809 research outputs found
A self-conscious Kurt Vonnegut: an analysis of Cat's Cradle, Slaughterhouse-Five and Breakfast of Champions
No full textThe works of Kurt Vonnegut stand as seminal in the American literary canon. Looking at three of his most influential novels, namely Cat's Cradle, Slaughterhouse-Five and Breakfast of Champions, this study aims to better understand the mechanisms which inform his fiction. Working chronologically through the novels, the study examines historical context, narrative technique, theoretical underpinnings and the social critique of each novel. Guided by an idea of the postmodern novel the study examines how these elements interact, concluding that by way of what may be considered "simple" yet self-conscious metafiction and prose as well as variations in narrative technique, Vonnegut is able to more accurately convey his opinions on the American situation as well as demonstrate his stance on the role of fiction and the writer in contemporary society. The study also considers closely the role of the reader and the author/reader/text relationship
p53 MUTATIONS ARE ASSOCIATED WITH HISTOLOGIC TRANSFORMATION OF FOLLICULAR LYMPHOMA
No full textThe majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma
p53 mutations are associated with histologic transformation of follicular lymphoma
No full textThe majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma
Nonparametric checks for count data models: an application to demand for health care in Spain
No full textThis paper presents model specification checking procedures for count data regression models which are consistent in the direction of nonparametric alternatives. The discussion is motivated in the context of a model of demand for health care in Spain. The parameters of the regression model are estimated by maximum likelihood based on Poisson and Negative Binomial specifications as well as by ordinary least squares and semiparametric generalized least squares. However, our interest is not only centered on the estimation ofthe regression parameters, but also the conditional probabilities of counts. Therefore, the specification of the conditional distribution function of counts is the main focus of attention. A useful preliminary diagnosis tool consists of comparing the conditional probabilities estimates by nonparametric regression and by maximum likelihood methods based on alternative models. We present formal specification procedures based on new developed testing methods for regression model checking. The test statistics are based on marked empirical processes which are not distribution free, but their critical values are well approximated by bootstrap. Such tests are valid for testing the functional form of the conditional mean and conditional probabilities resulting from alternative distributional specifications. In our health care demand model, the linear exponential regression model with a Negative Binomial seems to be appropiate for this data set
Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a defined personal and family history in an Ashkenazi Jewish woman (LAMBDA)
No full textINTRODUCTION: Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer. Women considering mutation testing usually have several personal and family cancer characteristics, so predicting mutation status from one factor alone could be misleading. The aim of this study was to develop a simple algorithm to estimate the probability that an Ashkenazi Jewish woman carries an ancestral mutation, based on multiple predictive factors. METHODS: We studied Ashkenazi Jewish women with a personal or family history of breast or ovarian cancer and living in Melbourne or Sydney, Australia, or with a previous diagnosis of breast or ovarian cancer and living in the UK. DNA samples were tested for the germline mutations 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. Logistic regression was used to identify, and to estimate the predictive strength of, major determinants. RESULTS: A mutation was detected in 64 of 424 women. An algorithm was developed by combining our findings with those from similar analyses of a large study of unaffected Jewish women in Washington. Starting with a baseline score, a multiple of 0.5 (based on the logistic regression estimates) is added for each predictive feature. The sum is the estimated log odds ratio that a woman is a carrier, and is converted to a probability by using a table. There was good internal consistency. CONCLUSIONS: This simple algorithm might be useful in the clinical and genetic counselling setting. Comparison and validation in other settings should be sought
Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma
No full textThe molecular pathogenesis of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of lymphoma, is unknown. A gene was cloned from chromosomal translocations affecting band 3q27, which are common in DLCL. This gene, BCL-6, codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors. In 33 percent (13 of 39) of DLCL samples, but not in other types of lymphoid malignancies, the BCL-6 gene is truncated within its 5' noncoding sequences, suggesting that its expression is deregulated. Thus, BCL-6 may be a proto-oncogene specifically involved in the pathogenesis of DLCL
6q DELETIONS DEFINE DISTINCT CLINICO-PATHOLOGIC SUBSETS OF NON-HODGKIN'S LYMPHOMA
No full textCommonly observed in lymphoid neoplasms, deletions of 6q have been correlated with histologic and clinical subsets of non-Hodgkin's lymphoma (NHL). Our recent analysis of loss of heterozygosity of 6q loci in NHL showed two regions of minimal molecular deletion (RMD), an RMD1 at 6q25-27 and an RMD2 at 6q21-23. To establish correlations between these RMDs and regions of minimal cytogenetic deletions (RCDs) on 6q, and to define associations between RCDs and clinico-pathologic features, we have analyzed chromosome 6 abnormalities in 459 consecutively ascertained, karyotypically abnormal cases of NHL. Among these, 126 (27.5%) cases had structural abnormalities of chromosome 6, of which 94 were deletions. Analysis of these deletions identified three RCDs. An RCD1 encompassing 6q25-27 was seen in 45 intermediate-grade NHL. An RCD2 at 6q21 was observed in 11 high-grade NHL, 9 of which were of the immunoblastic subtype. An RCD3 at 6q23 was noted in 18 low-grade NHL lacking a t(14;18) translocation. Of these 18 cases, 12 were small lymphocytic NHL and, in 2 of these, del(6q) was the sole karyotypic abnormality. In 20 cases of low-grade NHL with t(14;18), the deletions spanned both RCD1 and RCD3. These data suggested the presence of at least 3 tumor suppressor genes on 6q within RCD1, RCD2, and RCD3; they also showed associations between RCDs in 6q and subsets of NHL, including a specific association between a group of well-differentiated lymphoid neoplasms and RCD3. The apparent heterogeneity of breakpoints when all NHLs are considered together explains the inability of previous studies to reliably establish correlations between recurring 6q deletions and histologic and clinical features of NHL
DELETIONS INVOLVING TWO DISTINCT REGIONS OF 6q IN B-CELL NON-HODGKIN LYMPHOMA
No full textThe recurrent loss of genetic material from a specific chromosomal region in a given tumor type suggests the presence of a tumor-suppressor gene, the loss or inactivation of which may be relevant for tumorigenesis. In this study, we provide molecular evidence for the recurrent association between deletions on the long arm of chromosome 6 and B-cell non-Hodgkin lymphoma (B-NHL). Normal and tumor DNAs from 71 cases of B-NHL were studied for loss of constitutional heterozygosity (LOH) at 19 loci on chromosome 6 using a panel of restriction fragment length polymorphism (RFLP) probes. LOH, indicating deletion of all or part of 6q, was detected in 16 of 71 cases (22.5%), ranging from low-grade to high-grade B-NHL. The isolated loss of 6p or the loss of other chromosomes (8, 17, 22) tested as controls for specificity was not observed in any case. Comparison of the extent of the deletions among different cases allowed the identification of two distinct regions of minimal deletion (RMD) at 6q25 to 6q27 (RMD-1) and at 6q21 to 6q23 (RMD-2), respectively, suggesting the existence of two tumor-suppressor genes. These data support a role for 6q deletions in B-NHL pathogenesis and provide a basis for identifying the corresponding tumor-suppressor genes
IDENTIFICATION OF GENETIC LESIONS ASSOCIATED WITH DIFFUSE LARGE-CELL LYMPHOMA
No full textBACKGROUND:
The pathogenesis of several subtypes of non-Hodgkin's lymphoma (NHL) is associated with specific genetic lesions involving oncogenes and tumor-suppressor genes. These lesions include c-myc translocation and p53 inactivation in small noncleaved-cell lymphoma, and bcl-2 and bcl-1 translocation in follicular (FL) and mantle-zone lymphoma, respectively. Relatively little is known, however, about the pathogenesis of diffuse lymphoma with a large-cell component (DLLC; including large-, mixed-cell, and immunoblastic), the most relevant NHL type in terms of morbidity and mortality. Since DLLC can occur 'de novo' or via histologic transformation of follicular lymphoma, it is critical to identify lesions associated with both pathogenetic pathways.
DESIGN:
The present work is aimed at (i) identifying the role of cytogenetic and molecular lesions involving oncogenes or tumor-suppressor genes in the transformation of FL into DLLC in a series of 5 patients for whom sequential biopsies were available pre- and post-transformation and (ii) identifying novel proto-oncogenes involved in DLLC pathogenesis by molecular analysis of chromosomal translocations affecting band 3q27, which are common in DLLC.
RESULTS:
Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL. A novel proto-oncogene, bcl-6, coding for a zinc-finger transcription factor, was cloned from 3q27 breakpoints and shown to be structurally altered in 33% (13/39) of DLLC samples studied, but not in other types of lymphoid malignancies.
CONCLUSIONS:
These results indicate that inactivation of the p53 tumor-suppressor gene may complement bcl-2 activation and be involved in the transformation of FL into DLLC. Activation of the bcl-6 oncogene may represent one of the steps in the pathogenesis of 'de novo' DLLC. Both lesions should prove useful as diagnostic and prognostic markers in the clinical management of these tumors
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