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Biomedical subjects

Giovanni Parmigiani

Publications and source records attributed to Giovanni Parmigiani.

8 recordsLinked to original sources
PubMed2003

Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy.

Decreased nitric oxide synthase (NOS) activity induces left ventricular hypertrophy (LVH), but the transcriptional pathways mediating this effect are unknown. We hypothesized that specific NOS isoform deletion (NOS3 or NOS1) would activate different transcriptional programs in LVH. We analyzed cardiac expression profiles (Affymetrix MG-U74A) from NOS-/- mice using robust multi-array average (RMA). Of 12,422 genes analyzed, 47 genes were differentially expressed in NOS3-/- and 67 in NOS1(-/-) hearts compared with wild type (WT). Only 16 showed similar changes in both NOS-/- strains, most notably decreased heat-shock proteins (HSP10, 40, 70, 86, 105). Hypertrophied NOS1-/- hearts had unique features, including decreased myocyte-enriched calcineurin interacting protein and paradoxical downregulation of fetal isoforms (alpha-skeletal actin and brain natriuretic peptide). Cluster analyses demonstrated that NOS1 deletion caused more pronounced changes in the myocardial transcriptome than did NOS3 deletion, despite similar cardiac phenotypes. These findings suggest that the transcriptional basis for LVH varies depending on the inciting biochemical stimulus. In addition, NOS isoforms appear to play distinct roles in modulating cardiac structure.

Animals↗
PubMed2003

Statistical modeling and visualization of molecular profiles in cancer.

Current cancer classifications using morphological criteria produce heterogeneous classes with variable prognosis and clinical course. By measuring gene expression for thousands of genes in a single hybridization experiment, microarrays have the potential to contribute to more effective classifications based on molecular information. This gives hope to improve both prognosis and treatment. Statistical methods for molecular classification have focused on using high dimensional representations of molecular profiles to identify subclasses. These can be noisy, unstable, and highly platform-specific. In this article, we emphasize the notion of molecular profiles based on latent categories signifying under-, over-, and baseline expression. Following this approach, we can generate results that are more easily interpretable, more easily translated into clinical tools, more robust to noise, and less platform-dependent. We illustrate both the methods and the associated software for molecular class discovery on a data set of 244 microarrays comprising six known leukemia classes.

Child↗
PubMed2002

Human l1 retrotransposition is associated with genetic instability in vivo.

Retrotransposons have shaped eukaryotic genomes for millions of years. To analyze the consequences of human L1 retrotransposition, we developed a genetic system to recover many new L1 insertions in somatic cells. Forty-two de novo integrants were recovered that faithfully mimic many aspects of L1s that accumulated since the primate radiation. Their structures experimentally demonstrate an association between L1 retrotransposition and various forms of genetic instability. Numerous L1 element inversions, extra nucleotide insertions, exon deletions, a chromosomal inversion, and flanking sequence comobilization (called 5' transduction) were identified. In a striking number of integrants, short identical sequences were shared between the donor and the target site's 3' end, suggesting a mechanistic model that helps explain the structure of L1 insertions.

5' Flanking Region↗
PubMed2002

BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.

PURPOSE: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. PATIENTS AND METHODS: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. RESULTS: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. CONCLUSION: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.

Adult↗
PubMed2002

Prevalence of somatic alterations in the colorectal cancer cell genome.

Although a small fraction of human cancers have increased rates of somatic mutation because of known deficiencies in DNA repair, little is known about the prevalence of somatic alterations in the vast majority of human cancers. To systematically assess nonsynonymous somatic alterations in colorectal neoplasia, we used DNA sequencing to analyze approximately 3.2 Mb of coding tumor DNA comprising 1,811 exons from 470 genes. In total, we identified only three distinct somatic mutations, comprising two missense changes and one 14-bp deletion, each in a different gene. The accumulation of approximately one nonsynonymous somatic change per Mb of tumor DNA is consistent with a rate of mutation in tumor cells that is similar to that of normal cells. These data suggest that most sporadic colorectal cancers do not display a mutator phenotype at the nucleotide level. They also have significant implications for the interpretation of somatic mutations in candidate tumor-suppressor genes.

Colorectal Neoplasms↗
PubMed2002

Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression.

Pancreatic adenocarcinoma is among the most fatal of cancers, in part because of late diagnosis and a lack of effective therapies. Comprehensive studies are needed to better understand and address the cellular mechanisms and pathways of tumorigenesis. Serial analysis of gene expression was used to analyze gene expression profiles of pancreatic cancer cell lines, short-term cultures of normal pancreatic ductal epithelium, and primary pancreatic cancer tissue. A total of 294,920 tags representing 77,746 genes in 10 serial analysis of gene expression libraries were analyzed. A pancreatic cancer cell line (Hs766T) that exhibited a "normoid" profile of gene expression was identified. Several genes that may be involved in the fundamental nature of malignant changes in pancreatic ductal epithelium were suggested from those differentially and highly expressed in pancreatic cancer cells as compared with normal epithelium. Some overexpressed genes, such as S100A4, prostate stem cell antigen, carcinoembryonic antigen-related cell adhesion molecule 6, and mesothelin, suggest potential use as diagnostic markers. Others suggest potential novel therapeutic targets.

Carcinoma, Pancreatic Ductal↗
PubMed2002

Modeling and optimization in early detection programs with a single exam.

The choice of timing of screening examinations is an important element in determining the efficacy of strategies for the early detection of occult disease. In this article, we describe a flexible decision-making framework for the design of early detection programs, and we investigate the choice of timing when each individual in the screening program is examined only once. We focus on the theoretical relation between the optimal examination time and the distributions of sojourn times in health-related states. Specifically, we derive closed-form solutions of the optimal age using two specifications of utility functions, discuss the effects of natural history and utility specifications on the optimal solution, and present an application to early detection of colorectal cancer by once-only sigmoidoscopy or colonoscopy.

Age Factors↗