Biomedical subjects

C L Santos

Publications and source records attributed to C L Santos.

At least 19 recordsLinked to original sources

PubMed2003

Cytotoxic mannich bases of 1-arylidene-2-tetralones.

Various 1-arylidene-2-tetralones 1 had been shown previously to possess moderate cytotoxic properties unaccompanied by murine toxicity. The objective of the present investigation was to undertake different molecular modifications of representative members of series 1 with a view to discerning those structural features leading to increased potencies. All compounds were evaluated using human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. The Mannich bases 2, 4, 5 and 7 possessed increased potencies compared to the corresponding unsaturated ketones 1 and in general were potent cytotoxics having IC50 values in the 0.2-10 microM range. QSAR using the cytotoxicity data for 2a-e suggested that potency was positively correlated with the size of the substituents in the arylidene aryl ring. Compounds 2a-f were evaluated using a panel of approximately 53 human tumour cell lines and, when all cell lines were considered, were more potent than the reference drug melphalan. In particular, marked antileukemic activity was displayed. Molecular modeling was utilized in order to evaluate whether the shapes of the different compounds contributed to the varying potencies observed. Representative compounds demonstrated minimal or no inhibiting properties towards human N-myristoyltransferase (NMT) and did not bind to calf thymus DNA. This study has revealed a number of unique lead molecules as candidate anti-neoplastic agents serving as prototypes for future development.

Acyltransferases↗

PubMed2003

3,5-bis(phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones: a novel group of cytotoxic agents.

A series of novel 3,5-bis(phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones 3 have been synthesized which displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. In contrast, the related N-arylmaleamic acids 4 possessed little or no cytotoxicity in these four screens. Molecular modeling revealed certain interplanar and bond angles and interatomic distances which were perceived to contribute to the observed bioactivity as well as providing suggestions for future structural modifications of the piperidones 3. Evaluation of representative compounds in series 3 and 4 on the activity of human N-myristoyltransferase revealed that, at the maximum concentration utilized, namely 250 microM, only weak inhibiting properties were displayed by some of the compounds in series 4. Various members of series 3 and 4 were well tolerated in mice.

Animals↗

PubMed2003

Cytotoxic 4'-aminochalcones and related compounds.

A series of 4'-aminochalcones 1 and related maleamic acids 2 and Schiff bases 3 were designed and synthesized as candidate cytotoxic agents. The atomic charges on different atoms of representative compounds were calculated. Evaluation of the enones 1-3 against human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells revealed that approximately 40% of the IC50 values generated were less than 10 microM. In some cases cytotoxicity was correlated with the Hammett sigma values of the aryl substituents and less frequently with the aryl Hansch pi values. Evidence was obtained that in general these compounds displayed selective toxicity for certain malignant cells and were well tolerated in mice. This study has revealed various directions whereby the project may be amplified in the future with a view to finding compounds with increased cytotoxicity to tumour cells.

Animals↗

PubMed2001

Phenotypic and molecular analyses of yellow fever 17DD vaccine viruses associated with serious adverse events in Brazil.

The yellow fever (YF) 17D virus is one of the most successful vaccines developed to data. Its use has been estimated to be over 400 million doses with an excellent record of safety. In the past 3 years, yellow fever vaccination was intensified in Brazil in response to higher risk of urban outbreaks of the disease. Two fatal adverse events temporally associated with YF vaccination were reported. Both cases had features similar to yellow fever disease, including hepatitis and multiorgan failure. Two different lots of YF 17DD virus vaccine were administered to the affected patients and also to hundreds of thousands of other individuals without any other reported serious adverse events. The lots were prepared from the secondary seed, which has been in continuous use since 1984. Nucleotide sequencing revealed minor variations at some nucleotide positions between the secondary seed lot virus and the virus isolates from patients; these differences were not consistent across the isolates, represented differences in the relative amount of each nucleotide in a heterogeneous position, and did not result in amino acid substitutions. Inoculation of rhesus monkeys with the viruses isolated from the two patients by the intracerebral (ic) or intrahepatic (ih) route caused minimal viremia and no clinical signs of infection or alterations in laboratory markers. Central nervous system histological scores of rhesus monkeys inoculated ic were within the expected range, and there were no histopathological lesions in animals inoculated ih. Altogether, these results demonstrated the genetic stability and attenuated phenotype of the viruses that caused fatal illness in the two patients. Therefore, the fatal adverse events experienced by the vaccinees are related to individual, genetically determined host factors that regulate cellular susceptibility to yellow fever virus. Such increased susceptibility, resulting in clinically overt disease expression, appears to be extremely rare.

Animals↗

PubMed2001

Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases.

BACKGROUND: The yellow fever vaccine is regarded as one of the safest attenuated virus vaccines, with few side-effects or adverse events. We report the occurrence of two fatal cases of haemorrhagic fever associated with yellow fever 17DD substrain vaccine in Brazil. METHODS: We obtained epidemiological, serological, virological, pathological, immunocytochemical, and molecular biological data on the two cases to determine the cause of the illnesses. FINDINGS: The first case, in a 5-year-old white girl, was characterised by sudden onset of fever accompanied by headache, malaise, and vomiting 3 days after receiving yellow fever and measles-mumps-rubella vaccines. Afterwards she decompensated with icterus and haemorrhagic signs and died after a 5-day illness. The second patient-a 22-year-old black woman-developed a sore throat and fever accompanied by headache, myalgia, nausea, and vomiting 4 days after yellow fever vaccination. She then developed icterus, renal failure, and haemorrhagic diathesis, and died after 6 days of illness. Yellow fever virus was recovered in suckling mice and C6/36 cells from blood in both cases, as well as from fragments of liver, spleen, skin, and heart from the first case and from these and other viscera fragments in case 2. RNA of yellow fever virus was identical to that previously described for 17D genomic sequences. IgM ELISA tests for yellow fever virus were negative in case 1 and positive in case 2; similar tests for dengue, hantaviruses, arenaviruses, Leptospira, and hepatitis viruses A-D were negative. Tissue injuries from both patients were typical of wild-type yellow fever. INTERPRETATION: These serious and hitherto unknown complications of yellow fever vaccination are extremely rare, but the safety of yellow fever 17DD vaccine needs to be reviewed. Host factors, probably idiosyncratic reactions, might have had a substantial contributed to the unexpected outcome.

Acute Kidney Injury↗

PubMed2001

A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues.

A series of 3,5-bis(arylidene)-4-piperidones 1 and related N-acryloyl analogues 2 were prepared as candidate cytotoxic agents with a view to discerning those structural features which contributed to bioactivity. A number of the compounds were markedly cytotoxic toward murine P388 and L1210 leukemic cells and also to human Molt 4/C8 and CEM neoplasms. Approximately 40% of the IC50 values generated were lower than the figures obtained for melphalan. In virtually all cases, the N-acyl compounds were significantly more bioactive than the analogues 1. In general, structure-activity relationships revealed that the cytotoxicity of series 1 was correlated positively with the size of the aryl substituents, while in series 2, a -sigma relationship was established. In particular, various angles and interatomic distances were obtained by molecular modeling, and the presence of an acryloyl group on the piperidyl nitrogen atom in series 2 affected the relative locations of the two aryl rings. This observation, along with some differences in distances between various atoms in series 1 and 2, may have contributed to the disparity in cytotoxicity between 1 and 2. The results obtained by X-ray crystallography of representative compounds were mainly in accordance with the observations noted by molecular modeling. Selected compounds interfered with the biosynthesis of DNA, RNA, and protein in murine L1210 cells, while others were shown to cause apoptosis in the human Jurkat leukemic cell line. This study has revealed the potential of these molecules for development as cytotoxic and anticancer agents.

Acrylates↗

PubMed2001

Congenital aneurysm of the right atrium.

Congenital aneurysm of the right atrium is described in a 1-year-old girl who presented with cardiomegaly and symptoms of paroxysmal supraventricular tachycardia. Echocardiography and cineangiography both established the definitive diagnosis and surgical resection was successful. The rarity of this condition is pointed out and its main features outlined.

Female↗

PubMed2001

Endomyocardial fibrosis in children.

We describe 10 children with endomyocardial fibrosis who underwent surgical treatment between 1978 and 1999. Seven were male and 3 female, with an age range from 4 to 15 years, having a mean age of 11 years. All were in the final stage of heart failure. Three had biventricular disease, 6 had involvement of the right ventricle alone, and one had endomyocardial fibrosis confined to the left ventricle. There were 3 deaths (30%) in the postoperative period due to low cardiac output. The 7 survivors were followed up for a period ranging from 12 to 168 months, with a mean of 72 months. Two late deaths have occurred resulting from heart failure and infectious endocarditis. Five (50%) children are still alive. Two required 3 reoperations for dysfunction of the inserted valvar prosthesis. One patient is in functional Class IV, and 4 are in Class II to III, despite intensive medical treatment. It is concluded that surgery for endomyocardial fibrosis is an essentially palliative procedure and, especially in children, the results of surgical treatment leave much to be desired.

Adolescent↗

PubMed2001

Overexpression of epidermal growth factor and epidermal growth factor-receptor mRNAs in dyshormonogenetic goiters.

Thyroid malignancy has been induced by long-term endogenous thyrotropin (TSH) stimulation in experimental animals, leading to local and distant metastasis. It has been postulated that constant and prolonged endogenous TSH stimulation in dyshormonogenetic thyroid tissues could result in thyroid neoplasia. The possible role of growth factors and oncogenes in goitrogenesis and favoring neoplasia has also been mentioned. Overexpression of certain growth factors and/or their receptors, and of oncogenes implicated in growth promotion may play a significant role in the relatively frequent finding of thyroid malignancy in congenital goiters. In this study the expression of epidermal growth factor (EGF), epidermal growth factor receptor (EGF-R), transforming growth factor-beta (TGF-beta), c-myc, and p53 mRNAs was determined in 14 thyroid tissue samples: 6 from patients with thyroid peroxidase (TPO) gene mutations, 4 with thyroglobulin (Tg) gene defects and 4 normal thyroid tissues. EGF mRNA overexpression was seen in 7 of 10 dyshormonogenetic tissues (3.5 to 12.0 arbitrary optical densitometry units [AODU]) and considered significantly higher (p < 0.01) when compared to normal thyroid tissues (0.25 to 0.32 AODU). Moreover, overexpression of EGF-R mRNA was present in 6 of 10 dyshormonogenetic tissues (2.23 to 13.03 AODU) and considered significantly higher (p < 0.01) when compared to normal thyroid tissues (0.42 to 0.65 AODU). There was no difference in c-myc, p53, and TGF-beta mRNAs expression between dyshormonogenetic and normal tissues. The overexpression of EGF and EGF-R mRNAs found in dyshormonogenetic tissues may suggest that this growth factor may play a role in cellular proliferation and contribute to goiter formation.

Cell Division↗

PubMed2001

Three case studies of the GasNet model in discrete domains.

A new neural network model - the GasNet - has been recently reported in the literature, which, in addition to the traditional electric type, point-to-point communication between units, also uses communication through a diffilsable chemical modulator. Here we assess the applicability of this model in three different scenarios, the XOR problem, a food gathering task for a simulated robot, and a docking task for a virtual spaceship. All of them represent discrete domains, a contrast with the one where the GasNet was originally introduced, which had an essentially continuous nature. These scenarios are well-known benchmark problems from the literature and, since they exhibit varying degrees of complexity, they impose distinct performance demands on the GasNet. The experiments were primarily intended to better understand the model, by extending the original problem domain where GasNet was introduced. The results reported point at some difficulties with the current GasNet model.

Neural Networks, Computer↗

PubMed2001

In situ and in vitro senescence induced by KCl stress: nutritional imbalance, lipid peroxidation and antioxidant metabolism.

Sunflower (Helianthus annuus L. cv. SH222) plants and calli were exposed to KCl stress for three weeks. Calli were more tolerant to KCl than plants. KCl stress decreased NO(-)(3), Mn, Fe and B levels in whole plants and P, Ca and Mg in shoots. NO(-)(3), P, Ca, Mg, Mn, and B levels decreased in 100 mM-stressed calli. Chlorophyll content, F:(m) and (F:(m)-F:(0))/F:(m) ratio decreased in stressed leaves, while F:(0) increased only in leaves exposed to severe stress (100 and 150 mM). Membrane permeability and lipid peroxidation increased in plants under all stress conditions and in 100 and 150 mM stressed calli, but remained unchanged in 25 mM stressed calli. Salt stress also induced changes relating to antioxidant enzymes: plants under all stress conditions showed a decrease in catalase, peroxidase and SOD activities. Calli under moderate stress (25 mM KCl) showed an increase of catalase, peroxidase and SOD activities, but the activities of peroxidase and SOD decreased when calli were exposed to higher KCl concentrations. The decrease of antioxidant enzyme activities is in tune with lipid peroxidation and membrane permeability increases. On the other hand, calli adapted for 6 months to 100 mM KCl showed an increase of these enzyme activities compared to unstressed calli, while MDA production and membrane permeability were not significantly affected.

Antioxidants↗

PubMed2001

Cytotoxic and anticancer properties of some 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinols and related compounds.

A previous investigation revealed that various 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinols and related vinylogs were cytotoxic to both murine and human tumour cell lines. In particular, 1a and 2a were identified as useful prototypic molecules. Structural modifications of 1a and 2a were accomplished leading to 1b-e and 2b-d which displayed cytotoxicity towards murine P388 and L1210 leukemic cells as well as human Molt 4/C8 and CEM T-lymphocytes. Among the new compounds, the greatest average potencies against these four cell lines were displayed by 1b and 2b, having approximately one quarter and one half of the potency of the reference drug melphalan, respectively. The synthesis and bioevaluation of three open chain analogues of 1b-d, namely 3a-c, did not reveal unequivocally whether this molecular modification led to increases in cytotoxicity or not. Compounds 2a-d were substantially more active than melphalan using a panel of human tumour cell lines. In addition, several compounds displayed selective toxicity to both colon and leukemic cancer cells. The 4-piperidinol 2d was active in the in vivo hollow fibre assay. This study revealed compounds with greater potency than 1a and 2a and it has confirmed that 1,3,4-trisubstituted-4-piperidinols and related compounds are novel groups of candidate antineoplastic and anticancer agents.

Animals↗

PubMed2000

Sequential cytotoxicity: a theory evaluated using novel 2-[4-(3-aryl-2-propenoyloxy)phenylmethylene]cyclohexanones and related compounds.

Five series of novel compounds were synthesized in order to evaluate the theory of sequential cytotoxicity which seeks to exploit the view that various cancer cells are particularly susceptible to successive attacks by cytotoxic agents. The compounds prepared were various 2-[4-(3-aryl-2-propenoyloxy)phenylmethylene]cyclohexanone s 1 and the related Mannich bases 2. In addition the analogues 3-5 lacking an olefinic bond in the ester group were also synthesized, which were predicted to be less cytotoxic than the compounds of series 1 and 2. The atomic charges at the potential sites for interaction with cellular constituents were determined by molecular modeling calculations. The biodata obtained from murine and human neoplastic cells revealed that the predictions made regarding the viability of the theory were fulfilled in approximately two-thirds of the cases indicating that further investigation of this hypothesis is warranted. In addition, the significant potencies of some of the Mannich bases toward human tumor cell lines, in particular coupled to their selective toxicity toward human leukemic and colon cancer cells, confirms their usefulness in serving as lead molecules for further development. A preliminary investigation into the mode of action of representative compounds revealed their ability to induce apoptosis and inhibit the biosyntheses of ribonucleic acid and proteins.

Animals↗

PubMed1999

Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones.

Various 2-arylideneindanones 1, 2-arylidenetetralones 2, and 2-arylidenebenzosuberones 3 were synthesized with the aim of determining the relative orientations of the two aryl rings which favored cytotoxicity. Molecular modeling of the unsubstituted compound in each series revealed differences in the spatial arrangements of the two aryl rings, and evaluation of these compounds against P388, L1210, Molt 4/C8, and CEM cells as well as a panel of human tumor cell lines indicated that in general the order of cytotoxicity was 3 > 2 > 1. In particular 2-(4-methoxyphenylmethylene)-1-benzosuberone (3k) had the greatest cytotoxicity, possessing 11 times the potency of the reference drug melphalan when all five screens were considered. Series 3 was considered in further detail. First, excision of the aryl ring fused to the cycloheptanone moiety in series 3 led to some 2-arylidene-1-cycloheptanones 4 which had approximately one-third of the bioactivity of the analogues 3. Second, in some screens cytotoxicity was correlated negatively with the sigma values and positively with the MR constants of the substituents in the arylidene aryl ring of 3. Third, X-ray crystallography of five representative compounds (3i,k-n) revealed differences in the locations of the aryl rings which may have contributed to the variations in cytotoxicity. Finally three members of series 3 inhibited RNA and protein syntheses and induced apoptosis in human Jurkat T cells. This study has revealed that 2-arylidene-1-benzosuberones are a group of useful cytotoxic agents, and in particular 3k serves as a prototypic molecule for subsequent structural modifications.

Animals↗

PubMed1999

Obstruction of the right ventricular outflow tract caused by a tuberculoma in a patient with ventricular septal defect and aneurysm of the membranous septum.

Reported here is an obstruction of the right ventricular outflow tract caused by a tuberculoma in a 15-year-old boy who presented with a ventricular septal defect. The obstruction was discovered at surgery and the tuberculous aetiology was only demonstrated histologically. To the authors' knowledge, this is the first report of a tuberculoma of the heart associated with congenital heart disease.

Adolescent↗

PubMed1999

A novel mutation in the TPO gene in goitrous hypothyroid patients with iodide organification defect.

OBJECTIVE: To screen and subsequently sequence the TPO gene for mutations in patients with congenital goitre, hypothyroidism and evidence for an organification defect (positive perchlorate discharge test). PATIENTS: We have studied seven hypothyroid and congenitally goitrous patients from three unrelated families. DESIGN AND MEASUREMENTS: We have measured serum thyroid hormone levels, 131I uptake, serum TSH and serum Tg concentrations. Denaturing gradient gel electrophoresis (DGGE) of PCR amplified genomic DNA was used to screen for mutations in the TPO gene. RESULTS: DGGE identified the presence of two frameshift mutations: a GGCC duplication in exon 8 (homozygous in one family and heterozygous in the other family) and a heterozygous insertion of a single nucleotide (C) at position 2505-2511 in exon 14. In addition, we have detected an alteration in exon 11, not yet described in the literature, derived from a single nucleotide substitution of a C to G at position 2008, altering the well-conserved amino acid domain among the peroxidases superfamily. This mutation in exon 11 was present in two families that showed heterozygous mutation for exon 8 or for exon 14. CONCLUSIONS: These results could support the hypothesis for a putative compound heterozygosity pattern in the affected patients. The altered phenotype (goitre and hypothyroidism since birth) seems justifiable in view of the possible inactivating character of this novel mutation in exon 11.

Adolescent↗

PubMed1999

Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil.

Constitutively activating mutations in the thyrotropin (TSH) receptor have been identified as a major molecular cause of hyperfunctioning thyroid adenomas. A smaller subset of these benign tumors is caused by constitutive activation of the adenylyl cyclase cascade by somatic mutations in the Gsalpha gene. In this study, we analyzed hyperfunctioning thyroid adenomas from seven Brazilian patients for TSH receptor and G(s)alpha gene mutations. Solitary autonomous thyroid adenomas were identified by ultrasound and scintigraphy, and DNA was extracted from adenomatous and periadenomatous tissue. Exons 9 and 10 of the TSH receptor gene, and exons 8 and 9 of the G(s)alpha gene, were amplified by polymerase chain reaction (PCR) and subjected to direct sequence analysis. Six of seven adenomas harbored heterozygous mutations known to confer constitutive activity to the TSH receptor. In one case, aspartate 619 was substituted by glycine (D619G). In four adenomas, alanine 623 was replaced by valine (A623V). Both residues are located in the third intracellular loop. In one instance, aspartate 633 located in the sixth transmembrane domain was replaced by tyrosine (D633Y). In this patient, one allele also contained a change of aspartate 727 to glutamate (D727E). This substitution is thought to be a polymorphic variant of the wild-type but it has also been associated with toxic multinodular goiters. Functional comparison of D727 with E727 did not reveal differences in basal or TSH-stimulated cyclic adenosine monophosphate (cAMP)-dependent luciferase activity in transiently transfected cells. These results demonstrate a high prevalence of activating TSH receptor mutations in toxic adenomas in this small series from Brazil (approximately 86%). These findings are in agreement with reports from other countries with a marginal iodine intake but contrast with studies from regions with a high iodine intake where these mutations appear to be less prevalent.

Adenoma↗

PubMed1999

Phenocopies for deafness and goiter development in a large inbred Brazilian kindred with Pendred's syndrome associated with a novel mutation in the PDS gene.

Pendred's syndrome is an autosomal recessive disease characterized by goiter, impaired iodide organification, and congenital sensorineural deafness. The gene mutated in Pendred's syndrome, PDS (Pendred's syndrome gene), was cloned very recently and encodes the putative sulfate transporter pendrin. Pendred's syndrome may account for up to 10% of the cases with hereditary hearing loss, and pendrin mutations have also been found in a kindred with non-syndromic deafness. In this study, 41 individuals from a large, highly inbred pedigree from Northeastern Brazil were examined for features of Pendred's syndrome. Linkage studies and sequence analysis of the coding region of the PDS gene were performed with DNA from 36 individuals. The index patient, with the classical triad of deafness, positive perchlorate test, and goiter, was found to be homozygous for a deletion of thymidine 279 in exon 3, resulting in a frameshift and a premature stop codon at amino acid 96. This alteration resulted in truncation of the protein in the first transmembrane domain. Two other patients with deafness were found to be homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wild type allele. Surprisingly, 6 deaf individuals in this kindred were not homozygous for the PDS gene mutation; 3 were heterozygous and 3 were homozygous for the wild type allele, suggesting a probable distinct genetic cause for their deafness. All 3 homozygous individuals for the PDS mutation had goiters. However, goiters were also found in 10 heterozygous individuals and in 6 individuals without the PDS mutation and are most likely caused by iodine deficiency. In conclusion, we identified a novel mutation in the PDS gene causing Pendred's syndrome. The comparison of phenotype and genotype reveals, however, that phenocopies generated by distinct environmental and/or genetic causes are present in this kindred and that the diagnosis of Pendred's syndrome may be difficult without molecular analysis.

Adult↗