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Biomedical subjects

J Benitez

Publications and source records attributed to J Benitez.

At least 19 recordsLinked to original sources
PubMed2006

Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations.

Tumors arising in BRCA1 and BRCA2 mutation carriers appear to have specific pathological and gene expression profiles, which show a high level of concordance. BRCA1 tumors are high-grade, negative for hormone receptors, have a high proliferation rate, and are positive for some cell cycle promoter genes. BRCA2 tumors present a phenotype opposite to BRCA1 tumors but very similar to sporadic tumors, except that BRCA2 overexpress some DNA repair markers such as CHEK2, show high cytoplasmic expression of RAD51, and are negative for HER-2 amplification and expression. Some of these characteristics have also been found in cDNA expression studies, although more analysis are necessary in order to obtain new markers that can be associated with a germ line mutation in BRCA1 or BRCA2. In this way, some studies in normal tissues of BRCA1/2 carriers suggest that differences exist in the level of expression of some genes when compared with noncarriers. Finally, IHC studies in tumors carrying a mutation in CHEK2 are rare and show contradictory results, probably due to the low number of these cases. However, they represent an example showing how different mutations of the same gene may be associated with specific histological subtypes of cancer.

Breast Neoplasms↗
PubMed2005

Victimization of patients with schizophrenia and related disorders.

BACKGROUND: Previous research has predominately focused on patients with mental illness as the instigators, rather than the victims, of violence and criminal activity. However, patients with schizophrenia appear to experience a higher degree of victimization compared to general community samples. We aimed to establish the 1-month prevalence of violent and non-violent victimization in a sample of patients with schizophrenia spectrum disorders and to investigate the determinants of victimization. METHOD: Reports of violent and non-violent victimization were recorded in 348 patients in Dandenong, an outer metropolitan suburb of Melbourne, Australia along with the subjective perception of patients as to their degree of protection from being robbed or attacked. Patients reporting victimization were compared with those who did not, across a range of clinical and psychosocial variables. RESULTS: 11.2% of the sample reported being the victim of non-violent crime and 4.3% the victim of violent crime in the 1-month period. 23.2% reported dissatisfaction with their protection against being attacked or robbed. The major determinant of victimization was the lack of any meaningful daily activity. CONCLUSIONS: Patients with schizophrenia spectrum disorders are at increased risk of victimization, both of the violent and non-violent type. Further research is required to understand the pathways through which victimization occurs and to understand whether psychosocial interventions can reduce victimization in this patient population.

Activities of Daily Living↗
PubMed2003

Non-toxic type 2 ribosome-inactivating proteins (RIPs) from Sambucus: occurrence, cellular and molecular activities and potential uses.

Ribosome-inactivating proteins (RIPs) are a family of enzymes that trigger the catalytic inactivation of ribosomes. The most known member of the family is the highly poisonous two-chain ricin isolated from Ricinus communis L. Sambucus species contain a number of two-chain RIPs structurally and enzymatically related to ricin which have the noteworthy feature that, having an enzymatic activity on ribosomes, leading to the inhibition of protein synthesis, higher than ricin, they are lacking of the tremendous unspecific toxicity of ricin. Therefore, they have been called non-toxic type 2 RIPs. The most representative and studied members are nigrin b present in the bark of the common (black) elder Sambucus nigra L. and ebulin 1 present in the leaves of the dwarf elder Sambucus ebulus L. The molecular basis for the low unspecific activities of nigrin b and ebulin 1 as compared with ricin seems to be related with single changes of amino acids in the high affinity sugar binding sites of the B chains. These changes determine the intracellular traffic of these proteins and thus the cellular toxicity. Conjugation ofnigrin b or ebulin 1 to either transferrin or monoclonal antibodies provided highly active conjugates targeting cancer. Thus these non-toxic type 2 RIPs are promising tools for cancer therapy.

Amino Acid Sequence↗
PubMed2002

Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium.

The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.

Australia↗
PubMed2002

N-acetyltransferase 2 polymorphism is not related to the risk of advanced alcoholic liver disease.

BACKGROUND: Ethanol abuse is the most prevalent cause of liver cirrhosis in Spain. Genetic polymorphisms affect the activity of the enzymes involved in ethanol metabolism and in processing the toxic by-products generated in the liver. N-acetyltransferase 2 (NAT2) is a polymorphic phase 2 enzyme not involved in these processes, but recent data suggest that the most prevalent slow acetylator genotype protects against the risk of advanced alcoholic liver disease (ALD). We have identified six single nucleotide polymorphisms (SNP) at the NAT2 gene locus in order to disclose whether such an association exists. METHODS: Genomic DNA from 95 ALD patients (15 with superimposed hepatocellular carcinoma (HCC)) and from 258 healthy individuals was analysed for SNPs at the coding region of the NAT2 gene by means of allele-specific polymerase chain reaction. RESULTS: There are no differences in the relative frequencies of the eight identified NAT2 alleles (including the wild-type allele) nor in the distribution of predicted phenotypes (54% of slow acetylators in each group). Twelve patients with HCC (80%) were slow acetylators (P < 0.05). CONCLUSIONS: There is no relationship between the NAT2 genotype and the risk of ALD. Slow acetylator genotype may predispose to the development of HCC in severe ALD patients not infected by the hepatitis C virus.

Adult↗
PubMed2001

DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis.

Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.

Breast Neoplasms↗
PubMed2000

Hypermethylation of P16ink4a and P15ink4b genes as a marker of disease in the follow-up of non-Hodgkin's lymphomas.

The hypermethylation of p16ink4a and p15ink4b genes have been described as an inactivating mechanism alternative to deletions and mutations that accounts for a relatively high proportion of cancers, including non-Hodgkin's lymphomas (NHLs). To investigate whether detection of abnormal methylation could have clinical applications in the management and follow-up of lymphomas, we have analysed the behaviour and evolution of p16ink4a and p15ink4b methylation in 13 NHL cases undergoing chemotherapy. All cases were also analysed for the presence of monoclonal rearrangements of immunoglobulin or T-cell receptor genes. Six patients showed methylation in at least one of these genes at diagnosis, whereas in two other cases methylation appeared during the treatment. The other five cases were always unmethylated. Methylation was detected when any histological or molecular evidence of disease was present, suggesting a good correlation between methylation and disease. In some cases, we were able to detect methylation in patients at complete remission and without evidence of monoclonal cell population, indicating a high sensitivity of the PCR to detect methylation. These results suggest that p16ink4a and p15ink4b methylation could be good markers of disease and could be helpful in identifying lymphoma patients at risk of relapse.

Adult↗
PubMed2000

Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine.

Twenty-five healthy volunteers were given 100 mg caffeine orally and several estimates of cytochrome P450 1A2 (CYP1A2) activity were evaluated. The validation was performed by correlation of different parameters in plasma, saliva, and urine to two measures of caffeine clearance, CL(oral) and CL(137X-->17X) that served as standards of reference. Two subjects were excluded because of noncompliance with a caffeine-free diet. In the remaining 23 subjects, both plasma and saliva total clearances of caffeine were highly correlated with each other (r(s) = 0.97, p < 0.0001). The ratio 17X/137X restricted to one sampling point taken 4 hours after dose, showed a high correlation (r(s)) with CL(oral) and CL(137X-->17X) in plasma (0.84/0.83) and saliva (0.82/0.77) (p < 0.0001 for all the correlation values) where 17X is 1,7-dimethylxanthine (paraxanthine) and 137X is 1,3,7-trimethylxanthine (caffeine). Additionally, the ratio (AFMU + 1U + 1X + 17U + 17X)/137X in a 0-24 hours urine sampling showed the highest correlation with CL(137X-->17X) (r(s) = 0.85, p < 0.001) where AFMU is 5-acetylamino-6-formylamino-3-methyluracil, 1U is 1-methyluracil, 1X is 1-methylxanthine, and 17U is 1,7-dimethyluric acid. The major estimates of CYP1A2 activity were significantly less in nonsmoking females, and this probably was related to the use of oral contraceptives in this subpopulation. In summary, among caffeine-based approaches for CYP1A2, the authors recommend either plasma or saliva 17X/137X ratio and the urinary (AFMU + 1U + 1X + 17U + 17X)/137X ratio during a sampling interval of at least 8 hours, starting at time zero since caffeine intake. These indices are simple, reliable, and relatively inexpensive estimates of CYP1A2 activity to be used in the study of human populations.

Adult↗
PubMed2000

Clinically significant pharmacokinetic interactions between dietary caffeine and medications.

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.

Animals↗
PubMed1999

European multicenter study on LOH of APOC3 at 11q23 in 766 breast cancer patients: relation to clinical variables. Breast Cancer Somatic Genetics Consortium.

High frequencies of loss of heterozygosity (LOH) in chromosome 11q22-qter have been observed in various malignancies, including breast cancer. Previous studies on breast carcinomas by Winqvist et al (Cancer Res 55: 2660-2664) have indicated that a survival factor gene is located in band 11q23, and that the highly informative microsatellite polymorphism at the APOC3 locus would be a suitable tool to perform more extensive LOH studies. In this European multicentre study, we have examined the occurrence of APOC3 LOH and evaluated the effect of LOH of this chromosomal subregion on the clinical behaviour of the disease in a cohort of 766 breast cancer patients in more detail. LOH for APOC3 was found in 42% of the studied tumours, but it was not found to be significantly associated with any of the studied clinical variables, including cancer-specific survival time or survival time after recurrent/metastatic disease. According to the present findings, the putative survival factor gene on 11q23 is not located close enough to the APOC3 gene, but apparently at a more proximal location.

Adult↗
PubMed1999

Analysis of the INK4a/ARF locus in non-Hodgkin's lymphomas using two new internal microsatellite markers.

Inactivation of the INK4a/ARF locus is a frequent event in non-Hodgkin's lymphomas (NHLs), which may be attributed to deletion, point mutation, and 5' CpG methylation at its promoter region. In the present study we evaluated the occurrence of deletions and genetic instability of INK4a/ARF locus in 30 paired normal and tumor samples of B cell NHLs by conducting an allelotypic analysis with two new polymorphic markers, one located at the intron 1 of p16INK4a gene and the other one placed downstream exon 1beta of p19ARF. Comparison of these results with those obtained in a previous paper using flanking markers (D9S171, D9S942, D9S958 and IFNA) allowed us to detect two new cases of microsatellite instability (L-446 and L-442), and to confirm the occurrence of LOH at the INK4a/ARF locus in one tumor (M-3770). On the contrary, this locus is not affected in three different tumors (L-421, L-272 and L-159) which exhibited LOH at some of the flanking markers.

Chromosome Mapping↗
PubMed1999

Loss of heterozygosity at 11q23.1 and survival in breast cancer: results of a large European study. Breast Cancer Somatic Genetics Consortium.

Among the chromosomal regions commonly undergoing deletions in breast tumors is 11q23.1. The genes that are targets for loss of heterozygosity (LOH) in this region is not yet established. One of the candidate genes located in this region is ATM, responsible for the rare autosomal recessive disorder ataxia-telangiectasia (A-T). Interestingly, A-T heterozygotes may have an increased risk of cancer, in particular breast cancer, although this is still controversial. A common assumption has been that the target for the LOH at 11q23.1 in breast carcinoma is the ATM gene, but the area studied has been too large, the density of markers too low, and the number of tumors studied has been too small to draw any firm conclusions. The present study is a multicenter study including 918 breast cancer patients with clinical information and survival data available for most of them. Primary breast tumors were investigated for LOH using a high density of microsatellite markers spanning approximately 6 Mb around the ATM gene. Survival analyses showed that there are most likely one or more candidate genes in a 3-4 Mb region between the markers D11S1819 and D11S927 including the ATM gene. Cancer-specific survival was significantly reduced in patients whose tumors exhibited LOH of markers D11S2179 (within the ATM gene), D11S1778, D11S1294, and D11S1818. The highest survival hazard ratios were 1.8(C11.2-2.8, P = 0.010) and 2.1 (C11.4-3.0, P = 0.0004) for markers D11S2179 and D11S1818, respectively. One or more of these markers are therefore most likely to be located close to or within genes associated with breast cancer survival.

Adult↗
PubMed1998

Hypermethylation of p15/ink4b/MTS2 gene is differentially implicated among non-Hodgkin's lymphomas.

P15 (MTS2) gene is a candidate tumor suppressor gene localized adjacent to the p16 gene at 9p21. Deletions at the 9p21 region frequently affect both p16 and p15 genes, however, mutations in the coding sequence of the p15 gene have not been found in the majority of tumors analyzed, including non-Hodgkin's lymphomas. Abnormal methylation of the promoter region of p15 has been recently described as an alternative mechanism of inactivation of this gene. We analyzed 72 non-Hodgkin's lymphomas (NHL) for methylation at p15 exon 1 by PCR and Southern blot techniques using methylation-sensitive restriction enzymes. Abnormal methylation was found in eight cases (11%), most of them (three MALT, one anaplastic T cell lymphoma, one Burkitt and one follicular lymphoma) showing hypermethylation in the p16 gene also. In contrast, two pleomorphic T cell NHL showed a selective methylation at p15 gene, while the p16 gene remained unmethylated. The results show that methylation at the p15 gene is frequently associated with p16 methylation in NHL, and suggest that selective methylation of p15, although uncommon, could be a specific alteration implicated in T cell NHL.

Carrier Proteins↗
PubMed1998

Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study.

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).

Adult↗
PubMed1998

Analysis of midazolam and metabolites in plasma by high-performance liquid chromatography: probe of CYP3A.

Hydroxylation of midazolam (MDZ) is mediated almost exclusively by CYP3A isoforms. The authors describe a high-performance liquid chromatography assay involving MDZ, 1'-hydroxymidazolam, and 4-hydroxymidazolam in plasma. The compounds were eluted on an Ultrasphere ODS, 3-microm particle size, 7.5 cm x 4.6 mm reversed-phase column and monitored by ultraviolet absorbance at 254 nm. The composition of the mobile phase was 35.2% acetonitrile:4.8% methanol:60% buffer acetate (vol/vol/vol), 0.1 M, pH 4.7; the flow rate was 1 ml/minute. Calibration curves were linear (coefficients of correlation > 0.99) within the range of concentrations established (20 to 640 nM). Within- and between-day coefficients of variation were consistently better than 8%. The overall recovery was >90% and the lowest detectable concentration was 8 nM. This approach provides a simple, rapid, and sensitive assessment of MDZ and metabolites in plasma, with a very good accuracy and precision, which enables it as an in vivo marker of CYP3A activity in humans.

Adult↗
PubMed1998

Environmental influence on immune inhibition of release of herpes simplex virus from cells.

Immune inhibition of virus release (IVR) of herpes simplex virus type 1 (HSV-1) from baby hamster kidney cells (BHK-21) was mediated by antisera against BHK cells, HSV-1, human fibronectin and mouse heparan sulphate proteoglycan and was irreversible for at least 24 h following removal of antiserum. Enhancement of IVR by calf serum depletion of growth media was obtained in varying measure using each of these antisera and also by treatment of virus-infected cells by the lectin concanavalin A. Enhancement was reversible by replenishment of growth media with bovine serum components larger than 12 kD but this only occurred when replenishment was instituted prior to virus infection. There was also reversibility to varying degree following replenishment by ovine, equine and human serum which indicates that this phenomenon is not species specific. In addition to the presence of relevant antigens on the cell surface, IVR may also require an alteration in the cell membrane; this is evidenced by the absence of anticellular serum-mediated IVR when treatment was introduced less than 6 h after virus infection, suggesting that a certain level of alteration or possibly cell damage - in this case virus induced - is necessary. Enhancement of IVR by calf serum depletion would seem to operate through a specific alteration in the virus-infected cell membrane as serum-depleted cells did not show histological alteration and were able to replicate HSV-1 to usual titres; it is possible that this enhancement may represent an as yet unidentified host defence mechanism whereby extracellular release of virus will be reduced in ischaemic or necrotic tissue in the course of infectious inflammatory processes.

Animals↗