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Biomedical subjects

L Gomez

Publications and source records attributed to L Gomez.

At least 37 records · Page 2Linked to original sources
PubMed1999

Recombinant human interleukin-11 is unlikely to stimulate the growth of the most common solid tumors.

Recombinant human interleukin-11 (rhIL-11) has been shown to enhance recovery from thrombocytopenia and mucosal injury after cancer chemotherapy. Since RNA for the receptor and signal transducer for IL-11 is detected in many cell types including some cancer cells, it was theoretically possible that rhIL-11 could affect the growth of tumor cells. This study was intended to determine whether rhIL-11 stimulates the proliferation of human tumor colony-forming units (TCFUs) taken directly from patients. Tumor cells were cultured in soft agar and continuously exposed to three concentrations of rhIL-11 (1.0, 10.0 and 100.0 U/ml) for 14 days in the capillary cloning system. Growth stimulation was noted in two of 66 (3%) of evaluable specimens, including one of 14 evaluable non-small cell lung cancer and one of five evaluable colon cancer specimens. In these two specimens, there was no increased stimulation of TCFUs with escalating concentrations of rhIL-11. Interestingly, the highest concentration of rhIL-11 tested inhibited the growth of 16 specimens (24.2%; 95% confidence interval 13.9-34.5%). Growth inhibition demonstrated a concentration-response relationship (p < 0.001). These results suggest that rhIL-11 appears unlikely to stimulate the growth of the most common solid tumors.

Antineoplastic Agents↗
PubMed1999

Comparative activity of the cyclopropylpyrroloindole compounds adozelesin, bizelesin and carzelesin in a human tumor colony-forming assay.

Adozelesin, bizelesin and carzelesin are synthetic cyclopropylpyrroloindole (CPI) analogs, a class of potent antineoplastic agents modeled on the antitumor antibiotic CC-1065, that specifically bind to the minor groove of DNA and preferentially alkylate AT-rich regions. These compounds were evaluated against fresh human tumors in a human tumor colony-forming assay (HTCFA) to assess and to compare their relative antitumor spectra, concentration-response relationships and schedule-dependence. Human tumor colony-forming units were treated with adozelesin and bizelesin at concentrations of 0.02, 0.1 and 0.5 ng/ml as a continuous exposure for 14 days, and to 0.2, 1.0 and 5.0 ng/ml as a 1 h exposure. Carzelesin concentrations were 0.04, 0.2 and 1 ng/ml as a continuous exposure, and 0.6, 3.0 and 15.0 ng/ml as a 1 h exposure. A response was scored if there was 50% or less colony survival. The three analogs had similar antitumor activity against colon carcinoma, kidney carcinoma and melanoma colony-forming units. Adozelesin also displayed activity against both breast and non-small cell lung carcinoma colony-forming units, and carzelesin was active against ovarian carcinoma colony-forming units. Significantly positive concentration-response relationships were apparent with all three agents. Responses increased from below 15% at the lowest concentration to above 45% at the highest concentration for the three drugs on all schedules (p < 0.01). At the highest concentration, the overall response rate was significantly higher (p < 0.01) with carzelesin on the continuous schedule (71%) compared to the 1 h schedule (46%). However, overall response rates for adozelesin and bizelesin were similar on both schedules (1 h/continuous: adozelesin, 67/58%; bizelesin, 49/44%), indicating that adozelesin and bizelesin are less schedule dependent than carzelesin in the HTCFA. These results demonstrate that the CPIs have broad-spectrum activity against human tumor colony-forming units in the HTCFA at very low concentrations, as well as differences with regard to schedule dependence which may help guide the optimal clinical development of these agents.

Antineoplastic Agents↗
PubMed1999

Antitumor activity of MGI 114 (6-hydroxymethylacylfulvene, HMAF), a semisynthetic derivative of illudin S, against adult and pediatric human tumor colony-forming units.

MGI 114 (6-hydroxymethylacylfulvene, HMAF) is a novel semisynthetic antitumor compound derived from the sesquiterpene mushroom toxin illudin S. Although illudins did not demonstrate significant activity as antiproliferative agents in tumor-bearing animals, several properties including its potent inhibition of DNA synthesis and a unique interaction with DNA led to a structure-activity-based synthetic effort to obtain analogs with improved therapeutic potential. MGI 114 was selected for further development based on its antitumor activity in numerous preclinical tests. MGI 114 was evaluated against adult and pediatric human tumors taken directly from cancer patients and cultured in a human tumor colony-forming assay (HTCFA) to assess the antitumor spectra, concentration-response relationship, schedule dependence and activity of this agent against tumors considered resistant to conventional anticancer drugs. Human tumor colony-forming units were treated with HMAF at concentrations of 0.001, 0.01, 0.1 and 1 microg/ml, both as a 1 h exposure and as a continuous 14 day exposure. A response was scored if there was 50% or less colony survival. In vitro response rates in the range of 50-80% were observed against tumor colony-forming units originating from carcinomas of the colon, kidney, breast, lung cancer, ovary and melanoma. MGI 114 also demonstrated antitumor activity against neuroblastoma colony-forming units. Antitumor activity was not influenced by exposure time as demonstrated by the similar responses rates obtained with the 1 h and continuous exposure at all concentrations tested. However, there was a significant positive concentration-response relationship to both exposure duration with responses increasing from below 10% at the lowest concentration to over 70% at the highest concentration, except for the pediatric tumors on the 1 h exposure for which this relationship was less apparent. At the higher concentration tested, MGI 114 displayed substantial antiproliferative effects in the range of 70% against tumor specimens resistant to classic cytotoxic agents including irinotecan, paclitaxel, 5-fluorouracil, cisplatin, doxorubicin and cyclophosphamide. These results demonstrate that MGI 114 exhibits a broad spectrum of antitumor activity against both adult and pediatric primary tumor colony-forming units in a concentration-dependent manner both at short and prolonged exposure duration. The substantial in vitro activity of MGI 114 at concentrations achievable in clinical trials, together with its activity against tumors resistant to classic standard cytotoxic drugs, justifies the further clinical evaluation of this unique agent.

Adolescent↗
PubMed1999

Heterologous expression of a plant small heat-shock protein enhances Escherichia coli viability under heat and cold stress.

A small heat-shock protein (sHSP) that shows molecular chaperone activity in vitro was recently purified from mature chestnut (Castanea sativa) cotyledons. This protein, renamed here as CsHSP17. 5, belongs to cytosolic class I, as revealed by cDNA sequencing and immunoelectron microscopy. Recombinant CsHSP17.5 was overexpressed in Escherichia coli to study its possible function under stress conditions. Upon transfer from 37 degrees C to 50 degrees C, a temperature known to cause cell autolysis, those cells that accumulated CsHSP17.5 showed improved viability compared with control cultures. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of cell lysates suggested that such a protective effect in vivo is due to the ability of recombinant sHSP to maintain soluble cytosolic proteins in their native conformation, with little substrate specificity. To test the recent hypothesis that sHSPs may be involved in protection against cold stress, we also studied the viability of recombinant cells at 4 degrees C. Unlike the major heat-induced chaperone, GroEL/ES, the chestnut sHSP significantly enhanced cell survivability at this temperature. CsHSP17.5 thus represents an example of a HSP capable of protecting cells against both thermal extremes. Consistent with these findings, high-level induction of homologous transcripts was observed in vegetative tissues of chestnut plantlets exposed to either type of thermal stress but not salt stress.

Amino Acid Sequence↗
PubMed1999

Contribution of ipratropium bromide to the bronchodilator test in patients with chronic obstructive pulmonary disease.

The aim of the study was to analyze the bronchodilator test (BDT) response to ipratropium bromide (IB) in patients with chronic obstructive pulmonary disease (COPD) who do not respond to inhaled terbutaline. Sixty patients with stable COPD who showed a negative response to BDT, defined as an increase of less than 160 ml in the forced expiratory volume in the first second (FEV1) after inhaling 1500 microg of terbutaline, were recruited. Each patients randomly received 200 microg of IB or placebo in a single blinded fashion, and a spirometric study was made at 30 and 60 min. The increase in absolute values of FEV1 at 30 and 60 min after IB was significantly higher than after placebo. The means +/- SD were 126 +/- 93 vs. 70 +/- 96 ml at 30 min and 148 +/- 120 vs. 74 +/- 132 ml at 60 min (P=0.01). The BDT was positive in 57% of patients who received IB, considering a positive response as an increase of FEV1 greater than 160 ml (P=0.01). We conclude that the BDT was positive with high doses of IB in more than half of COPD patients who did not respond to terbutaline alone.

Aged↗
PubMed1998

Electric fish measure distance in the dark.

Distance determination in animals can be achieved by visual or non-visual cues. Weakly electric fish use active electrolocation for orientation in the dark. By perceiving self-produced electric signals with epidermal electroreceptors, fish can detect, locate and analyse nearby objects. Distance discrimination, however, was thought to be hardly possible because it was assumed that confusing ambiguity could arise with objects of unknown sizes and materials. Here we show that during electrolocation electric fish can measure the distance of most objects accurately, independently of size, shape and material. Measurements of the 'electric image' projected onto the skin surface during electrolocation revealed only one parameter combination that was unambiguously related to object distance: the ratio between maximal image slope and maximal image amplitude. However, slope-to-amplitude ratios for spheres were always smaller than those for other objects. As predicted, these objects were erroneously judged by the fish to be further away than all other objects at an identical distance. Our results suggest a novel mechanism for depth perception that can be achieved with a single, stationary two-dimensional array of detectors.

Animals↗
PubMed1998

Founder effect in GLC1A-linked familial open-angle glaucoma in Northern France.

Open-angle glaucoma (POAG) is a highly prevalent cause of visual impairment. Six families grouping 71 living patients affected with juvenile-onset and middle-age POAG (age at diagnosis ranging from 10 to 65 years) were linked to the GLC1A locus. All patients carried a mutation of an evolutionarily conserved asparagine residue to a lysine at position 480 (N480K) in the olfactomedin-homology domain, which is encoded by the third exon of the GLC1A gene. The N480K mutation was also identified in 14 unaffected carriers who are at high risk of developing POAG. Although four of the families had ancestors identified in Northern France, the pedigrees could not be interconnected by genealogical investigation. However, haplotype analysis indicated that all the carriers had inherited the N480K mutation from the same founder. Screening of a selected set of 67 POAG patients who originated from Northern France and underwent trabeculectomy before the age of 50, detected one patient with the N480K mutation associated with the same disease haplotype already characterized in the 6 families. This group of 72 POAG patients is the largest one having a GLC1A mutation in common and provides a unique tool to investigate the factors influencing the variable expressivity of the GLC1A gene.

Adolescent↗
PubMed1998

Activity of pivaloyloxymethyl butyrate, a novel anticancer agent, on primary human tumor colony-forming units.

The anti-proliferative effects of pivaloyloxymethyl butyrate (AN-9), a butyric acid (BA) derivative with potent tumor-differentiating properties both in vitro and in vivo, was evaluated against colorectal, breast, lung, ovarian, renal cell, bladder, and other types of tumor colony-forming units in a human tumor cloning assay. A total of 76 evaluable specimens were exposed to AN-9 continuously, 48 of these were also exposed to BA continuously for direct comparison of the two agents, and 20 specimens were exposed to AN-9 for two hours. An in vitro inhibitory response was defined as a > or = 50% decrease in tumor colony formation in treated cells compared to untreated controls. Superior anti-tumor activity was observed with the continuous exposure to AN-9 (39% in vitro response at 100 microM and 70% at 200 microM) than with the two-hour exposure (20% at 100 microM and 25% at 200 microM). At a continuous concentration of 200 microM, AN-9 demonstrated greater tumor-specific activity than BA against melanoma (100% vs. 67%), ovarian (67% vs. 40%), breast (63% vs. 0%), non-small cell lung (60% vs. 10%), and colorectal tumor colony-forming units (62% vs. 20%). AN-9 is a novel differentiating agent with activity against colony-forming units derived from a variety of primary human tumors, including those that are considered relatively chemoresistant, and may thus provide a therapeutic alternative or addition to standard cytotoxic agents, if appropriate drug concentrations can be achieved in patients.

Antineoplastic Agents↗
PubMed1998

Activity of (-)-2'-deoxy-3'-oxacytidine (BCH-4556) against human tumor colony-forming units.

BACKGROUND: BCH-4556 ((-)-2'-deoxy-3'-oxacytidine) is an L-nucleoside analogue shown to have broad preclinical anti-cancer activity, particularly against solid neoplasms such as prostate, renal, and hepatoma in vitro and in vivo, in contrast to cytosine arabinoside (ara-C) which is preferentially active against leukemia. MATERIALS AND METHODS: The antitumor activity of BCH-4556 was evaluated using human tumor colony-forming unit (HTCFU) assay, in which fresh tumor specimens were taken directly from patients with and without prior chemotherapy. RESULTS: Overall, in vitro responses (50% or less survival compared to untreated controls) were observed in 11% (two of 18), 29% (five of 17) and 50% (nine of 18) of specimens treated for one hour with BCH-4556 at 1, 10 and 100 micrograms/ml, respectively; and 16% (nine of 55), 32% (24 of 74), 48% (35 of 73) and 65% (11 of 17) of specimens treated continuously with BCH-4556 at 0.1, 1, 10 and 100 micrograms/ml, respectively. With the one-hour schedule, a significant difference in response rates was noted between 100 micrograms/ml and 1 microgram/ml (P = 0.02). With the continuous schedule, significant differences in response rates were observed between 1 microgram/ml and 0.1 microgram/ml (P = 0.02), between 10 micrograms/ml and 0.1 microgram/ml (P = 0.0001), as well as between 10 micrograms/ml and 1 microgram/ml (P = 0.01). A trend suggesting the superiority of continuous exposure was observed in paired specimens (n = 18) at comparable drug concentrations. Activity was noted against ovarian (nine of 16 = 56%), renal (three of four = 75%), and melanoma (two of two = 100%) HTCFU at 10 micrograms/ml using the continuous schedule. Comparisons between BCH-4556 and paclitaxel were made in 32 specimens at 10 micrograms/ml using the continuous exposure. Twenty-three specimens showed similar responses with both drugs; seven showed better responses with BCH-4556; and two showed better responses with paclitaxel (P = 0.18). CONCLUSIONS: Promising activity was observed with BCH-4556 against ovarian, renal, and melanoma HTCFU. There appeared to be a positive relationship between BCH-4556 concentration and response using both one-hour and continuous exposures. Continuous exposure to BCH-4556 provided high response rates especially at concentrations above 10 micrograms/ml. For both one-hour and continuous exposures, BCH-4556 had similar, and at times, greater potency than paclitaxel against the same tumor specimens in the present study.

Antineoplastic Agents↗
PubMed1998

Neutropenic enterocolitis: spectrum of the disease and comparison of definite and possible cases.

Twenty-nine cases of neutropenic enterocolitis (NEC) were identified from 1992 to June 1996, and their clinical, microbiological, and radiologic characteristics were reviewed. Eighteen of 29 episodes were considered to be definite NEC since abdominal computed tomographic or ultrasonographic findings (n = 14) and/or pathological findings (n = 7) were consistent with the diagnosis, whereas 11 were classified as possible NEC since these findings were normal or nondiagnostic. Abdominal pain, diarrhea, and fever occurred in nearly all cases in both groups, whereas bloody stools were more frequent and the duration of diarrhea was longer in definite cases. Other clinical, laboratory, and microbiological findings were of variable frequencies, with no apparent differences between groups. All 29 patients received medical/supportive treatment, and only five deaths were related to NEC. We conclude that NEC has a broad spectrum of clinical presentation, but patients whose imaging studies are positive appear to have a more serious form of the disease. Medical management appears appropriate in most cases, as the associated mortality rate is < 20%.

Adult↗
PubMed1998

Site-directed mutagenesis of active site residues in a class I endochitinase from chestnut seeds.

Despite the intensive research on plant chitinases, largely bolstered by their antifungal properties, little is known at present about the structure-activity relationships of these enzymes. Here we report the identification of essential active site residues in endochitinase Ch3, a class I enzyme abundant in chestnut seeds. Knowledge-based protein modeling as well as structural and sequence comparisons were performed to identify potential catalytic residues. Different mutated proteins were then generated by site-directed mutagenesis, expressed in Escherichia coli , and characterized for their chitinolytic activity. Glu124 and Glu146, the only carboxylic residues properly located into the active site cleft to participate in catalysis, were both mutated to Gln and Asp. Our results suggest that Glu124 functions as the general acid catalyst whereas Glu146 is likely to act as a general base. Other mutations involving three highly conserved active site residues, Gln173, Thr175, and Asn254, also impaired the chitinolytic activity of Ch3. The effects of these variants on the fungus Trichoderma viride revealed that catalysis is not necessary for antifungal activity. Similarly to its homologous nonenzymatic polypeptides hevein and stinging nettle lectin, the N-terminal chitin-binding domain of Ch3 appears to interfere itself with hyphal growth.

Amino Acid Sequence↗
PubMed1998

Antiproliferative effects of recombinant human bone morphogenetic protein-2 on human tumor colony-forming units.

Bone morphogenetic protein-2 (BMP-2) is a differentiation factor for normal osteoblasts. BMP-2 is structurally related to transforming growth factor-beta which inhibits cell proliferation and enhances apoptosis. A recent study has shown the presence of BMP-2 receptors on several cancer cell lines. In this study, we attempted to determine if recombinant human BMP-2 (rhBMP-2) can modulate the proliferation of human tumor colony-forming units taken from 113 patients. Tumor cells were cultured in soft agar and continuously exposed to three concentrations of rhBMP-2 (10, 100 and 1000 ng/ml) for 14 days in the capillary cloning system. There were 65 evaluable specimens, including 17 breast cancers, 15 ovarian cancers, 14 non-small cell lung cancers and five prostate cancers. Importantly, rhBMP-2 did not stimulate the tumor cell proliferation. A significant inhibition (50% or less survival of tumor colony-forming units) was seen in 16 of 65 specimens (24.6%) at 1000 ng/ml, including five of 14 non-small cell lung cancers, five of 17 breast tumors and two of 15 ovarian tumors. A concentration-response relationship was observed (p<0.001 by Mantel-extension test). The results of this study encourage further evaluation of the antiproliferative effects of rhBMP-2 against human cancers.

Bone Morphogenetic Protein 2↗
PubMed1997

Association of the AChRalpha-subunit gene (CHRNA), DQA1*0101, and the DR3 haplotype in myasthenia gravis. Evidence for a three-gene disease model in a subgroup of patients.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction having multigene control. HLA-linked loci and the HB*14 micro-satellite marker located within the CHRNA gene which encodes the muscular acetylcholine receptor (AChR) alpha-subunit, the target self-antigen, were previously associated with MG. Combined analysis of these loci revealed a significant increase of DQA1*0101 alleles in HB*14+ vs. HB*14- patients and of DQA1*0501 alleles in HB*14/DQA1*0101 patients. Importantly, the effect of DQA1*0101 was independent of allelically associated DQB1 and DRB1 genes. In contrast, the effect of DQA1*0501 could not be dissociated from that of DRB1*03 and DQB1*0201 on the extended DR3 haplotype. These results indicate that a combination of three genes, of which two are linked to HLA, contributes to disease susceptibility in a subgroup of MG patients.

Adult↗
PubMed1997

Clinical spectrum of X-linked hyper-IgM syndrome.

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Bone Marrow Transplantation↗
PubMed1997

No evidence for an association of AChR beta-subunit gene (CHRNB1) with myasthenia gravis.

Using a polymorphic dinucleotide repeat, we have investigated the contribution of the gene encoding the beta-subunit of the muscle acetylcholine receptor (CHRNB1), the target autoantigen, to the susceptibility to myasthenia gravis (MG). We have combined a case-control study (comparing 143 patients and 162 controls) and a transmission-disequilibrium test bearing on 35 simplex families with heterozygous parents. There was no evidence for an association of CHRNB1 with MG, even after subgrouping patients according to thymus histology, or other clinical criteria. Interestingly however, the shortest four variants of the CHRNB1 microsatellite were seen only in patients with thymus hyperplasia and in none of the control subjects (P < 0.0025).

Adult↗
PubMed1997

Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma.

Primary open-angle glaucoma (POAG) is a highly prevalent cause of irreversible blindness which associates cupping of the optic disc and alteration of the visual field, elevation of intraocular pressure being a major risk factor. Provided diagnosis is made at an early stage, treatments are available to prevent visual impairment. A locus, GLC1A, has been mapped on chromosome 1q23-q25 in several families affected with juvenile-onset POAG (JOAG) and also in some families affected with juvenile and middle-age onset POAG. Recently, three mutations of the TIGR (Trabecular meshwork-Induced Glucocorticoid Response) gene were shown to be responsible for the disease in several American families and in unrelated POAG patients. We now describe five new mutations in eight French families. All mutations known to date appear to concentrate in the evolutionarily conserved C-terminal domain of TIGR which bears homology to frog olfactomedin, an extracellular matrix glycoprotein of the olfactory epithelium, to rat and human neuronal olfactomedin-related proteins and to F11C3.2, a protein from Caenorhabditis elegans . Moreover, this conserved domain of TIGR is encoded by a single exon to which mutation screening could be limited. Surprisingly, the TIGR message, which is abundantly transcribed in the trabecular meshwork and also in the ciliary body and the sclera, is not expressed in the optic nerve whose degeneration is, however, the primary lesion of POAG.

Adolescent↗
PubMed1997

Purification and in vitro chaperone activity of a class I small heat-shock protein abundant in recalcitrant chestnut seeds.

A 20-kD protein has been purified from cotyledons of recalcitrant (desiccation-sensitive) chestnut (Castanea sativa) seeds, where it accumulates at levels comparable to those of major seed storage proteins. This protein, termed Cs smHSP 1, forms homododecameric complexes under nondenaturing conditions and appears to be homologous to cytosolic class I small heat-shock proteins (smHSPs) from plant sources. In vitro evidence has been obtained that the isolated protein can function as a molecular chaperone; it increases, at stoichiometric levels, the renaturation yields of chemically denatured citrate synthase and also prevents the irreversible thermal inactivation of this enzyme. Although a role in desiccation tolerance has been hypothesized for seed smHSPs, this does not seem to be the case for Cs smHSP 1. We have investigated the presence of immunologically related proteins in orthodox and recalcitrant seeds of 13 woody species. Our results indicate that the presence of Cs smHSP 1-like proteins, even at high levels, is not enough to confer desiccation tolerance, and that the amount of these proteins does not furnish a reliable criterion to identify desiccation-sensitive seeds. Additional proteins or mechanisms appear necessary to keep the viability of orthodox seeds upon shedding.

Amino Acid Sequence↗