Search PubMed⌕ Search

Biomedical subjects

C Jacobs

Publications and source records attributed to C Jacobs.

At least 91 records · Page 5Linked to original sources
PubMed1997

Ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer: update and preliminary survival analysis.

The primary objective of this study was to define the maximum tolerated dose and toxicity profile of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given as a 24-hour infusion, in conjunction with ifosfamide/carboplatin/etoposide (ICE) chemotherapy in patients with advanced lung cancer. Paclitaxel was escalated from 75 to 225 mg/m2 in 25-mg/m2 increments. All patients received granulocyte colony-stimulating factor 5 microg/kg/d from day 4 until the neutrophil count was > or = 10,000/microL. The study population consisted of 41 patients with a median age of 60 years and a median follow-up of 20.7 months. Stage distribution included 5% stage IIIA, 46% stage IIIB, and 49% stage IV. Histology consisted of 61% adenocarcinoma, 12% squamous cell carcinoma, 10% large cell carcinoma, 15% small cell carcinoma, and 2% mixed. The predominant toxicity was hematologic; 63% of patients experienced grade 4 neutropenia and 49% developed grade 4 thrombocytopenia. Fever and neutropenia occurred in 34% of patients. Hematologic toxicity was, in all cases, short-term and reversible and was not dose related. With few exceptions, nonhematologic toxicity was not clinically important. Among 39 patients evaluable for response, 36% achieved a remission (8% complete, 28% partial, 41% had stable disease, and 23% experienced disease progression). Among 33 patients with non-small cell lung cancer, the response rate was 27% (one complete response, eight partial responses, 15 had stable disease, and nine had progressive disease). Among six patients with small cell carcinoma, the response rate was 83% (two complete responses, three partial responses, and one had stable disease). The median survival of all 41 patients was 13.6 months. Survival was almost identical between stage IIIA and stage IV subsets. We conclude that it is possible to safely administer full-dose single-agent paclitaxel with granulocyte colony-stimulating factor support in conjunction with full-dose ifosfamide/carboplatin/etoposide chemotherapy. While response rates observed were not particularly notable, median survival is considerably longer than that usually achieved with combination chemotherapy in advanced lung cancer.

Adult↗
PubMed1997

Variation in long-term engraftment of a large consecutive series of lambs transplanted in utero with human hematopoietic cells.

We investigated the survival and chimeric engraftment characteristics of a large consecutive series of lambs that were transplanted with human hematopoietic cells in utero. Approximately 50% of the fetal sheep survived. Neither the transplantation of human cells into fetal sheep, nor the parity of the ewe was associated with increased mortality, as compared with the risk of surgery alone. However, a breed-associated mortality was noted. Sixty percent of surviving recipient lambs contained donor, human hematopoietic cells in blood and bone marrow (BM) cells. Chimerism ranged from 0.0001-1%. Human hematopoietic progenitors were identified in the BM in 8 of 12 chimeric sheep examined. Some lambs engrafted with human cells maintained a human chimerism for up to at least 2 years. Our data demonstrate that a large proportion of fetal sheep are capable of engrafting human cells, albeit at widely variable levels of engraftment.

Abortion, Veterinary↗
PubMed1996

[Ethical problems posed by treatments of terminal chronic uremia].

Among about 650,000 patients treated worldwide by maintenance dialysis methods for end-stage renal failure, approximately 85% undergo hemodialysis and 15% peritoneal dialysis. For the 25,000 patients thus treated in France in 1991, expenditures ranged between 8 to 10 billion French Francs. These socio-economic factors necessarily generate a conflict between resource allotment and medical ethics. One of the questionable options requiring decisions at the onset of treatment is the patient's age. An age-based patient selection is actually unfounded. In a recent French cohort of 213 patients treated exclusively with peritoneal dialysis and whose mean age at start of treatment was 79 +/- 4 years, the survival rate at three years was 45%. Patient selection for either a given mode or abstention from treatment should be based on a careful analysis of comorbidities associated with end stage renal failure. This selection process is sometimes very difficult to achieve successfully since some patients initially considered as being in an irreversible condition may greatly improve their status after a few weeks or months of dialysis. The dilemma is to decide whether or not initiate dialysis or to "give the patient a chance", looking forward to discontinue the treatment if no significant improvement is obtained. A successful kidney transplantation is widely accepted as the best treatment for end-stage renal failure. Unfortunately the number of organ donors (mainly cadaveric) remains insufficient to meet the demand, again raising a difficult issue of patient selection. In the future, further complex problems will emerge with the introduction of xenotransplantation. These and many other issues, including availability of treatments in developing countries have been and will continue to be subjects for debate among nephrologists, the medical community at large and also health care authorities as well as equipment manufacturers, with the ultimate aim of providing low-cost treatment for all the patients in the world who require a long-term life saving therapy.

Ethics, Medical↗
PubMed1996

A clinical phase I/II study of recombinant human interleukin-1 receptor in glucocorticoid-resistant graft-versus-host disease.

Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation. GVHD is accompanied by the release of inflammatory cytokines, including interleukin (IL)-1, and previous work has demonstrated that IL-1 participates in the pathogenesis of GVHD. The recombinant human IL-1 receptor (rhuIL-1R) is the soluble form of the type I IL-1 receptor that can bind to IL-1 and prevent cellular activation. We report a phase I/II trial utilizing the rhuIL-1R in the treatment of allogeneic bone narrow transplant patients not improving with glucocorticoid therapy. RhuIL-R was given at four dose levels for 21 days to 14 patients with progressive or persistent acute GVHD. The study drug had no clinical or persistent hematopoiesis and the treatment was tolerated by patients without toxicity at all dose levels. Eight of 14 patients (57%) had an improvement of GVHD after rhuIL-1R therapy. Improvement in GVHD was noted at each dose level, although a dose-response effect for rhuIL-1R treatment was not observed. This work supports the concept that IL-1 plays a role in the inflammation associated with acute GVHD. A controlled study of the rhuIL-1R for treatment of prophylaxis of GVHD is warranted.

Adult↗
PubMed1996

Human amniotic tumor that induces new bone formation in vivo produces growth-regulatory activity in vitro for osteoblasts identified as an extended form of basic fibroblast growth factor.

Tumors occasionally stimulate bone formation and cause osteoblastic metastases. Although this occurs most frequently in widespread prostate cancer, human prostate cancer cells are difficult to grow in culture without changing their phenotype, and the few available prostatic cancer lines do not increase bone formation in vivo. To identify tumor-derived osteoblast-stimulatory factors, we studied a long-established human tumor cell line derived from human amnion that has, in the past, been reported to cause bone formation in vivo when inoculated into nude mice. Tumor cells were inoculated into nude mice and induced extensive new bone formation. To characterize osteoblast growth factors produced by these tumor cells, solid tumor was isolated from the mice and extracted at neutral pH. Biological activity, assessed by stimulation of proliferation of MG-63 osteoblast-like cells, was used to monitor purification after heparin-Sepharose column chromatography, Mono-S, and C4 reverse-phase high-performance liquid chromatography. An extend amino-terminal form of basic fibroblast growth factor (FGF) was purified by its capacity to stimulate proliferation in MG-63 cells and partially sequenced. Basic FGF is also known to stimulate proliferation in MG-63 cells and other osteoblasts in vitro and bone formation in vivo. In summary, these human tumor cells stimulate new bone formation in vivo and produce an osteoblast stimulating activity in vitro, which has been identified as a form of basic FGF.

Amino Acid Sequence↗
PubMed1996

Recombinant human interleukin-1 receptor type I in the treatment of patients with active rheumatoid arthritis.

OBJECTIVE: To determine the safety and efficacy of recombinant soluble human interleukin-1 receptor type I (rHuIL-1RI) administered subcutaneously in patients with active rheumatoid arthritis (RA). METHODS: Twenty-three patients with active RA (>5 swollen joints) were enrolled into a randomized, double-blind, 2-center study. Patients received subcutaneous doses of rHuIL-1RI or placebo for 28 consecutive days. Patients were treated with 125, 250, 500, or 1,000 micrograms/m2/day of rHuIL-1RI. Physical examinations and laboratory assessments were performed at baseline (day 1), and 8, 15, 22, 29, 43, and 57 days after the start of the study. Analysis of peripheral blood by flow cytometry was performed on days 1 and 29 to determine the effects of rHuIL-1RI on the distribution and phenotypic characteristics of circulating inflammatory cells. RESULTS: Four of 8 patients who received rHuIL-1RI at 1,000 micrograms/m2/day demonstrated improvement in at least 1 of 8 individual measures of disease activity; however, only 1 of these 4 patients experienced clinically relevant improvement as defined by predetermined criteria. None of the patients treated with smaller doses of rHuIL-1RI, and none of the placebo-treated control patients, experienced any improvement as defined by the predetermined criteria. Monocyte cell surface IL-1alpha was significantly reduced following treatment with rHuIL-1RI at each dosage. Administration of rHuIL-1RI was stopped prematurely because of dose-limiting rashes in 2 patients treated with 1,000 micrograms/m2/day. No other adverse events prevented completion of the study. CONCLUSION: Only 1 patient, who was treated with the highest concentration of rHuIL-1RI employed (1,000 micrograms/m2/day), demonstrated clinically relevant improvement in this phase I study on this small group of patients with active RA. Dose-limiting toxicity was also observed in 2 patients treated with this highest concentration of rHuIL-1RI. Treatment with rHuIL-1RI did result in a reduction of monocyte cell surface IL-1alpha, which indicates that the dosages of rHuIL-1RI employed were functional.

Arthritis, Rheumatoid↗
PubMed1996

Characterization of a putative p53 binding site in the promoter of the mouse tissue inhibitor of metalloproteinases-3 (TIMP-3) gene: TIMP-3 is not a p53 target gene.

We have recently cloned the promoter of the mouse tissue inhibitor of metalloproteinases-3 (TIMP-3) gene and have identified a putative p53 binding site (5'-GGGCTTGCTT GACGTCCA GAACAGGGTC-3'), which contains two p53 consensus binding motifs (bold) with two nucleotide mismatches (underlined) in the second motif and an 8 bp spacer in between. Since both p53 and TIMP-3 are involved in cell cycle progression, we tested the hypothesis that TIMP-3 is a p53 downstream effector gene, mediating p53 activity. A good correlation between p53 protein levels and TIMP-3 expression was found among mouse liver cell lines. However, when TIMP-3 promoter driven luciferase constructs were tested for p53 responsiveness in these cells, the construct containing the putative p53 binding site did not show significant difference from the one having the p53 site deleted. The gel retardation assay showed that the oligo (T3) made from the putative p53 binding site in the mouse TIMP-3 promoter did not bind to p53 protein, nor did an oligo (T3W) with a correction for the two mismatched nucleotides in the second motif. When the 8 bp spacer was removed, however, the oligo T3WSF (same as the T3W with spacer free) but not T3SF (T3 without spacer) binds to p53, indicating that both the spacer between two motifs and consensus binding sites determined the p53 binding. It is worth noting that under a less stringent assay condition (0.2 microg instead of 1.0 microg of dI/dC), T3SF did weakly bind to p53. Lastly, the compounds that induce p53 transactivation activity did not induce TIMP-3 expression. We concluded from this study that TIMP-3 is not a p53 downstream effector gene.

Animals↗
PubMed1996

Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3.

Tissue inhibitor of metalloproteinases-3(TIMP-3), a novel member of TIMP family genes, has been recently cloned and shown to be expressed in preneoplastic but not in neoplastic mouse JB6 epidermal cells (Sun et al. 1994 Cancer Res., 54, 11139). This down regulation of the gene appears to be attributable at least in part to alteration of gene methylation (Sun et al. 1995 J. Biol. Chem., 270, 19312). Little is known, however, about the role of TIMP-3 in human cancers. We screened several human tumor cell lines for TIMP-3 expression and found that a colon carcinoma line, DLD-1, did not express TIMP-3. If down regulation of TIMP-3 is causally related to carcinogenesis, re-expression by transfection may reverse the tumor cell phenotype. We therefore overexpressed human TIMP-3 in DLD-1 cells. TIMP-3 transfectants showed a serum-dependent growth inhibition in monolayer culture and a decreased growth potential in nude mice in a manner dependent on the level of TIMP-3 expression. A transfectant expressing a high level of active hTIMP-3 completely lost the ability to form tumors following s.c. injection into nude mice. We also tested TIMP-3 expressing cells and neocontrol TIMP-3 negative cells for their ability to grow in liquid suspension culture, since both cells grew in semi-solid soft agar. As compared to neocontrol cells, TIMP-3 overexpressors formed large aggregates, followed by cell death. This effect was not mimicked by BB94, a broad MMP inhibitor. We conclude from this study that (i) TIMP-3 overexpression in human colon carcinoma cells induces growth arrest in low serum conditions and inhibits in vivo tumor growth and (ii) the TIMP-3-induced large aggregate formation and subsequent cell death under suspension growth cannot be explained by its MMP inhibitory activity.

Animals↗
PubMed1996

Chronic effects of endothelin-3 on blood pressure and renal haemodynamics in rats.

BACKGROUND: Renal vasoconstriction and systemic hypertension are well-known effects of bolus or short-term endothelin administration. However, the role of endothelin as a circulating hormone remains largely unknown. METHODS: The present study explores the effects of endothelin-3 (ET-3) on renal haemodynamics and systemic blood pressure during a 3-h and a 3-day intravenous infusion in rats. Male Sprague-Dawley (SD) rats were infused with vehicle (group 1) or ET-3 (group 2), 10 ng/kg per min; group 3, 50 ng/kg per min) delivered via osmotic minipumps into the right jugular vein for 3 days. On day 3 after pump implantation, rats were anaesthetized with Inactin and surgically prepared for assessment of mean arterial blood pressure (MABP), renal plasma flow (RPF), glomerular filtration rate (GFR), and renal vascular resistance (RVR). The same parameters were assessed during a 3-h ET-3 infusion study in SD rats (group 4, vehicle; group 5, ET-3, 10 ng/kg per min; group 6, ET-3, 50 ng/kg per min). RESULTS: In 3-day infused rats, ET-3 induced a significant decrease in RPF (-22+/-7% and -26+/-8% for group 2 and group 3 respectively, P<0.05 vs group 1) and an increase in RVR (+40+/-11% for groups 2 and 3; P<0.05 vs group 1); 50 ng/kg per min ET-3 significantly decreased GFR (-17%, P<0.05 vs group 1). MABP was not significantly affected by endothelin infusion. In acute infusion studies a decrease of the same magnitude was seen for the renal haemodynamics values. 50 ng/kg per min ET-3 increased MABP; a systemic effect that disappeared after the 3-day infusion. CONCLUSIONS: This study suggests that intravenously administered ET-3 in the rat has only a transient effect on systemic blood pressure, whereas it induces alterations in renal haemodynamics after both acute and chronic perfusions.

Animals↗
PubMed1996

cis Elements and trans factors are both important in strain-specific regulation of the leukotoxin gene in Actinobacillus actinomycetemcomitans.

Actinobacillus actinomycetemcomitans, the etiologic agent of localized juvenile periodontitis, produces a potent leukotoxin that kills human neutrophils. The production of leukotoxin RNA can vary more than 50-fold among isolates of A. actinomycetemcomitans, and strains expressing high levels of leukotoxin RNA are most often found at sites of periodontal disease. To assess the relative contributions of transcription factors and promoter sequences in setting the disparate levels of leukotoxin RNA found, we have undertaken classical cis/trans analyses. First, the leukotoxin promoter regions from moderately leukotoxic (Y4) and minimally leukotoxic (ATCC 33384) strains of A. actinomycetemcomitans were cloned, sequenced, and compared with the previously sequences leukotoxin promoter region of the high-producer strain JP2. The Y4 and ATCC 33384 promoter regions each contain a 528-bp segment that is absent from JP2. Interestingly, the analysis of various deletion constructs in A. actinomycetemcomitans indicated that Y4, despite the large insertion, initiates leukotoxin RNA synthesis at the same promoter as JP2 does. To perform cis/trans analyses, these three leukotoxin promoter regions were cloned into a plasmid upstream of the reporter gene beta-galactosidase. Each plasmid was transformed into JP2, Y4, and ATCC 33384, and the beta-galactosidase levels were determined. The results indicated that the sequences responsible for down-regulating leukotoxin RNA levels in Y4 relative to JP2 are found within the transcribed region of the Y4 leukotoxin operon. Importantly, in ATCC 33384, strain-specific trans factors and promoter sequence differences are equally significant in determining the lower levels of leukotoxin RNA. We hypothesize that either strain ATCC 33384 has a negative regulatory protein (which is missing or mutated in JP2/Y4) or that JP2 and Y4 carry an activator that is missing or mutated in ATCC 33384.

Aggregatibacter actinomycetemcomitans↗
PubMed1996

Clinical and magnetic resonance imaging features of L-2-hydroxyglutaric acidemia: report of three cases in comparison with Canavan disease.

We report three cases of L-2-hydroxyglutaric acidemia and three cases of Canavan disease. The L-2-hydroxyglutaric acidemia cases are the first biochemically proven Turkish cases. Magnetic resonance imaging findings in the cases and similarities between the two diseases are emphasized. Both diseases are characterized by predominant subcortical white-matter involvement and dentate nuclei lesions with variable basal ganglia involvement. Canavan disease differs from L-2-hydroxyglutaric acidemia by the presence of typical brainstem involvement.

Canavan Disease↗
PubMed1996

Transplantation of CD34+ hematopoietic progenitor cells.

We have developed an avidin-biotin immunoadsorption technique in conjunction with a monoclonal anti-CD34 antibody that is capable of selecting CD34+ progenitor cells from marrow and mobilized peripheral blood. Clinical studies with these CD34+ selected cells have shown that the cells are capable of rapid and durable engraftment. In addition, there is significantly less infusional toxicity to the patient because the volume in which the CD34+ selected cells are contained is much less than that of a typical marrow or apheresis buffy coat. Selection of CD34+ progenitor cells also offers other potential advantages, including T-cell depletion of allografts and tumor cell depletion of autografts. CD34+ selection can also be used to facilitate other manipulations of marrow and peripheral blood, including gene transfection, ex vivo stem cell expansion, tumor purging, and progenitor cell banking. Future graft engineering studies are expected to clarify these relationships and enable refinement of the graft to the point at which GVHD can be minimized, graft survival maximized, and relapse-free survival prolonged.

Antigens, CD34↗