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Biomedical subjects

B C Gomes

Publications and source records attributed to B C Gomes.

At least 19 recordsLinked to original sources
PubMed2001

Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB.

The tumor necrosis factor (TNF) receptor family are ligand-regulated transmembrane proteins that mediate apoptosis as well as activation of the transcription factor NF-kappaB. Exogenous expression of DR6, a recently identified member of the TNF receptor family, induced apoptosis in untransformed or tumor-derived cells and the apoptotic function of DR6 was inhibited by co-expression of Bcl-2, Bcl-x(L) or the inhibitor-of-apoptosis (IAP) family member, survivin. Expression of a dominant negative mutant of FADD failed to protect from DR6-mediated apoptosis indicating that unlike TNFR1 and Fas, DR6 induced apoptosis via a FADD-independent mechanism. Despite the ability of exogenous DR6 expression to induce apoptosis, DR6 mRNA and protein were found to be elevated in prostate tumor cell lines and in advanced stages of prostate cancer. Analysis of several anti-apoptotic proteins revealed that Bcl-x(L) levels and serine 32 phosphorylation of IkappaB, the natural inhibitor of NF-kappaB, were similarly elevated in cells expressing high levels of DR6, suggesting that NF-kappaB-regulated survival proteins may protect from DR6-induced apoptosis and that DR6 is a target of NF-kappaB regulation. Treatment of LnCAP cells with TNF-alpha resulted in increases in both DR6 mRNA and protein levels, and this induction was suppressed by inhibitors of NF-kappaB. Similarly, treatment of cells expressing high levels of DR6 with indomethacin and ibuprofen, compounds also known to perturb NF-kappaB function, resulted in a dose-dependent decrease in DR6 protein and mRNA levels. These results demonstrate that TNF-alpha signaling induces the expression of a member of its own receptor family through activation of NF-kappaB.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Livin, a novel inhibitor of apoptosis protein family member.

A novel human inhibitor of apoptosis protein (IAP) family member termed Livin was identified, containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. The mRNA for livin was not detectable by Northern blot in most normal adult tissues with the exception of the placenta, but was present in developmental tissues and in several cancer cell lines. Highest levels were observed in two melanoma-derived cell lines, G361 and SK-Mel29. Transfection of livin in HeLa cells resulted in protection from apoptosis induced by expression of FADD, Bax, RIP, RIP3, and DR6. Similar to other IAP family members, the anti-apoptotic activity of Livin was dependent on the BIR domain. Livin was also capable of inhibiting DEVD-like caspase activity triggered by tumor necrosis factor-alpha. In vitro binding studies demonstrated a direct interaction between Livin and the active form of the downstream caspases, caspase-3 and -7, that was dependent on the BIR domain of Livin. In addition, the unprocessed and cleaved forms of caspase-9 co-immunoprecipitated with Livin in vivo, and recombinant Livin could inhibit the activation of caspase-9 induced by Apaf-1, cytochrome c, and dATP. The subcellular distribution of the transfected Livin was analyzed by immunofluorescence. Both Livin and Survivin were expressed in the nucleus and in a filamentous pattern throughout the cytoplasm. In contrast to the apoptotic activity, the COOH-terminal RING domain mediated its subcellular localization patterning. Further studies found that transfection of an antisense construct against livin could trigger apoptosis specifically in cell lines expressing livin mRNA. This was associated with an increase in DNA fragmentation and in DEVD-like caspase activity. Thus, disruption of Livin may provide a strategy to induce apoptosis in certain cancer cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria.

A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-kappaB activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis. Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis.

Amino Acid Sequence↗
PubMed1995

A filtration-based assay to quantitate granulocyte-macrophage colony-stimulating factor binding.

Filtration-based binding assays have numerous advantages over centrifugation-based assays, yet they have not been established for many protein ligands due to the high nonspecific binding of the protein to the membrane filter. This paper describes a vacuum filtration method that permits quantitative evaluation of [125I]GM-CSF binding to its receptor on intact cells. The method includes the use of glass fiber filters presoaked in a solution of polyvinylpyrrolidone and Tween 20 to greatly reduce nonspecific binding of the protein ligand. The ratio of specific:nonspecific binding observed with this filtration assay was comparable to values reported for centrifugation assays. [125I] GM-CSF binding to HL-60 cells was shown to be time-dependent, saturable, and specific. The estimated Kd (70 pM) and Bmax (160 r/cell) were similar to values reported using centrifugation assays. This filtration method is much less labor-intensive, has greater sample throughput, and allows for a more rapid determination of GM-CSF binding compared to the centrifugation-based assay. Although developed to quantitate the binding of GM-CSF to its receptor on intact cells, this assay is also applicable to other cytokines and can be used with both intact cells and isolated plasma membrane preparations.

Cell Line↗
PubMed1995

Nonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, intratracheally active, pyridone-based trifluoromethyl ketone.

Further modification of the 3-amino substituent in a trifluoromethyl ketone-based series of 3-amino-6-phenylpyridin-2-ones that had been optimized for oral activity led to analogs that were potent intratracheal inhibitors in a model of HLE-induced lung damage in the hamster. The best 3-amino substituent for intratracheal activity is [4-[N-[(4-chlorophenyl)sulfonyl]-carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED50 of approximately 2 nmol/animal and, qualitatively, afforded a very similar dose-response relationship to that found with a peptidic trifluoromethyl ketone inhibitor, ICI 200,355.

Administration, Inhalation↗
PubMed1994

Nonpeptidic inhibitors of human leukocyte elastase. 2. Design, synthesis, and in vitro activity of a series of 3-amino-6-arylopyridin-2-one trifluoromethyl ketones.

A series of potent nonpeptidic inhibitors of the enzyme human leukocyte elastase (HLE) is reported. These inhibitors contain a 3-amino-2-pyridone ring as a central template in which the pyridone carbonyl and 3-position NH group are thought to form important hydrogen bonding interactions with the Val-216 residue of HLE. Substitution of the 6-position of the pyridone ring by various alkyl and aryl groups was found to afford increases in the in vitro potency of these inhibitors. A 6-position phenyl group, compound 10f, was found to result in a large increase in binding affinity, which was not obtained when the phenyl group was placed in either the 4- or 5-position of the molecule. Compound 10f was found to have good selectivity for HLE over other proteolytic enzymes, with the exception of bovine pancreatic chymotrypsin (BPC). Substitution of the 6-phenyl group in these molecules was found to decrease binding affinity for BPC without adversely affecting affinity for HLE.

Acetamides↗
PubMed1994

Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones.

A series of nonpeptidic inhibitors of human leukocyte elastase (HLE) is reported. These trifluoromethyl ketone-based inhibitors contain a 3-amino-6-phenylpyridone group as a central template. The effect of varying the N-3 substituent in these inhibitors on in vitro potency, physical properties, and oral activity in a hamster based, HLE-induced lung damage model is described. The variety of substituents at this position that have little effect on in vitro potency supports the idea that this region of the molecule does not interact strongly with the enzyme. One exception to this generality is 13k, which is substituted with a (4-acetamidophenyl)sulfonyl group. This compound has a K(i) of 0.7 nM and is, in vitro, the most potent inhibitor in the series. In contrast, variation of the N-3 substituent was found to have a dramatic effect on activity after oral administration. Several analogs, including the parent amine, 7, formamide, 2u, benzyl sulfamide, 13e, and benzyl sulfonamide, 13f, show significant activity when administered at an oral dose of 2.5 mg/kg. Support for the modeling-based design concepts was obtained through in vitro SAR results and X-ray crystallographic analysis of the complex between 13d and porcine pancreatic elastase (PPE), a closely related enzyme.

Acetamides↗
PubMed1993

Acrolein increases airway sensitivity to substance P and decreases NEP activity in guinea pigs.

The effects of acrolein exposure on airway responses to intravenous substance P were determined in guinea pigs exposed to vehicle or 1.6 ppm acrolein for 7.5 h on 2 consecutive days and examined 1, 4, 8, 15, and 28 days after exposure by use of pulmonary mechanics and bronchoalveolar lavage (BAL). Lung, trachea, liver, and BAL fluid were also assayed for neutral endopeptidase (NEP) activity 1, 7, and 28 days after exposure. Pulmonary inflammation and epithelial damage were prominent 1 day after acrolein exposure. NEP activity was decreased in the lungs, trachea, and liver 1 and 7 days after acrolein. Twenty-eight days after exposure, NEP activity in the lungs and liver was not significantly different in vehicle- and acrolein-exposed guinea pigs but was still reduced in tracheal tissue. The BAL NEP activity in acrolein-exposed guinea pigs was approximately twice that of vehicle control guinea pigs at all three time points. Acrolein caused a prolonged increase in airway sensitivity to substance P. Experiments performed in the presence of thiorphan suggested that the acrolein-induced reduction in NEP may contribute to increased airway sensitivity to aerosolized substance P, but the increase in airway sensitivity to intravenous substance P may occur by additional mechanisms.

Acrolein↗
PubMed1992

Periodontal considerations in children.

The initial elimination of gingival involvement is not a great problem in children and the adolescent. The difficulty lies in maintaining gingival health once it has been re-established, particularly during puberty. The answer lies in frequent recalls during which the importance of plaque control must be re-emphasized, the use of the periodontal probe introduced to the patient, and problem areas dealt with immediately. Recalls at frequent intervals is one of the best ways of combating patient non-compliance.

Adolescent↗
PubMed1991

Inhibition of human neutrophil elastase by ICI 200,355.

To examine the pathogenetic role of neutrophil elastase in airway hypersecretion, we have studied the novel inhibitor of this enzyme, [4-(4-bromophenylsulfonylcarbamoyl)benzoyl-L-valyl-L-proline 1 (RS)-(1-trifluroacetyl-2-methylprolyl)amide] (ICI 200, 355). This compound was a potent (Ki = 0.6 +/- 0.22 nM) inhibitor of human neutrophil elastase and a much weaker inhibitor of other hydrolases. ICI 200,355 also inhibited the ongoing destruction of insoluble elastin by human neutrophil elastase. ICI 200,355 produced a concentration-dependent inhibition of the secretory response induced by human neutrophil elastase (10(-8) M), with an IC50 of 1.6 x 10(-8) M. ICI 200,355 had no effect on baseline secretion or on the secretory response to chymase, cathepsin G or Pseudomonas aeruginosa elastase. Thus, ICI 200,355 appears to be a useful tool for investigating the role of human neutrophil elastase in inflammatory disorders associated with hypersecretion, such as cystic fibrosis, chronic bronchitis, and asthma.

Elastin↗
PubMed1990

Periodontal considerations of the removable partial overdenture.

1. An overdenture, whether complete or partial, is an excellent mode of treatment in the mutilated dentition for the preservation of the residual ridge. 2. Selection of patients for an overdenture should be based on past history of dental neglect, the status of the teeth and their periodontium, including present oral hygiene status, and patient motivation. The patients with a history of dental neglect, poor oral hygiene, and lack of motivation in having the teeth and the periodontium restored to health as well as strict compliance to a home-care regimen and recall schedule are not good candidates for treatment with an overdenture. 3. The choice of teeth or roots to serve as overdenture abutments must include their periodontal evaluation, which should consist of a detailed periodontal examination, diagnosis, prognosis, and treatment when this is indicated, including chemical protection (fluoride gel) and an oral hygiene regimen tailored to individual needs. 4. The knowledge and expertise in the selection and implementation of appropriate periodontal treatment modalities is of paramount importance in restoring optimum periodontal health to the overdenture abutments before overdenture fabrication. 5. The maintenance phase of the overdenture abutments as well as of the existing natural teeth is of critical importance in the preservation of health of these abutments and teeth. This maintenance phase should consist of periodic recalls based on individual needs; a detailed periodontal evaluation, including patient's motivation and status of oral hygiene and denture hygiene; and detection of caries. If necessary, appropriate periodontal and/or restorative therapy should be performed, and oral hygiene measures reinforced. This will ensure longevity of both abutment teeth or roots and of the existing natural teeth resulting in a long-term success of an overdenture. 6. Because there is evidence of high incidence of periodontal disease and dental caries in overdenture wearers, and because this evidence is attributed mainly to lack of motivation and compliance of adequate oral hygiene as well as to frequency of recall visits, patients should be made aware of the importance of their role in the maintenance phase of treatment and in the factors that lead to ultimate success of overdenture therapy. 7. With (a) proper selection of the patient and the abutment teeth, (b) adequate periodontal and restorative health and treatment to ensure optimum health prior to RPOD construction, (c) a well-designed home-care regimen and frequency of recalls, and (d) proper execution of maintenance care, changes for long-term success of overdenture therapy will be much improved.

Dental Abutments↗
PubMed1988

An organ culture system designed to study interaction of fetal rat calvaria with human head and neck squamous cell carcinoma.

The development of permanent cell lines of human head and neck squamous cell carcinoma in culture has enabled these cell lines to be used to investigate the interaction of the tumor cells with bone. After the squamous carcinoma lines on fetal rat skulls were implanted the explants with their added tumor were maintained in long-term tissue culture by use of the procedures developed for growing these tumor cells. Results confirm direct interaction with the bone by the malignant cells. Specific surface and cytoplasmic markers have been demonstrated by use of monoclonal antibodies against the tumor cells. Furthermore, tumor angiogenesis without the addition of any endogenous endothelial components has been verified. Investigations into the degree of bone infiltration and susceptibility of these interacting tumor cells to various factors, radiation therapy, and chemotherapeutic agents have been carried out. The establishment of a model system for bony invasion by squamous cell carcinoma of the head and neck permits the investigation of the mechanism of tumor invasion and the study of various potential treatment modalities.

Animals↗
PubMed1986

Histologic study of the inhibition of bone resorption in organ cultures by myo-inositol-2-monophosphate.

This study examines chemically and histologically the relative abilities of inositol monophosphate (IP1), inorganic phosphate (Pi), ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene disphosphonate (Cl2MDP) to inhibit parathyroid hormone (PTH)--induced resorption of fetal rat long bones in organ culture. Pregnant rats injected with 45Ca on the 18th day of gestation were killed the next day and their fetuses removed. Half of each pair of dissected long bones was incubated in a chemically defined control medium while the contralateral half was incubated in medium containing PTH or PTH plus the compound to be tested. 45Ca released into the medium was indicative of the amount of bone resorption. Bones were then processed histologically and examined microscopically. All compounds inhibited resorption to some extent with IP1 and Pi being less effective than EHDP or C12MDP at comparable phosphate concentrations. However, the disphosphonates damaged osteoclasts whereas IP1 and Pi did not. This suggests that IP1 may inhibit resorption by a different mechanism perhaps related only to prevention of crystal dissolution.

Animals↗
PubMed1984

Tetracyclines inhibit parathyroid hormone-induced bone resorption in organ culture.

Several tetracyclines (minocycline, doxycycline, tetracycline), in levels approximating physiologic concentrations, were found to inhibit parathyroid hormone-induced bone resorption in organ culture; the specificity of this effect was demonstrated by comparison with other (non-tetracycline) types of antibiotics. The ability of tetracyclines to inhibit bone resorption is consistent with the recent proposal by Golub et al. that these antibiotics can inhibit mammalian collagenolytic enzymes by a mechanism unrelated to the drug's antibacterial efficacy, a property which could be therapeutically useful in diseases characterized by excessive collagen breakdown.

Animals↗
PubMed1984

Four-year longitudinal study of the periodontal health status of overdenture patients.

Seven patients with a total of 12 roots were treated with overdentures (maxillary, mandibular, or both) and recalled at 6-month intervals for a period of 4 years. A periodontist evaluated the periodontal health status of the abutment roots after complete periodontal therapy, immediately prior to placement of the overdentures, and at all recall visits. The gingival tissues around all the abutments were slightly erythematous and edematous and bled on probing. There were no statistically significant changes in pocket depth or in apparent width of attached gingiva on an intra-arch basis. However, statistically significant changes were found on comparison between the maxillary and mandibular arches. Over the 4-year period 50% of the roots remained immobile, 25% of the roots that were initially mobile exhibited no mobility, and 25% of the roots decreased in mobility. Five of 14 roots in eight patients (35.7% of the abutment roots) developed dental caries. Periodic recalls to reinforce plaque control measures, to provide adjunctive periodontal therapy, and to correct and adjust the prostheses of patients treated with overdentures are important factors in the longterm success of this treatment modality. Biomechanically, treatment of patients with overdentures is a valid practical alternative to complete dentures.

Dental Abutments↗
PubMed1984

Inhibitory effect of inositol phosphates on parathyroid hormone-induced bone resorption in organ cultures.

This study investigates the ability of phytic acid, its inositol phosphate derivatives (inositol penta-, tetra-, tri-, di-, and monophosphate), and inorganic phosphate to inhibit parathyroid hormone (PTH)-induced resorption of fetal rat long bones in organ culture. Pregnant rats injected with 45Ca on the 18th day of gestation were killed the next day and their fetuses removed. Half of each pair of dissected long bones was incubated in a chemically defined control medium, while the contralateral half was incubated in medium containing PTH or PTH plus the phosphate compound to be tested. 45Ca released into the medium was indicative of the amount of bone resorption. All phosphate compounds tested inhibited resorption. The inositol phosphates should be studied further to assess their suitability as therapeutic agents for treatment of metabolic bone diseases involving increased turnover.

Animals↗