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PubMed2006

The XRCC1 -77T->C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage.

X-ray repair cross-complementing 1 (XRCC1) is required for single-strand break repair in human cells and several polymorphisms in this gene have been implicated in cancer risk and clinical prognostic factors. We examined the frequency of the 5'-untranslated region (5'-UTR) variant -77T-->C (rs 3213235) in 247 French breast cancer (BC) patients, 66 of whom were adverse radiotherapy responders, and 380 controls and determined the haplotypes based on this and the previously genotyped variants Arg194Trp, Arg280His and Arg399Gln. The -77T-->C variant alone showed no significant association with BC risk or therapeutic radiation sensitivity. The H5 haplotype (variant allele codon 280, wild-type allele other positions) was associated with increased BC risk [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.12-3.23] and the H3 haplotype (wild-type allele all four positions) was inversely associated with therapeutic radiation sensitivity compared with the reference group (H1 haplotype, -77C, wild-type allele codons 194, 280, 399) (OR, 0.39; 95% CI, 0.16-0.92). However given that the global tests for association were not significant these results should be interpreted carefully. Lymphoblastoid cell lines heterozygous for the H1/H3 haplotypes had a significantly higher cell survival (P=0.04) after exposure to ionising radiation (IR) than those with the H1/H1 haplotypes, in agreement with the association study. However no haplotype-specific differences in XRCC1 expression or cell cycle progression were noted in the 24 h following IR exposure. These results suggest that the -77T-->C genotype or another variant in linkage disequilibrium influences the cellular response to DNA damage, although the underlying molecular mechanisms remain to be established.

Breast Neoplasms↗
PubMed2003

Haplotype sharing analysis with SNPs in candidate genes: the Genetic Analysis Workshop 12 example.

Haplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct influence on affection and harbors more than 70 SNPs. Haplotype sharing analysis depends heavily on previous haplotype estimation. Using GENEHUNTER haplotypes, strong evidence was found for most SNPs in the isolated population sample, thus providing evidence for an involvement of this gene, but the maximum -log(10)(p) values for the haplotype sharing statistics (HSS) test statistic did not correspond to the location of the true variant in either population. In comparison, transmission disequilibrium test (TDT) analysis showed the strongest results at the disease-causing variant in both populations, and these were outstanding in the general population. In this example, TDT analysis appears to perform better than HSS in identifying the disease-causing variant, using SNPs within a candidate gene in an outbred population. Simulations showed that the performance of HSS is hampered by closely spaced SNPs in strong linkage disequilibrium with the functional variant and by ambiguous haplotypes.

Chromosome Mapping↗
PubMed2005

CT of nontraumatic thoracic aortic emergencies.

Computed tomography (CT), especially multidetector row CT (MDCT), is often the preferred imaging test used for evaluation of nontraumatic thoracic aortic abnormalities. Unenhanced images, usually followed by contrast-enhanced arterial imaging, allow for rapid detailed aortic assessment. Understanding the spectrum of acute thoracic aortic conditions which may present similarly (aortic dissection, aneurysm rupture, penetrating atherosclerotic ulcer, intramural hematoma) will ensure that patients are diagnosed and treated appropriately. Familiarity with imaging protocols and potential mimics will prevent confusion of normal anatomy and variants with aortic disease.

Aortic Dissection↗
PubMed2001

[Evaluation of prognostic factors in breast cancer EC I-II and the importance of local recurrence].

OBJECTIVE: [corrected] We evaluated the prognostic factors in patients with breast cancer EC-I-II treated in the Instituto Nacional de Cancerología in Mexico and compared patients with or without local or/and systemic recurrence. METHOD: This is a retrospective study in patients treated with conservative surgery between 1983 and 1993 with a diagnosis of invasive breast cancer and tumors <4 cm All pathological variables were analyzed and we performed studies on c-erb.B2, P53, estrogene and progesterone receivers, cellular ploidy and cellular percentage on face "S" of the cellular cycle. All these variables were compared in two groups, one with recurrences and the other without recurrences, with the same symptoms and demographics characteristics. RESULTS: From 1270 patients with breast cancer EC I-II, 139 patients were submitted to conservative surgery, 14 patients of this group recurred and were compared with 32 patients that did not, out of a total of 46 patients. We found that SBR greater than five (P = 0.046), poor differentiated tumors (P = 0.04), tumors with vascular permeability (P = 0.020) and with intraductal characteristics of a comedocarcinoma (P = 0.004) had a worse prognosis and increased the risk of local recurrences. CONCLUSIONS: In patients with breast cancer the pathological variants are more important than the so called secondary prognostic variables. Besides the pathological variants, it is acceptable only the use of hormonal receptors and the presence of c-erb-b2.

Adenocarcinoma↗
PubMed1992

Effects of amino acid substitutions outside an antigenic site on protein binding to monoclonal antibodies of predetermined specificity obtained by peptide immunization: demonstration with region 94-100 (antigenic site 3) of myoglobin.

Amino acid substitutions outside protein antigenic sites are very frequently assumed to exert no effect on binding to antiprotein antibodies, especially if these are monoclonal antibodies (mAbs). In fact, a very popular method for localization of residues in protein antigenic sites is based on the interpretation that whenever a replacement causes a change in binding to antibody, then that residue will be located in the antigenic site. To test this assumption, mAbs of predetermined specificity were prepared by immunization with a free (i.e., without coupling to any carrier) synthetic peptide representing region 94-100 of sperm whale myoglobin (Mb). The cross-reactivities and relative affinities of three mAbs with eight Mb variants were studied. Five Mb variants which had no substitutions within the boundaries of the designed antigenic site exhibited remarkable, and in two cases almost complete, loss in cross-reactivity relative to the reference antigen, sperm whale Mb. Two myoglobins, each of which had one substitution within region 94-100, showed little or no reactivity with the three mAbs. It is concluded that substitutions outside an antigenic site can exert drastic effects on the reactivity of a protein with mAbs against the site and that caution should be exercised in interpreting cross-reactivity data of proteins to implicate residues directly in an antigenic site.

Amino Acid Sequence↗
PubMedDate not supplied

Fine needle aspiration cytologic findings in metastatic basaloid squamous cell carcinoma of the head and neck.

Basaloid squamous cell carcinoma of the head and neck is a variant of squamous carcinoma the cytomorphology of which has not been examined previously. The cytologic features of metastatic basaloid squamous cell carcinoma in fine needle aspiration specimens from nine patients are described. The primary tumors, when known, were located in the base of the tongue, tonsil, epiglottis, nasopharynx, hypopharynx and false vocal cord. Each neoplasm had large fragments or clusters of crowded cells and scattered single cells in the cytologic smears. The cells had round or oval, hyperchromatic nuclei that often had single, small nucleoli. The nuclei usually were small or medium sized, but six tumors had a few cells the nuclei of which were large and pleomorphic. The cytoplasm was typically scant, and only three cases had occasional keratinized cells. Necrosis was present in six neoplasms. Three neoplasms, originally diagnosed as small cell undifferentiated carcinoma, contained numerous single cells and small clusters of cells with nuclear molding. On review, however, smears from these neoplasms also contained a few large fragments of tightly cohesive cells with larger, vesicular nuclei. Another basaloid squamous cell carcinoma had been interpreted elsewhere as an adenoid cystic carcinoma because of the presence of pseudoglandular structures with stromal cores. Although the cytologic features of basaloid squamous cell carcinoma may mimic those of other poorly differentiated carcinomas in fine needle aspiration specimens, they are sufficiently distinctive that a diagnosis of this variant of squamous cell carcinoma can be suggested for a patient whose primary neoplasm is located in the upper aerodigestive tract.

Adult↗
PubMed2006

Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis.

Lysosomal beta-hexosaminidase A (Hex A) is essential for the degradation of GM2 gangliosides in the central and peripheral nervous system. Accumulation of GM2 leads to severely debilitating neurodegeneration associated with Tay-Sachs disease (TSD), Sandoff disease (SD) and AB variant. Here, we present the X-ray crystallographic structure of Hex A to 2.8 A resolution and the structure of Hex A in complex with NAG-thiazoline, (NGT) to 3.25 A resolution. NGT, a mechanism-based inhibitor, has been shown to act as a chemical chaperone that, to some extent, prevents misfolding of a Hex A mutant associated with adult onset Tay Sachs disease and, as a result, increases the residual activity of Hex A to a level above the critical threshold for disease. The crystal structure of Hex A reveals an alphabeta heterodimer, with each subunit having a functional active site. Only the alpha-subunit active site can hydrolyze GM2 gangliosides due to a flexible loop structure that is removed post-translationally from beta, and to the presence of alphaAsn423 and alphaArg424. The loop structure is involved in binding the GM2 activator protein, while alphaArg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. The beta-subunit lacks these key residues and has betaAsp452 and betaLeu453 in their place; the beta-subunit therefore cleaves only neutral substrates efficiently. Mutations in the alpha-subunit, associated with TSD, and those in the beta-subunit, associated with SD are discussed. The effect of NGT binding in the active site of a mutant Hex A and its effect on protein function is discussed.

Acetylglucosamine↗
PubMed1998

Role of gp41 glycosylation sites in the biological activity of human immunodeficiency virus type 1 envelope glycoprotein.

The requirement for glycosylation in the transmembrane protein, gp41, of human immunodeficiency virus type 1 envelope protein for fusion activity has been studied. By using a mutant gene in which three conserved sites have been removed and which shows no fusion ability, genes were constructed which replace one, two, or three sites in all possible combinations. Following expression of the resultant proteins using the vaccinia T7 system, each Env variant was assessed by visual and quantitative syncytium assays. Our data indicate that two sites are sufficient for high levels of fusion and that the single site at position 621 is the most critical of all positions. We interpret our data in the light of previous contradictory reports on the role of gp41 glycosylation in bioactivity and the emerging structure of gp41.

Animals↗
PubMed2003

An unusual case of CD4+ CD7+ CD56+ acute leukemia with overlapping features of type 2 dendritic cell (DC2) and myeloid/NK cell precursor acute leukemia.

Type 2 dendritic cell (DC2) acute leukemia has been recently described. We report here an unusual case of a 17-yr-old adolescent with overlapping features of DC2 and myeloid/NK cell precursor acute leukemia as defined by Suzuki et al. The patient presented with lymphadenopathy and hepatosplenomegaly without extranodal manifestations in skin or elsewhere. The morphologic, cytochemical and immunophenotypic features were compatible with those described in DC2 acute leukemia, with co-expression of CD4, CD56 and CD123 antigens. The novel markers BDCA-4 and BDCA-2 considered specific for DC2s were co-expressed. However, bright CD7 positivity along with a dim expression of CD33 (57%) and CD117 (27%) were also noted. Additionally, there was bright expression of NG2 monoclonal antibody 7.1, a frequent finding in myeloid/NK cell precursor acute leukemia. The interpretation of the immunophenotypic profile leads to the hypothesis on the existence of borderline cases between DC2 and myeloid/NK cell precursor acute leukemia. Still, other hypotheses can not be overlooked, such as the possibility for a kind of variant monoblastic leukemia or of another rare entity of acute unclassified leukemia.

Adolescent↗
PubMed2006

Pitfalls in integrated CT-PET of the thorax: implications in oncologic imaging.

Integrated computed tomography-positron emission tomography (CT-PET) scanners improve localization of regions of increased [18F]-fluoro-2-deoxy-D-glucose (FDG) uptake and staging accuracy by allowing the near-simultaneous acquisition of coregistered, spatially matched functional and morphologic data in the same examination. However, many benign lesions can accumulate FDG and be potential pitfalls in interpretation. With the increased use of CT-PET in oncologic imaging, misinterpretation of these potential pitfalls can have significant clinical ramifications and alter staging and management. In this article, we review the physiologic uptake of FDG, normal variants, and potential pitfalls in the integrated CT-PET imaging of the thorax and their implications in oncologic imaging.

Artifacts↗
PubMed2005

Effect of interocular delay on disparity-selective v1 neurons: relationship to stereoacuity and the pulfrich effect.

The temporal properties of disparity-sensitive neurons place important temporal constraints on stereo matching. We examined these constraints by measuring the responses of disparity-selective neurons in striate cortex of awake behaving monkeys to random-dot stereograms that contained interocular delays. Disparity selectivity was gradually abolished by increasing interocular delay (when the delay exceeds the integration time, the inputs from the 2 eyes become uncorrelated). The amplitude of the disparity-selective response was a Gaussian function of interocular delay, with a mean of 16 ms (+/-5 ms, SD). Psychophysical measures of stereoacuity, in both monkey and human observers, showed a closely similar dependency on time, suggesting that temporal integration in V1 neurons is what determines psychophysical matching constraints over time. There was a slight but consistent asymmetry in the neuronal responses, as if the optimum stimulus is one in which the right stimulus leads by about 4 ms. Because all recordings were made in the left hemisphere, this probably reflects nasotemporal differences in conduction times; psychophysical data are compatible with this interpretation. In only a few neurons (5/72), interocular delay caused a change in the preferred disparity. Such tilted disparity/delay profiles have been invoked previously to explain depth perception in the stroboscopic version of the Pulfrich effect (and other variants). However, the great majority of the neurons did not show tilted disparity/delay profiles. This suggests that either the activity of these neurons is ignored when viewing Pulfrich stimuli, or that current theories relating neuronal properties to perception in the Pulfrich effect need to be reevaluated.

Action Potentials↗
PubMed1998

Deconstructing heterosexuality: life stories from gay New York, 1931-1941.

By 1940, the sexual identity of heterosexuality became established in American popular culture. In the late 1930s, a path-breaking study of homosexuality was conducted by a multidisciplinary team of medical and scientific specialists, under the sponsorship of the Committee for the Study of Sex Variants. The "sex variants" study was based on a sample of volunteers from New York's lesbian and male homosexual community. This article focuses on a narrative analysis of the case study texts of the male sample. Using deconstruction as an interpretive strategy, the texts are examined in relation to the culturally dominant sexual ideology of heterosexuality. Implications are drawn about the relevance of life stories to identity politics.

Female↗
PubMed1983

Alpha and beta subunits of glycoprotein hormones in argyrophil pituitary tumors with small granule cells.

A group of 33 functionless pituitary tumors with small argyrophil groups (SAG) were collected from a series of 200 pituitary adenomas (16.5% of all adenomas). Histologically, the tumors showed an unusually high frequency of trabecular patterns, perivascular pseudo-rosettes, and oncocytoid transformation. Immunoreactivity for glycoprotein hormone alpha-chain was found in more or less numerous cells of 20 cases (64.5% of SAG tumors). Thirteen of these cases also showed specific beta-chain immunoreactivity, especially for follicle-stimulating hormone (FSH) beta-chain, which was present in 11 tumors. Various admixtures of immature, oncocytic, sparsely granulated, and densely granulated cells were observed ultrastructurally, with prevalence of the latter cell variants in tumors showing immunoreactive cells and prevalence of the former cell variants in tumors lacking immunoreactive cells. It is suggested that some relationship may exist between SAG cell (glycoprotein hormone precursor cells?) tumors--or at least part of them--and glycoprotein hormone cell lines. Anyway, whatever their origin and interpretation, SAG cell tumors seem to represent a distinct clinicopathologic entity.

Adenoma↗
PubMed2002

[Schizophrenia and molecular genetics].

BACKGROUND: Schizophrenia is a severe mental disorder with a lifetime risk in the population of 1%. Despite extensive research, the underlying neurobiological mechanisms remain largely unknown. MATERIAL AND METHODS: Based on relevant research literature, an overview of the molecular genetics of schizophrenia is given. RESULTS AND INTERPRETATION: Family, twin and adoption studies have shown that schizophrenia has a high heritability, indicating a significant genetic component to its aetiology. There is positive linkage to chromosomal regions which probably contain susceptibility genes of moderate effect. Genetic variants in different candidate genes and different chromosome abnormalities are apparently associated with increased susceptibility to schizophrenia. However, the genetic mechanisms of schizophrenia are still largely unknown. As a result of recent advancements in molecular genetic knowledge and methods, high-throughput techniques are now available in functional genomic research that will enable genome-wide search for susceptibility genes. This has to be combined with a new clinical approach where schizophrenia is characterized based on symptoms and traits that might more directly reflect fundamental processes of relevance to the disorder.

Chromosome Mapping↗
PubMed1998

Prinzmetal's angina and emotions: A neglected psychosomatic entity.

Prinzmetal's angina, a form of angina precipitated by vasoconstriction or spasm, appears to be a somatic phenomenon, but there is evidence, from research and case reports, of a major psychological component. In this study, individuals with Prinzmetal's angina were interviewed to determine the nature of their interpersonal relationships and their intrapsychic state at the time of onset of their chest pain. In addition, short developmental histories were obtained. The authors found that onset of chest pain was related to experiencing intense affect, and multiple levels of interpersonal and intrapsychic conflict, with strong conscious and unconscious, emotional and ideational links to previous traumas.

Adult↗
PubMed2003

Association between lipoprotein lipase (LPL) gene and blood lipids: a common variant for a common trait?

S447X, a serine substitution by a stop codon on base 99 of exon 9 of the lipoprotein lipase (LPL) gene, has beneficial effects on blood lipids. Other LPL alleles are associated with lipid levels, but whether one of these variants predominates remains elusive. We performed a systematic survey to identify single-nucleotide polymorphisms (SNPs) in all 10 LPL exons and flanking regions by resequencing the gene in 95 subjects. Of 24 variants, 14 were common (> or = 3%). We assayed the common SNPs in 186 cases with atherogenic lipid profiles (low HDL, high LDL) and 185 nonatherogenic controls (high HDL, low LDL). Only S447X and exons 6 (base +73) and 10 (base -11) were individually associated with case-control status (P<0.05, adjusted for major nongenetic covariates with known lipid effects). There were no significant SNP x gender interactions. In adjusted multi-SNP and haplotypic analyses, S447X was interpretable as the sole predictor, with a 2-3-fold reduction in the odds of being atherogenic vs. nonatherogenic (adjusted OR, 0.39; 95% CI, 0.21-0.73). S447X and base -11 of exon 10 were statistically interchangeable because they are strongly associated (r=0.92, P<0.0001), but we posit that the LPL association with lipid profile is more likely attributable to the functional S447X rather than the nonfunctional exon 10 SNP. It appears that the S447X variant of LPL may be another rare example (like APOE4, factor V-Leiden, and PPAR gamma Pro12Ala) of a common variant predisposing to a common disorder.

Case-Control Studies↗
PubMed1993

Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis.

BACKGROUND: Assessment methods for atopic dermatitis (AD) are not standardized, and therapeutic studies are difficult to interpret. AIMS: To obtain a consensus on assessment methods in AD and to use a statistical method to develop a composite severity index. METHODS: Consensus definitions were given for items used in the scoring system (extent, intensity, subjective) and illustrated for intensity items. Slides were reviewed to address within- and between-observer variability by a group of 10 trained clinicians, and data were statistically evaluated with a two-way analysis of variance. Two variants of an assessment system were compared in 88 patients at 5 different institutions. Data were analyzed using principal-component analysis. RESULTS: For 5 intensity items studied (erythema, edema/papulation, oozing/crusts, excoriations, lichenification), within- and between-observer variability was good overall, except for edema/papulation which was difficult to assess with slides. In the series of 88 patients, principal-component analysis allowed to extract two unrelated components: the first one accounting for 33% of total variance was interpreted as a 'severity' component; the second one, accounting for 18% of variance, was interpreted as a 'profile' component distinguishing patients with mostly erythema and subjective symptoms and those with mostly lichenification and dryness and lower subjective symptoms. Of the two evaluation systems used, the one using the rule of nine to assess extent was found more workable than the one using a distribution x intensity product. A scoring index (SCORAD) combining extent, severity and subjective symptoms was mathematically derived from the first system and showed a normal distribution of the population studied. CONCLUSION: The final choice for the evaluation system was mostly made based on simplicity and easy routine use in outpatient clinics. Based on mathematical appreciation of weights of the items used in the assessment of AD, extent and subjective symptoms account for around 20% each of the total score, intensity items representing 60%. The so-designed composite index SCORAD needs to be further tested in clinical trials.

Adolescent↗