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PubMed2026

Evaluation of the efficacy of optical genome mapping in prenatal diagnosis: a retrospective cohort study.

BACKGROUND: Optical genome mapping (OGM) is an emerging cytogenetic method for concurrently detecting structural variants (SVs) and copy number variants (CNVs). However, its clinical application in prenatal diagnosis remains underexplored. METHODS: This study retrospectively evaluated the clinical validity of OGM in prenatal diagnosis by comparing with two routine genetic testing methods: karyotyping and chromosomal microarray analysis (CMA). Both positive and negative cases detected by routine genetic methods were enrolled to evaluate the technical concordance of OGM and its capability to improve diagnostic rate in negative cases. The exclusion criteria were balanced centromeric translocations, mosaic cases with cellular fractions < 20%, and loss of heterozygosity (LOH) < 25 Mb. All samples subjected to OGM testing were anonymized and analyzed blindly. The results from OGM were compared with those from routine genetic testing, and statistical analyses were performed to assess technical concordance and diagnostic rate. RESULTS: Of 217 samples (166 positive samples and 51 negative samples for routine genetic testing), all were successfully tested with OGM, including 2 umbilical cord blood samples, 4 chorionic villi samples, and 211 cultured amniotic fluid samples. Of the 207 reportable chromosomal aberrations from 166 positive samples, the blinded concordance between OGM and CMA, karyotyping, and combination of karyotyping plus CMA was 97.81%, 96.36%, and 97.10%, respectively. OGM missed six aberrations initially, including one LOH, two marker chromosomes, and three microdeletions. However, after reanalysis, its concordance improved to 100% with CMA and 99.03% with karyotyping plus CMA. OGM also diagnosed one additional case of a 3-kb deletion in 51 negative samples, improving the diagnostic rate by 1.96%. Moreover, OGM reclassified the pathogenicity of two microdeletions from pathogenic to uncertain significance in 2 positive cases. Furthermore, OGM clarified the diagnosis suspected by routine genetic testing and improved diagnostic accuracy in some cases. CONCLUSION: As far as we know, this is the largest retrospective study on OGM in prenatal diagnosis, and it includes a broad range of sample types. The results showed that OGM exhibits high concordance among the tested methods and increases the diagnostic rate. Thus, OGM has the potential to become a first-line technique for prenatal diagnosis in the future.

Humans↗

PubMed2003

The evolutionarily conserved gonadotropin-releasing hormone II modifies food intake.

GnRH is an evolutionarily conserved peptide of which there are multiple structural variants. One form, GnRH II, is the most widespread in vertebrates, but its primary function remains unclear. In female musk shrews, administration of GnRH II, but not GnRH I, reinstates mating behavior previously inhibited by food restriction. Because this finding suggests that the function of GnRH II may be linked to energetic status, we tested whether GnRH II directly affects food intake. Adult female musk shrews were maintained on ad libitum feeding or food restricted for 48 h, after which they were infused centrally with GnRH I (1 microg), GnRH II (1 microg), or saline. Food intake was recorded 90 min, and 3, 6, 24, and 48 h after infusion. GnRH II administration, but not saline or GnRH I, reduced 24-h food intake in ad libitum animals. Short-term food intake (90 min and 3 h) of both ad libitum and underfed shrews receiving GnRH II was also reduced by as much as 33%, relative to the food intake of saline-infused controls. GnRH I infusion did not affect short-term food intake differently than saline infusion in shrews fed ad libitum. In underfed females, GnRH I had an effect on short-term food intake that was intermediate to saline and GnRH II. We conclude that, in addition to its permissive role in regulating reproduction, GnRH II may also modulate food intake in mammals. Because GnRH II is present in primate brain, it may also serve a similar function in humans.

Animals↗

PubMed2004

A critical role for the evolutionarily conserved gonadotropin-releasing hormone II: mediation of energy status and female sexual behavior.

GnRH is an evolutionarily conserved neuropeptide, of which there are multiple structural variants; the function of the most widespread variant, GnRH-II, remains undefined. GnRH-II may affect reproductive behavior; GnRH-II administration to female musk shrews reinstates mating behavior previously inhibited by food restriction. To determine whether this action of GnRH-II is universal, we conducted the following studies in mice. Ovariectomized mice were primed with estradiol benzoate and progesterone once a week and tested for sexual behavior. Females showing a lordosis quotient (LQ) of 50 or higher on the fourth trial underwent food deprivation (FD) for either 24 or 48 h before an additional behavior test. FD for 48 h significantly reduced LQ compared with ad libitum-fed females. Next, females were FD for 48 h or maintained on ad libitum feeding and retested for sexual behavior after an intracerebroventricular infusion of either GnRH-I, GnRH-II, or saline. GnRH-II, but not GnRH-I, significantly increased LQ in FD females compared with FD females treated with saline. Lordosis was unaffected by GnRH-II in females maintained on ad libitum feeding. To assess whether the GnRH-I receptor mediates GnRH-II's behavioral effects, underfed females were pretreated with the type 1 GnRH receptor antagonist Antide and retested for sexual behavior. Antide pretreatment did not prevent GnRH-II from promoting mating behavior, suggesting that GnRH-II's behavioral actions are mediated through the type 2 GnRH receptor. We speculate that GnRH-II acts via its own receptor as a regulatory signal in mammals to ensure that reproduction is synchronized with energetically favorable conditions.

Animals↗

PubMed1988

The acute effects of growth hormone on amino acid transport and protein synthesis are due to its insulin-like action.

GH has acute stimulatory effects on amino acid transport and protein synthesis in a variety of tissues, but it has not been established whether these effects are expressions of the growth-promoting property of GH or of its separate insulin-like action. The 20,000-dalton structural variant of human GH (20K hGH) has been shown to have a high ratio of growth-promoting to insulin-like activity compared to native hGH (22K hGH), suggesting that it could be used as a tool to address the above question. Therefore, experiments were conducted to compare the relative abilities of native 22K hGH and 20K hGH, when added in vitro, to stimulate amino acid transport and protein synthesis in the isolated diaphragm of the female hypophysectomized rat. Paired intact hemidiaphragms were preincubated for 1 h in the absence or presence of various concentrations of 22K or 20K hGH. Then, 3-O-[14C]methylglucose was added to the medium to measure sugar transport as a test of insulin-like activity, and either alpha-[3H]aminoisobutyric acid acid or [3H] phenylalanine was also added to measure amino acid transport or protein synthesis, respectively, during a final hour of incubation. When the responses to the various concentrations of 22K and 20K were compared, 20K hGH was only about 20% as effective as 22K in stimulating 3-O-methylglucose transport, reflecting its markedly attenuated insulin-like activity on the diaphragm. Similarly, 20K hGH was only 20% as effective as 22K hGH in stimulating alpha-aminoisobutyric acid transport and phenylalanine incorporation into protein in the same muscles. Therefore, these findings support the idea that the rapid stimulatory effects of GH on amino acid transport and protein synthesis are expressions of the insulin-like action of GH and are not components of the response of target cells to its growth-promoting action.

3-O-Methylglucose↗

PubMed1988

Gonadotropin-releasing hormone molecular forms in mammalian hypothalamus.

Multiple forms of GnRH have been detected in brain tissue of species from all nonmammalian vertebrate classes, but in mammals it is generally believed a single molecular form of GnRH is present. We have investigated the possibility that additional structural variants of GnRH are present in mammalian (sheep, rat, and human) hypothalamus. Hypothalami were extracted with acetic acid and subjected to gel filtration chromatography and reverse phase HPLC systems specifically designed to separate GnRH analogs. Column fractions were assayed for immunoreactive GnRH using a library of specific antisera raised against the five known vertebrate GnRHs. Biological activity of the fractions was assessed by measuring their ability to release LH and FSH from cultured rat pituitary cells and/or LH release from dispersed chicken pituitary cells. Receptor binding activity was also measured in fractions from the human extract, using rat pituitary membranes. Several immunoreactive and biologically active forms of GnRH were found in sheep, rat, and human hypothalami. The major immunoreactive peptide consistently coeluted with mammalian GnRH. The other forms were not identifiable as any of the other known vertebrate GnRHs. Control experiments suggest these are modified forms of mammalian GnRH, which are artifacts generated during HPLC purification. Chromatographic and immunological studies indicate these forms of GnRH include peptides eluting both earlier and later than mammalian GnRH and which appear to be modified in the middle region and/or at the COOH-terminus of the molecule. Novel immunoreactive forms of GnRH, distinct from modified mammalian GnRH, were not apparent in any of the species. In chicken and rat pituitary cell bioassays and in rat receptor binding studies, the mammalian form of GnRH in HPLC fractions of the sheep and human hypothalamus displayed activity appropriate for this immunoreactive peak being mammalian GnRH. Some of the additional immunoreactive peaks (thought to be modified forms of mammalian GnRH) also displayed LH-releasing activity in the chicken and rat systems. Gonadotropin-releasing activity or receptor binding activity due to a second, novel, GnRH-like substance in HPLC fractions of the sheep and human hypothalamus was not detected. These data provide evidence for a single form of GnRH in sheep, rat, and human hypothalamus, unlike species from other vertebrate classes where two or more GnRHs are present within a single tissue.

Animals↗

PubMed1988

Structural and immunohistochemical characterization of insulin-like growth factor I and II receptors in the murine central nervous system.

The description of the cellular localization of insulin-like growth factor (IGF) receptors in the central nervous system (CNS) remains incomplete, as do the descriptions of changes in their characteristics with respect to different developmental stages. We, therefore, performed affinity labeling studies in microsomal membrane preparations of adult and fetal rat brain and liver tissues with [125I]IGF-I and [125I]IGF-II. These studies demonstrated tissue- and developmental stage-specific structural variants of type I receptor alpha-subunits as well as type II receptors. The adult rat brain type I alpha-subunit had an apparent mol wt (Mr) of 127,000, whereas those of adult and fetal rat liver measured 140,000. Fetal rat brain microsomes, however, had two types of type I receptor alpha-subunits measuring 130,000 and 120,000 Mr. The larger subunit from fetal brain consistently migrated at an apparent Mr of 3,000, greater than subunits from adult brain. Both type I and II receptors were more abundant in fetal liver and brain than in adult tissues. Affinity labeling was also performed directly to monolayers of cultured fetal brain neurons and newborn astrocytes. These studies detected both type I and II receptors on the surfaces of both types of cells. However, only the high Mr (140,000) form of the type I alpha-subunit was detected in cultured CNS cells, suggesting that expression of low Mr variant receptors is altered in vitro. Type II receptors were demonstrated by immunohistochemistry in adult rat hypothalamic neurons. However, the majority of neurons did not react with type II receptor antibody. This finding implies that only a minority of hypothalamic neurons are capable of responding to IGF-II via type II receptors. On the other hand, all astrocytes had striking type II receptor immunoreactivity. This signifies a more general biological role for this receptor in astrocytes compared with neurons. These results suggest that different tissue-, developmental stage-, and cell-specific processes are mediated by IGF receptors and suggests new directions in which to explore potential biological actions for these receptor-ligand systems in the CNS.

Affinity Labels↗

PubMed1988

Glycosylated prolactin in porcine plasma: immunoblotic measurement from birth to one year of age.

As much as 40% of PRL in the pituitary gland of the pig is glycosylated. To help determine the physiological significance of this structural variant of PRL, we have measured glycosylated PRL (G-PRL) in the plasma of growing pigs from birth to 1 yr of age. An immunoblotting method developed originally for human plasma was used. With some modifications, the method could detect G-PRL in as little as 0.2 ml porcine plasma. Concanavalin-A affinity chromatography confirmed the glycoprotein nature of the plasma G-PRL band. Quantitative estimates of the immunoblotting results revealed marked differences with age in the secretion of the two monomeric forms of PRL. G-PRL concentrations averaged 138% higher than those of non-G-PRL between birth and 2 months of age, but lower thereafter. Chronologically, both forms displayed similar patterns between birth and 2 months, the concentration remaining unchanged or decreasing slightly. After 2 months, however, concentrations of non-G-PRL increased markedly; the increase was characterized by great fluctuations. G-PRL concentrations, on the other hand, increased only moderately, but the increase was consistent until the end of the study period. The results demonstrate the circulating nature of G-PRL in the pig and suggest that the variant may play a physiological role in the growth and development of the animal.

Aging↗

PubMed1989

A second form of gonadotropin-releasing hormone (GnRH), with chicken GnRH II-like properties, occurs together with mammalian GnRH in marsupial brains.

GnRH peptides in the hypothalami of marsupials (tammar wallaby, short-nosed bandicoot, and eastern quoll) and a monotreme (echidna) were investigated by reverse phase HPLC and RIA with region-specific antisera. In the wallaby hypothalamic extract, a single form of GnRH was present, which eluted in the same position as synthetic mammalian GnRH on HPLC and was recognized by antibodies directed against the NH2- and COOH-termini of mammalian GnRH as well as by antibodies to the middle region. Two GnRH molecular forms were demonstrated in the bandicoot and quoll hypothalamic extracts. One form eluted in the same position as synthetic mammalian GnRH on HPLC and was quantified equally by two mammalian GnRH antisera. The second form eluted in the same position as synthetic chicken GnRH II and was recognized by specific antibodies to this molecule. Quantification of this immunoreactive peak with two chicken GnRH II antisera was not equal, suggesting that the peptide has similar properties to, but may not be identical to, chicken GnRH II. Immunoreactive GnRH was also detected in the echidna hypothalamic extract. These findings demonstrate that in some mammals more than one form of GnRH is present in the brain of a single species, as has previously been found in species from all nonmammalian vertebrate classes. The finding in marsupial brain of a peptide with properties of chicken GnRH II, which has previously been reported in species of Aves, Reptilia, Amphibia, Osteichthyes, and Chondrichthyes, supports our hypothesis that this widespread structural variant may represent an early early evolved and conserved form of GnRH.

Aging↗

PubMed1991

Isolation and characterization of three forms of joining peptide from adult human pituitaries: lack of adrenal androgen-stimulating activity.

Three structural variants of the joining peptide (JP) fragment of POMC have been purified from human pituitaries. Ion exchange and reverse phase tissue extraction procedures were combined with reverse phase HPLC to achieve complete purification of each form of JP. Fragments resulting from tryptic hydrolysis of each form were characterized by amino acid analysis and fast atom bombardment mass spectrometry. The predominant form of human JP, accounting for about 50% of the total purified, was found to be conjugated to glutathione through the lone cysteine residue at position 9. The other two variants were identified as human JP with a free cysteine residue and human JP dimer and accounted for 35% and 15%, respectively, of the total purified. Recently, human JP-(1-18) has been suggested as having adrenal androgen-stimulating activity. None of the three JP variants or their respective 1-20 amino-terminal fragments resulting from tryptic hydrolysis showed any ability to promote the secretion of dehydroepiandrosterone sulfate by cultured human fetal adrenal cells. Similarly, no potentiation of the stimulatory effects of ACTH-(1-39) was observed. The three variants of human JP as well as JP purified from rat, porcine, and bovine pituitaries were tested for their ability to stimulate androgenic steroids from dispersed fetal rabbit adrenal cells. None showed any significant biological activity either in stimulating steroid secretion or in potentiating the action of ACTH-(1-39).

Adrenal Glands↗

PubMed1996

Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor.

The incretin hormone glucagon-like peptide-1 (GLP-1) is an important regulator of postprandial insulin secretion. In addition to its insulinotropic actions on pancreatic beta-cells, GLP-1 enhances glucose disposal by insulin-independent mechanisms, suggesting that GLP-1 receptors are located on extrapancreatic tissues. In this study, we examined the tissue distribution of GLP-1 receptor (GLP-lR) messenger RNA (mRNA) in rat by RNAse protection, RT-PCR, and in situ hybridization. We identified GLP-1R mRNA in the lung, pancreatic islets, stomach, and kidney by the RNAse protection assay. RT-PCR analysis also detected GLP-1R mRNA in the hypothalamus and heart. In situ hybridization experiments identified receptor mRNA in the gastric pits of the stomach, large nucleated cells in the lung, crypts of the duodenum, and pancreatic islets. No localized specific grains were found in kidney, skeletal muscle, heart, liver, or adipocytes. These results indicate that sequences corresponding to the cloned rat islet GLP-1 receptor are expressed in the pancreatic islets, lung, hypothalamus, stomach, heart, and kidney but not in adipose, liver, and skeletal muscle. Further, the GLP-1 receptor expressed in the kidney and heart may be structural variants of the known receptor. Therefore, the observed extrapancreatic actions of GLP-1 may not be strictly confined to interactions with the defined GLP-1 receptor.

Adipocytes↗

PubMed1994

Specific binding to vitamin D response elements of chicken intestinal DNA-binding activity is not related to the vitamin D receptor.

In this report we confirm that the putative vitamin D response element (VDRE), located between -320 and -306 in the chicken calbindin-D28K gene, is not a binding site for the vitamin D3 receptor (VDR). In examining the ability of chicken intestinal nuclear extracts (CINE) to bind known VDREs, we observed a specific VDRE-binding activity, which is distinct from VDR. In fact, VDR-depleted CINE retains the ability to bind the rat osteocalcin VDRE. The VDRE-binding activity binds DNA with high affinity and contacts it at the same guanine residues as VDR. Its specificity in binding structural variants of the AGGTCA repeat is broader than that of VDR, as direct repeats spaced by 3, 4, and 5 base pairs are almost equally effective competitors when added to the probe in molar excess. Palindromic arrangements of the same motif are lower affinity competitors. The retinoid-X receptor is involved in the binding complex, as incubation of CINE with antibody to retinoid-X receptor results in a quantitative supershift. Antibodies to retinoic acid receptors (RAR alpha and -beta), T3 receptor, or chicken ovalbumin up-stream promoter-transcription factor had no apparent effect. These data suggest that species specificity is a relevant aspect of VDR/VDRE recognition, and that a novel factor(s), different from VDR, might be involved in the effect of vitamin D on gene expression.

Animals↗

PubMed1999

No association between Glu/Asp polymorphism of NOS3 gene and ischemic stroke.

Endothelial nitric oxide synthase (NOS3) gene has been shown to modulate the degree of cerebral ischemia following stroke in animal models and is thus a candidate genetic risk factor for stroke. We compared 265 ischemic stroke cases with 293 controls and found no difference in distribution of the common structural variant Glu/Asp in codon 298 of exon 7 in the NOS3 gene. Our data do not support the hypothesis that NOS3 is a genetic risk factor for stroke.

Aged↗

PubMed1999

Semi-automated rapid isoelectric focusing of apolipoproteins C from human plasma using Phastsystem and immunofixation.

Apolipoproteins (apo) C-I, C-II, and C-III play crucial roles in intravascular lipid metabolism. Whereas apo C-II is an obligate cofactor for lipoprotein lipase, apo C-III was shown to inhibit its action. Apo C-I can be a potent cofactor of human lecithin:cholesterol acyltransferase. Structural mutants and deficiencies of apo C-II lead to hypertriglyceridemia. A similar phenotype is associated with apo C-III mutants and is inducible by overexpression of human apo C-III in transgenic animals. No structural variant has so far been reported for apo C-I. The present paper describes a rapid semi-automated procedure for isoelectric focusing analysis of these C-apolipoproteins from whole plasma or serum and their visualization by immunofixation and silver staining. The procedure allows detection of charged variants of C-apolipoproteins. As applied to 295 patients with coronary heart disease and 85 controls, it also serves to detect deficiency syndromes of these apolipoproteins. The procedure provides reliable, easy and quick analysis of C-apolipoproteins applicable as a routine or screening procedure not restricted to specialized laboratories.

Acrylic Resins↗

PubMed2026

PSIP1::TBL1X: a recurrent gene fusion in pancreatic neuroendocrine tumors.

Effective treatment of metastatic neuroendocrine tumors (NETs) is limited by a lack of targeted therapies and clinically useful predictive biomarkers. We applied complementary genomic profiling technologies, including optical genome mapping (OGM) and whole exome sequencing (WES), to 70 liver metastases of NETs from multiple anatomical primary sites to identify actionable genomic alterations. We detected recurrent fusions involving TBL1X (PSIP1::TBL1X) and BEND2 (CHD7::BEND2 and NEO1::BEND2) by OGM in pancreatic neuroendocrine tumors (pNETs). The expression of the PSIP1::TBL1X fusion was confirmed by PacBio Iso-Seq long-read transcriptome sequencing and nested rtPCR, and fusion protein expression was established by western blotting. Expression of the PSIP1::TBL1X fusion was also assayed in a separate cohort of 31 specimens from 28 pNET cases by rtPCR. Across both cohorts, PSIP1::TBL1X was identified in 11% of pNET patients with available metastatic tissue, but was not detected in primary tumor specimens. All PSIP1::TBL1X fusion isoforms were found to retain early exons of PSIP1 and the complete coding sequence of TBL1X. Consistent with prior reports, BEND2 fusions were associated with high-grade tumors and may represent a clinically useful biomarker for aggressive disease. Notably, TBL1X and BEND2 fusions did not co-occur with ATRX/DAXX mutations, defining a distinct molecular subgroup of pNETs. This study highlights the importance of structural variant profiling in molecular profiling studies and supports a revised view of the role of gene fusions in neuroendocrine malignancies.

Humans↗

PubMed2005

Guanylyl cyclases across the tree of life.

This review explores the origins, diversity and functions of guanylyl cyclases in cellular organisms. In eukaryotes both cGMP and cAMP are produced by the conserved class III cyclase domains, while prokaryotes use five more unrelated catalysts for cyclic nucleotide synthesis. The class III domain is found embedded in proteins with a large variety of membrane topologies and other functional domains, but the vertebrate guanylyl cyclases take only two forms, the receptor guanylyl cyclases with single transmembrane domain and the soluble enzymes with heme binding domain. The invertebrates additionally show a soluble guanylyl cyclase that cannot bind heme, while the more basal metazoans may lack the heme binding enzymes altogether. Fungi, the closest relatives of the metazoans, completely lack guanylyl cylases, but they appear again in the Dictyostelids, the next relative in line. Remarkably, the two Dictyostelid guanylyl cyclases have little in common with the vertebrate enzymes. There is a soluble guanylyl cyclase, which shows greatest sequence and structural similarity to the vertebrate soluble adenylyl cyclase, and a membrane-bound form with the same configuration as the dodecahelical adenylyl cyclases of vertebrates. There is a difference, the pseudosymmetric C1 and C2 catalytic domains have swapped position in the Dictyostelium enzyme. Unlike the vertebrate guanylyl cyclases, the Dictyostelium enzymes are activated by heterotrimeric G-proteins. Swapped C1 and C2 domains are also found in the structurally similar guanylyl cyclases of ciliates and apicomplexans, but these enzymes additionally harbour an amino-terminal ATPase module with ten transmembrane domains. G-protein regulation could not be demonstrated for these enzymes. Higher plants lack class III cyclase domains, but an unexplored wealth of guanylyl cyclases is present in the green alga Chlamydomonas. Progenitors of all structural variants of the eukaryote guanylyl cyclases are found among the prokaryote adenylyl cyclases. This and the close similarity of many guanylyl cyclases to adenylyl cyclases suggests a paraphyletic origin for the eukaryote enzymes with multiple events of conversion of substrate specificity.

Animals↗

PubMedDate not supplied

Ultrastructure of adrenal cortical carcinoma.

The ultrastructural features of 30 adrenal cortical carcinomas have been reviewed and compared with those seen in adrenal cortical adenomas, adrenal cortical hyperplasia, and the normal cortex. A broad range of ultrastructural appearances was found among the carcinomas, but the differences were mainly in the amount of cytoplasmic lipid, number of lysosomes, and quantity and architecture of the mitochondria and endoplasmic reticulum. Structural variants among the carcinomas included lipid-rich, oncocytic, and glycogen-rich cells. Electron microscopy can be extremely useful in differential diagnoses that include adrenal cortical carcinoma.

Adenoma↗

PubMed1977

Variation in hemoglobin A2.

The structure, properties and function of, and some biosynthetic and genetic aspects of, Hb A2 are described. The structural variants of Hb A2 are reviewed and their geographical distribution presented. Hb A2, Hb A2-Flatbush and Hb A2-Babinga are characteristic of negro populations and may have originated in Western or Central Africa. Hb A2-Sphakia is characteristic of Canadian Amerindian and Hb A2-Indonesia of Indonesian/Malay populations. Hb A2-NYU has only been found sporadically and most frequently in persons of Eastern European origin. The other three variants of Hb A2 have only been reported in a single person or in single families. Some conditions which are associated with changes in Hb A2 levels are reviewed.

Africa, Central↗

PubMed1997

Properties of intraepithelial neoplasia relevant to cancer chemoprevention and to the development of surrogate end points for clinical trials.

Cancer chemoprevention is defined as the prevention of cancer by the administration of diet supplements or drugs. A drug discovery effort should therefore focus on finding agents that will avert the process of intraepithelial neoplasia which precedes invasive cancer. Over 30 agents developed by the chemoprevention program at the National Cancer Institute are being tested against intraepithelial neoplasia of many organ sites in more than 80 clinical trials. Two basic mechanisms underlie the onset and development of intraepithelial neoplasia. First is the development of the two precursor lesions of chronic diffuse epithelial hyperplasia and genomic instability, the latter being produced by "mutator" mutations in genes responsible for genomic stability, by gene copy amplification or loss from DNA breakage-fusion-anaphase-bridge cycles, by unequal sister chromatid exchange, and by accumulation of double minutes. Second is the development of multicentric intraepithelial neoplastic lesions which independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (i) the development of better technology for early diagnosis, (ii) the development of multiple agents that block intralesional proliferation at steps along the signal pathway of mitotic signal transduction and along the signal pathway of synthesis of daughter cell components, (iii) the development of nontoxic anti-inflammatory agents, anitoxidants, antimutagens, and proapoptotics, (iv) the avoidance of "clonal escape" through use of drug combinations, and (v) the use of computer-assisted quantitative image analysis to assay modulation of surrogate end points in chemoprevention clinical trials.

Anticarcinogenic Agents↗