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Biomedical subjects

L Ryan

Publications and source records attributed to L Ryan.

At least 73 records · Page 4Linked to original sources
PubMed1998

Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.

PURPOSE: The administration of fluorouracil (5-FU) by continuous intravenous infusion (CI) is an alternative to the bolus administration of 5-FU in patients with advanced colorectal cancer. Although more than 1,200 patients have been enrolled onto randomized trials that compared these two treatment modalities, there is still no definitive evidence of an advantage of 5-FU CI, and the magnitude of this advantage, if any, is also controversial. A meta-analysis was performed to assess this benefit in terms of tumor response and survival, and to compare the toxicity profiles of these two modalities of administration of 5-FU. DESIGN: Individual data of 1,219 patients included in six randomized trials served as the basis for this meta-analysis, which was conducted by an independent secretariat in close collaboration with the investigators. RESULTS: Tumor response rate was significantly higher in patients assigned to 5-FU CI than in patients assigned to 5-FU bolus (22% v 14%; overall response odds ratio, 0.55; 95% confidence interval [95% CI], 0.41 to 0.75; P = .0002). Overall survival was also significantly higher in patients assigned to 5-FU CI (overall hazards ratio [HR], 0.88; 95% CI, 0.78 to 0.99; P = .04), although the median survival times were close. Multivariate analyses showed that randomized treatment and performance status were the only two significant predictors of tumor response, whereas the same plus primary tumor site were independent significant predictors of survival (patients with rectal cancer did somewhat better). Grade 3 or 4 hematologic toxicity was more frequent in patients assigned to 5-FU bolus (31% v 4%; P < 10(-16)), whereas hand-foot syndrome was more frequent in the 5-FU CI group (34% v 13%; P < 10(-7)). CONCLUSION: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival. The hematologic toxicity is much less important in patients who receive 5-FU CI, but hand-foot syndrome is frequent in this group of patients.

Antimetabolites, Antineoplastic↗
PubMed1998

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

Colorectal Neoplasms↗
PubMed1997

Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: a frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial.

Human colonic cancer is associated with multiple genetic deletions, mutations, and alterations in gene expression; in contrast, gene amplification has not been recognized as a prominent characteristic of human colonic tumors. Although the c-myc gene is overexpressed in approximately 70% of human colonic cancers, previous studies have not detected frequent gene amplification or rearrangement of c-myc in these tumors, although such amplification has been reported in chemically induced rodent colon cancer and quantitative analysis of gene copy number has shown the gene to be amplified at a low level in mucinous and poorly differentiated human colon carcinomas. Using rigorously controlled blot methodology, we have established that the c-myc gene, located at 8q21, exhibited amplification of 87% to 35-fold in 7 of 10 human colonic carcinoma cell lines. This was highly significant even at a low level of amplification in HT29 cells (P < 0.0001). Cytogenetic analysis by G-banding did not detect aneuploidy involving chromsome 8q, suggesting that the amplification for the c-myc gene on 8q was relatively specific, and this was consistent with a lack of amplification detected for the c-mos gene on 8q24, which was assayed similarly. The same methodology then revealed amplification of c-myc from 1.5-fold to 5-fold in 32% of tumors from 149 patients entered into a multi-institutional Phase III study of adjuvant therapy for colon cancer. c-myc status was not related to time to recurrence or death, but low levels of c-myc amplification identified a subset of patients who showed a statistically significant increase in disease-free survival, and a corresponding trend to longer overall survival, in response to adjuvant therapy with 5-fluorouracil plus levamisole. Presence of c-myc amplification was not related to incidence of p53 mutations.

Carcinoma↗
PubMed1997

Memory for verbal information in individuals with HIV-associated dementia complex. HNRC Group.

Patterns of memory performance were examined for 9 participants with HIV-associated dementia (HAD), 15 HIV-seropositive participants without dementia, and 15 HIV-seronegative controls. Episodic and semantic memory were assessed using the California Verbal Learning Test, the Boston Naming Test, and Verbal Fluency tests. The HAD group showed deficits in episodic memory, with relative sparing of semantic memory. In addition, results suggest a retrieval deficit in HAD rather than a deficit in retention of information. This pattern is consistent with the presence of a subcortical dementing process and supports findings from previous neuropathological, neuroimaging, and neuropsychological studies suggesting that subcortical brain dysfunction is frequently associated with HIV disease (e.g., Navia, Jordan, & Price, 1986).

AIDS Dementia Complex↗
PubMed1997

Induction of tumor necrosis factor production from monocytes stimulated with mannuronic acid polymers and involvement of lipopolysaccharide-binding protein, CD14, and bactericidal/permeability-increasing factor.

Well-defined polysaccharides, such as beta1-4-linked D-mannuronic acid (poly[M]) derived from Pseudomonas aeruginosa, induce monocytes to produce tumor necrosis factor (TNF) through a pathway involving membrane CD14. In this study we have investigated the effects of soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), and bactericidal/permeability-increasing factor (BPI) on poly(M) binding to monocytes and induction of TNF production. We show that LBP increased the TNF production from monocytes stimulated with poly(M). Addition of sCD14 alone had only minor effects, but when it was added together with LBP, a rise in TNF production was seen. BPI was found to inhibit TNF production from monocytes stimulated with poly(M) in the presence of LBP, LBP-sCD14, or 10% human serum. Binding studies showed that poly(M) bound to LBP- and BPI-coated immunowells, while no significant binding of poly(M) to sCD14-coated wells in the absence of serum was observed. Binding of poly(M) to monocytes was also examined by flow cytometry, and it was shown that the addition of LBP or 10% human serum clearly increased the binding of poly(M) to monocytes. BPI inhibited the binding of poly(M) to monocytes in the presence of LBP, LBP-sCD14, or 10% human serum. Our data demonstrate a role for LBP, LBP-sCD14, and BPI in modulating TNF responses of defined polysaccharides.

Alginates↗
PubMed1997

Association between air pollution and low birth weight: a community-based study.

The relationship between maternal exposure to air pollution during periods of pregnancy (entire and specific periods) and birth weight was investigated in a well-defined cohort. Between 1988 and 1991, all pregnant women living in four residential areas of Beijing were registered and followed from early pregnancy until delivery. Information on individual mothers and infants was collected. Daily air pollution data were obtained independently. The sample for analysis included 74,671 first-parity live births were gestational age 37-44 weeks. Multiple linear regression and logistic regression were used to estimate the effects of air pollution on birth weight and low birth weight (< 2,500 g), adjusting for gestational age, residence, year of birth, maternal age, and infant gender. There was a significant exposure-response relationship between maternal exposures to sulfur dioxide (SO2) and total suspended particles (TSP) during the third trimester of pregnancy and infant birth weight. The adjusted odds ratio for low birth weight was 1.11 (95% CI, 1.06-1.16) for each 100 micrograms/m3 increase in SO2 and 1.10 (95% CI, 1.05-1.14) for each 100 micrograms/m3 increase in TSP. The estimated reduction in birth weight was 7.3 g and 6.9 g for each 100 micrograms/m3 increase in SO2 and in TSP, respectively. The birth weight distribution of the high-exposure group was more skewed toward the left tail (i.e., with higher proportion of births < 2,500 g) than that of the low-exposure group. Although the effects of other unmeasured risk factors cannot be excluded with certainty, our data suggests that TSP and SO2, or a more complex pollution mixture associated with these pollutants, contribute to an excess risk of low birth weight in the Beijing population.

Adult↗
PubMed1996

Missing cause of death information in the analysis of survival data.

Goetghebeur and Ryan proposed a method for proportional hazards analyses of competing risks failure-time data when the failure type is missing for some cases. This paper evaluates the properties of the method using data from a clinical trial in Hodgkin's disease. We generated several patterns of missingness in the cause of death in 'pseudo-studies' derived from the study database. We found that the proposed method provided regression coefficients and inferences that were less biased than those from other methods over an increasing percentage of missingness in the failure type when missingness is random, when it depends on an important covariate, when it depends on failure type, and when it depends on follow-up time. We present suggestions for study design with planned missingness in the failure type.

Adult↗
PubMed1996

Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer.

BACKGROUND: Phase II studies of fluorouracil (5-FU) administered by protracted intravenous infusion have suggested an improved response rate and decreased toxicity profile when compared with 5-FU given by bolus injection in patients with metastatic colorectal cancer. Additional studies have suggested further enhancement of infusion 5-FU activity when it is combined with low-dose weekly cisplatin administration. PURPOSE: This phase III study in adults with metastatic colorectal cancer was planned as a comparison of objective response rates, toxicity, and survival in patients receiving bolus versus protracted-infusion 5-FU with or without cisplatin. METHODS: Four hundred ninety-seven previously untreated patients with advanced, measurable metastatic colorectal cancer were randomly assigned to receive treatment A (bolus 5-FU at 500 mg/m2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m2), treatment B (bolus 5-FU at 500 mg/m2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m2, plus weekly cisplatin at 20 mg/m2), treatment C (5-FU at 300 mg/m2 per day by continuous infusion), or treatment D (5-FU at 300 mg/m2 per day by continuous infusion plus weekly cisplatin at 20 mg/m2). All drugs were administered intravenously. Enrollment in the trial occurred from August 1987 through December 1990, and follow-up was through September 1995. The Kaplan-Meier method was used to estimate overall and disease-free survival, and Cox regression models were used to assess the effects of patient characteristics on survival. All P values resulted from two-sided tests. RESULTS: Objective tumor response was observed in 28 (18%) of 153 patients receiving treatment A, in 45 (28%) of 159 patients receiving treatment C (C versus A; P = .045), and in 47 (31%) of 153 patients receiving treatment D (D versus A; P = .016). Because of excessive toxicity, treatment B was discontinued after only 12 patients had begun treatment. Median time to disease progression was 5.1 months for patients in arm A compared with 6.2 and 6.5 months for patients in arms C and D, respectively (C versus A, P = .007; D versus A, P = .017). Patterns of toxic effects differed substantially among the treatment arms. Forty-five percent of the patients receiving bolus 5-FU alone (A) experienced grade 3-4 leukopenia, with two sepsis-related deaths. Hand-foot syndrome and mucositis were the major treatment-limiting toxic effects for patients in the two treatment arms involving infusion. Despite the improvement in response rates and time to disease progression with infusion 5-FU with or without cisplatin (C and D, respectively) (P = .003), the overall survival for the three groups (A, C, and D) was similar (P = .307). This may have been due in part to a longer median survival time of 10.4 months for patients in arm A, compared with an anticipated survival of 7 months. CONCLUSION: 5-FU given as a continuous infusion produced a higher objective response rate, a modest prolongation in time to disease progression, and less life-threatening myelosuppression in patients than bolus 5-FU. Concomitant treatment with low-dose cisplatin caused added toxicity and complexity of treatment and did not provide a major clinical benefit. No statistically significant survival differences were observed among the three treatment groups.

Antimetabolites, Antineoplastic↗
PubMed1996

Design of multiple binary outcome studies with intentionally missing data.

We discuss the design and analysis of studies involving multiple binary outcomes in which only a subset of these outcomes can be measured on each individual. Such studies with "intentionally missing data" may arise due to practical or economic constraints; several examples from toxicology serve as illustrations. A global test statistic based on generalized estimating equations is presented and evaluated under a variety of missing patterns and correlation structures. Extensions of the global test statistic to allow for clustered data are also described. The relative efficiency of the global test statistic with missing data relative to that for complete data is investigated, both under a common dose effect alternative and when exposure has differential effects on the multiple endpoints. The implications of these efficiency calculations on study design are explored, and several recommendations are provided.

Animals↗
PubMed1995

Decline in working memory associated with HIV infection. HNRC Group.

HIV infection has been associated with decline in a number of cognitive functions that are components of 'working memory'. Thus, tests of working memory that require the interaction of these components may be particularly sensitive to cognitive dysfunction that arises from HIV infection. To assess this possibility, working memory was examined in 147 HIV-seropositive (HIV+) and 38 HIV-seronegative (HIV-) males using the Reading Span Test and the Digit Span subtest from the Wechsler Memory Scale-Revised (WMS-R). Speed of information processing, a component of some working memory tasks, was assessed with a version of the Sternberg Memory Scanning task. Results indicated that symptomatic HIV+ subjects were impaired relative to HIV- control subjects on the Reading Span and Digit Span tests. Asymptomatic and mildly symptomatic HIV+ groups exhibited a trend toward impairment on these tests, and on the whole, a greater proportion of HIV+ subjects than HIV- subjects were impaired. The groups did not differ significantly in information processing speed. These results indicate that deficits in working memory are apparent in at least a subset of HIV-infected individuals. These deficits are most apparent in symptomatic HIV+ individuals, but the decline may begin during the asymptomatic phase of infection.

Adult↗
PubMed1995

'Going public' and 'watching sick people'--the clinic setting as a factor in the experiences of gay men participating in AIDS clinical trials.

This paper reports findings from a study which was concerned to investigate the experiences of gay men living with HIV disease on anti-HIV clinical drug trials in Australia. Participation observation of a Phase 1 clinical trial and in-depth interviews with both trial participants on a range of clinical trials and trial nurses provided data which point to the centrality of the clinic setting in structuring the experiences of trial participants. The importance of the clinic site is particularly evident in respect of issues of information control and, particularly for asymptomatic trial participants, confrontation with future ill selves. A further key issue which emerged relates to the epidemiological profile of the HIV epidemic in Australia in which gay men are disproportionately represented; the HIV trial site is a sexualized space, presence there is commonly assumed to mean that the individual is gay, given the cultural co-categorization of homosexuality and HIV. These findings have implications for accrual to anti-HIV clinical trials, for compliance rates and for health care intervention programmes, in particular those which are concerned to monitor and support those participating in AIDS clinical trials. The findings are also of broad relevance to the wider issue of quality of life of gay men with HIV disease taking experimental anti-HIV therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Effects of anti-CD18 and LPS on CD14 expression on human monocytes.

In this study we show that the cytokine stimulatory effect of LPS on human monocytes is enhanced by addition of monoclonal antibodies against CD18 (alpha CD18 MoAbs). Incubation of monocytes with alpha CD18 MoAbs overnight increased the CD14 expression as detected by Leu-M3, but not with My-4. These results indicate that CD18 participates in LPS-induced TNF-alpha production as well as in regulating CD14 expression on monocytes. Addition of LPS to monocytes resulted in a reduction in the CD14 expression after 1/2, 1, 2 and 4 h, but increased CD14 expression was seen after LPS stimulation overnight. By doing double labelling of the monocyte population for CD14 and CD16 it was found that the reduction in CD14 expression occurred in the CD14+/CD16+ sub-population, while the increase in CD14 expression was seen in both the CD14+/CD16- and the CD14+/CD16+ cells. alpha CD14 MoAbs that were able to inhibit LPS-induced cytokine production from monocytes (3C10 and My-4) were considerably less able to detect the increase in CD14 expression after LPS stimulation than alpha CD14 MoAbs that did not inhibit LPS-induced cytokine production (Leu-M3 and alpha CD14Serva). Our data indicate that My-4 and Leu-M3 define two populations of CD14+ cells on LPS stimulated human monocytes.

Antibodies, Monoclonal↗
PubMed1995

The involvement of CD14 in stimulation of TNF production from peripheral mononuclear cells isolated from PNH patients.

Peripheral blood mononuclear cells (PBMC) from six patients with paroxysmal nocturnal haemoglobinuria (PNH) were analysed by flow cytometry for expression of CD14 and for ability to respond to bacterial lipopolysaccharide and beta 1-4 linked polymannuronic acid by TNF secretion. Expression of cell surface CD14 could not be detected on cells from the PNH patients, whereas the levels of expression of other monocyte antigens, e.g. CD33 and CD13, were comparable to that of cells from healthy subjects. The cells from the patients with PNH responded with secretion of significantly less TNF after stimulation with LPS and polymannuronic acid than mononuclear cells from healthy subjects, suggesting an impaired ability in PNH to respond to bacterial infection by TNF secretion from monocytes. Soluble CD14 appeared to be involved in the residual activation of CD14 negative PBMC, and the sera of these patients contained normal or slightly elevated levels of soluble CD14. After allogeneic bone marrow transplantation in one patient the monocytes expressed CD14 at normal levels and responded normally with respect to their ability to generate TNF upon stimulation.

Adult↗
PubMed1995

Characterization of an additional articular cartilage vesicle fraction that generates calcium pyrophosphate dihydrate crystals in vitro.

OBJECTIVE: We previously identified a unique fraction of porcine articular cartilage vesicles, sedimentable at 8 x 10(6) g/min, which generate calcium pyrophosphate dihydrate crystals (CPPD) in vitro. We sought to identify and characterize other fractions of articular cartilage digest, sedimentable at lower g forces, which may also contain mineralizing vesicles. METHODS: Electron microscopy and alkaline phosphatase and nucleoside triphosphate pyrophosphohydrolase (NTPPPH) assays were used to analyze each fraction. Radiometric mineralization assays, Fourier transform infrared (FTIR) spectroscopy, and compensated polarized light microscopy were used to analyze crystals formed by these fractions. RESULTS: Vesicles of varying sizes identical to epiphyseal cartilage matrix vesicles were seen in all sedimentable fractions examined, but were the exclusive component of fractions sedimentable at 3 x 10(6) g/min, termed the heavy vesicle fraction (HVF), and at 8 x 10(6) g/min, now termed the light vesicle fraction (LVF). All vesicle containing fractions supported ATP dependent calcium pyrophosphate precipitation. The HVF and LVF precipitated 30 x more calcium than vesicle poor supernatant (p < 0.01) and 1.5-4 x more than cell-free unfractionated digest (p < 0.01). HVF differed from LVF in that it contained 3-4 x higher NTPPPH specific activity (p < 0.05). HVF resembled LVF in that both precipitated crystals consistent with CPPD by FTIR spectroscopy and compensated polarized light microscopy. CONCLUSION: These data expand our previous estimate of the total number of vesicles available for biologic mineralization and demonstrate heterogeneity of vesicle fractions. They support a key role for vesicles in CPPD crystal formation.

Alkaline Phosphatase↗
PubMed1994

Genes encoding actin-related proteins of Drosophila melanogaster.

Recently, several laboratories have described proteins of yeasts, mammals and Drosophila melanogaster that are 35 to 55% identical to conventional actins, but, as yet, little is known about their functions. We have initiated a systematic study by using degenerate oligonucleotides specifying two highly conserved nucleotide-binding peptides of actin, in conjunction with polymerase chain reaction techniques, to isolate Drosophila genes that encode actin-related proteins. Here we summarize the isolation of four such genes and compare the sequences of the proteins that they encode. Computer searches of databases revealed that three of the encoded proteins are homologs of yeast or mammalian actin-related proteins, implying that the corresponding proteins participate in functions common to many cell types. The fourth gene encodes a novel protein that, apparently is expressed within testes. The four genes are located within the 14D, 53D, 66B and 87C subdivisions of polytene chromosomes.

Actins↗
PubMed1994

Soluble CD14 from urine copurifies with a potent inducer of cytokines.

Here we report that soluble CD14 isolated from the urine of nephrotic patients (uCD14) contains a potent cytokine inducing activity. CD14 derived from urine appeared to consist of two major polypeptides of about 54 and 48 kDa. In uCD14 isolated from three different nephrotic patients the cytokine-inducing activity appeared to co-migrate with the 48-kDa polypeptide which upon sequencing had the same N-terminal sequence as native CD14. Treatment of human monocytes and the human astrocytoma cell line U373 with uCD14 resulted in a strong secretion of tumor necrosis factor (TNF) and interleukin-6, respectively. The cytokine-inducing activity of the uCD14 preparations was unaffected by the absence of serum. This is in contrast to the activation of human monocytes and U373 cells by lipopolysaccharide (LPS) which is highly dependent on the presence of serum. The cytokine-inducing activity was not affected by LPS-binding protein (LBP) or polyclonal rabbit antibodies against LBP. The TNF-inducing activity of uCD14 was also heat labile in contrast to the cytokine-inducing activity of LPS, which was relatively heat resistant. The results suggest that CD14 may exist in at least two forms of which one is involved in cytokine induction.

Acute-Phase Proteins↗
PubMed1994

Characterization of binding and TNF-alpha-inducing ability of chitosans on monocytes: the involvement of CD14.

Chitosans with different chemical composition were found to induce TNF-alpha production from human monocytes. Their ability to induce TNF-alpha was found to be highly dependent on neutral-solubility and molecular weight. Monoclonal antibodies against CD14 inhibited TNF-alpha production from monocytes stimulated with neutral-soluble chitosans. Binding studies indicated that lipopolysaccharides (LPS) and neutral-soluble chitosans share a binding site on monocytes which involves CD14. TNF-alpha production from monocytes stimulated with chitosans was dependent on serum. LPS-binding protein (LBP) enhanced the chitosan-induced TNF-alpha production only to a minor degree, suggesting that serum proteins other than LBP play an important role in the stimulatory effect.

Acute-Phase Proteins↗