the | 15585623 | [
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Thymidylate synthase 5'- and 3'-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. | combined genotypes with four protective alleles (the TSER 3R3R and TS3'UTR 0bp/0bp) was associated with significantly decreased SCCHN risk (OR = 0.60; 95% CI = 0.37-0.98). In addition; the TS3'UTR 0bp genotypes were associated in an allele dose-dependent manner with a decreased risk of overall stage IV oral cancer (OR = 0.84; 95% CI = 0.52-1.34 for the 6bp/0bp genotype and OR = 0.26; 95% CI = 0.08-0.87 for the 0bp/0bp genotype; P(trend) = 0.035).The TSER and TS3'UTR polymorphisms are associated with SCCHN | 15585623 | [
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Thymidylate synthase 5'- and 3'-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. | risk. The TSER 3R and TS3'UTR 0bp alleles seemed to jointly protect against SCCHN. In particular; the 0bp allele seemed to protect against oral cancer progression. | 15585623 | [
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Fas ligand expression in metastatic renal cell carcinoma during interleukin-2 based immunotherapy: no in vivo effect of Fas ligand tumor counterattack. | It has been hypothesized that tumor cells expressing Fas ligand (FasL) might be able to counterattack and neutralize tumor-infiltrating lymphocytes. We assessed the effect of FasL tumor counterattack on the clinical outcome of interleukin-2 (IL-2)-based immunotherapy in metastatic renal cell carcinoma.Tumor core needle biopsies were obtained before IL-2-based immunotherapy in 86 patients and repeated within the first cycle in 57 patients. Tumor cells expressing FasL and intratumoral lymphocyte subsets expre | 15585624 | [
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Fas ligand expression in metastatic renal cell carcinoma during interleukin-2 based immunotherapy: no in vivo effect of Fas ligand tumor counterattack. | ssing CD4; CD8; CD56; and CD57 were analyzed by immunohistochemistry.At baseline; negative FasL staining in tumor cells was seen in 10 of 86 (12%) biopsies; whereas intense FasL staining was seen (a) in fewer than 10% of tumor cells in 26 (30%) biopsies; (b) in 11 to 50% of tumor cells in 25 (29%) biopsies; (c) in 51 to 90% of tumor cells in 18 (21%) biopsies; and (d) in >90% of tumor cells in 7 (8%) biopsies. On treatment; tumor FasL expression did not change from baseline levels. Moreover; tumor FasL expr | 15585624 | [
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Fas ligand expression in metastatic renal cell carcinoma during interleukin-2 based immunotherapy: no in vivo effect of Fas ligand tumor counterattack. | ession was not correlated with objective response or survival whereas the absolute number of CD4(+); CD8(+); CD56(+); and CD57(+) cells per mm(2) tumor tissue at baseline was significantly higher in responding patients compared with nonresponding patients (P = 0.01; P = 0.008; P = 0.015; and P < 0.001; respectively). During the first course of immunotherapy; the absolute number of CD4(+); CD8(+); and CD57(+) cells per mm(2) tumor tissue was significantly higher in responding patients compared with nonrespon | 15585624 | [
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Subsets and Splits