GoPubMed: exploring PubMed with the Gene Ontology.
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The biomedical literature grows at a tremendous rate and PubMed comprises already over 15 000 000 abstracts. Finding relevant literature is an important and difficult problem. We introduce GoPubMed, a web server which allows users to explore PubMed search results with the Gene Ontology (GO), a hierarchically structured vocabulary for molecular biology. GoPubMed provides the following benefits: first, it gives an overview of the literature abstracts by categorizing abstracts according to the GO and thus allowing users to quickly navigate through the abstracts by category. Second, it automatically shows general ontology terms related to the original query, which often do not even appear directly in the abstract. Third, it enables users to verify its classification because GO terms are highlighted in the abstracts and as each term is labelled with an accuracy percentage. Fourth, exploring PubMed abstracts with GoPubMed is useful as it shows definitions of GO terms without the need for further look up. GoPubMed is online at www.gopubmed.org. Querying is currently limited to 100 papers per query. (+info)
Identification and characterization of novel nicotinic receptor-associated proteins in Caenorhabditis elegans.
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Nicotinic acetylcholine receptors (nAChRs) mediate fast excitatory neurotransmission in neurons and muscles. To identify nAChR accessory proteins, which may regulate their expression or function, we performed tandem affinity purification of the levamisole-sensitive nAChR from Caenorhabditis elegans, mass spectrometry of associated components, and RNAi-based screening for effects on in vivo nicotine sensitivity. Among the proteins identified was the calcineurin A subunit TAX-6, which appeared to function as a negative regulator of nAChR activity. We also identified five proteins not previously linked to nAChR function, whose inactivation conferred nicotine resistance, implicating them as positive regulators of nAChR activity. Of these, the copine NRA-1 colocalized with the levamisole receptor at neuronal and muscle plasma membranes, and, when mutated, caused reduced synaptic nAChR expression. Loss of SOC-1, which acts in receptor tyrosine kinase (RTK) signaling, also reduced synaptic levamisole receptor levels, as did mutations in the fibroblast growth factor receptor EGL-15, and another RTK, CAM-1. Thus, tandem affinity purification is a viable approach to identify novel proteins regulating neurotransmitter receptor activity or expression in model systems like C. elegans. (+info)
Increase of survival benefit in advanced resectable colon cancer by extent of adjuvant treatment: results of a randomized trial comparing modulation of 5-FU + levamisole with folinic acid or with interferon-alpha.
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BACKGROUND: The benefit of adjuvant therapy in curatively resected lymph node-positive colon cancer was established using 5-fluorouracil (5-FU) and levamisole (LEV) for 12 months. 5-FU cytotoxicity can be modulated by folinic acid (FA) or interferon-alpha (INF-alpha). The aim of this study was to investigate the efficacy of modulating 5-FU+ LEV by either FA or IFN-alpha in the adjuvant treatment of high-risk colon cancer. METHODS: Patients with curatively resected colon cancer (stages UICC IIb and III) were stratified according to T, N, and participating center and randomized to receive a 12-month treatment using 5-FU + LEV alone or in combination with FA or IFN-alpha. RESULTS: A total of 855 of 904 entered patients (94.6%) were eligible. The median follow-up of all eligible patients was 4.6 years. Addition of FA to 5-FU + LEV improved recurrence-free and overall survival in comparison with 5-FU + LEV alone (P = 0.007 and P = 0.004, respectively, 1-sided). The 5-year overall survival rates were 60.5% (95% confidence interval, 54.3-66.7) and 72.0% (95% confidence interval, 66.5-77.5) for 5-FU + LEV and 5-FU + LEV + FA, respectively. Addition of INF-alpha showed a tendency to improve recurrence-free survival, however, without altering overall survival. Toxicities (WHO III + IV) were generally tolerable except one toxic death in the control arm and were observed in 9.9% of the patients receiving 5-FU + LEV alone and in 13.3% and in 30.7% of patients receiving additional FA and IFN-alpha, respectively. CONCLUSIONS: Addition of IFN-alpha was associated with increased toxicity without markedly influencing the outcome and should therefore not be recommended for adjuvant treatment. Addition of FA increased the 5-year recurrence-free and overall survival rate by 9.3 and 11.5 percentage points, respectively. 5-FU + LEV + FA for 12 months may be an effective adjuvant treatment option for locally advanced high-risk colon cancer. (+info)
Stability of levamisole oral solutions prepared from tablets and powder.
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PURPOSE: To study the stability of levamisole oral solutions (25 mg/mL) prepared from powder and tablets stored at 4 +/- 3 degrees C and 23 +/- 2 degrees C in amber glass prescription bottles. METHODS: Levamisole 25 mg/mL solutions were prepared from commercially available 50-mg tablets or from pure powder in sterile water. Levamisole concentrations were determined in duplicate by a stability-indicating HPLC method at 0, 1, 2, 3, 4, 7, 14, 30, 60 and 90 days. The initial and final pHs of solutions were measured. RESULTS: The recovery of levamisole from tablets was 100 +/- 2.1%. No color or odour changes were observed during the study period. The oral solutions prepared from powder were stable at least 90 days stored at 4 and 23 degrees C. The oral solutions prepared from tablets were stable at least 90 days at 4 degrees C and 15 days when stored at 23 degrees C. The initial pH of solutions prepared from powder and tablets were 5.30 and 4.55, respectively. Initial and final pH values were significantly different (p<0.001) for the two solutions. CONCLUSIONS: Levamisole 25 mg/mL oral solutions can be prepared from tablets or powder with sterile water for irrigation and stored for 90 days under refrigeration, taking account of the lack of microbiological contamination. (+info)
Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study.
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The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95% CI: 0.80-1.30) and 0.94 (95% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients. (+info)
Ectophosphorylation of CD36 regulates cytoadherence of Plasmodium falciparum to microvascular endothelium under flow conditions.
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The adhesion of Plasmodium falciparum-infected erythrocytes (IRBCs) to human dermal microvascular endothelial cells (HDMECs) under flow conditions is regulated by a Src family kinase- and alkaline phosphatase (AP)-dependent mechanism. In this study, we showed that the target of the phosphatase activity is the ectodomain of CD36 at threonine-92 (Thr92). Mouse fibroblasts (NIH 3T3 cells) transfected with wild-type CD36 or a mutant protein in which Thr92 was substituted by Ala supported the rolling and adhesion of IRBCs. However, while the Src family kinase inhibitors PP1 and PP2 and the specific AP inhibitor levamisole significantly reduced IRBC adhesion to wild-type CD36 transfectants as with HDMECs, the inhibitors had no effect on IRBC adhesion to the mutant cells. Using a phosphospecific antibody directed at a 12-amino-acid peptide spanning Thr92, we demonstrated directly that CD36 was constitutively phosphorylated and could be dephosphorylated by exogenous AP. Endothelial CD36 was likewise constitutively phosphorylated. The phosphospecific antibody inhibited IRBC adhesion to HDMECs that could be reversed by preincubating the antibody with the phosphorylated but not the nonphosphorylated peptide. Pretreatment of HDMECs with AP abrogated the effect of PP1 on IRBC adhesion. Collectively, these results are consistent with a critical role for CD36 dephosphorylation through Src family kinase activation in regulating IRBC adhesion to vascular endothelium. (+info)
Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089.
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PURPOSE: In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients. PATIENTS AND METHODS: From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year. RESULTS: After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival. CONCLUSION: The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers. (+info)
Comparison of the immunogenicity of hamster cells transformed by adenovirus and Herpes simplex virus.
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Hamsters vaccinated with adenovirus-transformed cells, modified by acetoacetylation or concanavalin A treatment, or with small numbers of living cells were partly or completely protected against challenge with 3 times 10-6 living cells. Treatment of vaccine cells with iodoacetate, Mitomycin C, neuraminidase plus Mitomycin C did not produce efficient vaccines. Herpes simplex virus-transformed cells treated by any of these procedures did not prevent, and frequently even enhanced, the growth of the homologous living cells; enhancement was often greater in female than in male hamsters. Protective and enhancing vaccines did not induce a different level of cell-mediated immunity, as detected by lymphocytotoxicity tests, which were positive for both homologous transformed cells and nontransformed hamster cells. In contrast, specific complement-dependent cytotoxic antibodies active only on adenovirus-transformed cells were induced by the protective acetoacetylated vaccine prepared from adenovirus-transformed cells; these antibodies were not present after nonprotective vaccinations. The appearance of herpes simplex virus tumors was delayed by treatment with the immunostimulant, Levamisole, or by preimmunization with Newcastle disease virus grown in SV40-transformed cells, but not by Newcastle disease virus grown in herpes simplex virus-transformed cells. Thus, only nonspecific treatments were able to impede herpes simplex virus tumor growth, while protection against adenovirus tumor was accompanied by specific cytotoxic antibodies. (+info)