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PubMed2006

Differentiation of the various lesions causing an abnormality of the endometrial cavity using MR imaging: emphasis on enhancement patterns on dynamic studies and late contrast-enhanced T1-weighted images.

The objectives of this study were to determine the usefulness of magnetic resonance (MR) imaging in the differentiation of various lesions causing an abnormality of the endometrial cavity by evaluating the imaging features on dynamic contrast-enhanced study and late contrast-enhanced T1-weighted images (T1WI). Contrast-enhanced MR imaging of 59 pathologically proven lesions that showed an abnormality of the endometrial cavity, including 32 endometrial cancers, five sarcomas, nine hyperplastic polyps, nine submucosal myomas, three hyperplasia, and one adenomyoma, were retrospectively reviewed. The enhancement degree and patterns on dynamic contrast-enhanced study and late contrast-enhanced T1WI were compared among different pathologies. On dynamic contrast-enhanced study, 72% (23/32) of endometrial cancers showed early peak enhancement to be reached within 1 min following intravenous administration of contrast material. On late-contrast-enhanced T1WI, lesions showed weak enhancement with gradual washout. Ninety-five percent (21/22) of benign lesions and 100% (5/5) of sarcomas showed late peak enhancement to be reached in 2-3 min following intravenous administration of contrast material. On late contrast-enhanced T1WI, both of these lesions showed persistent strong enhancement. Different enhancement patterns on dynamic contrast-enhanced MR imaging and late contrast-enhanced T1WI can provide a useful clue in the differentiation of various lesions causing an abnormality of the endometrial cavity.

Adult↗
PubMed2005

Model analysis of flux enhancement across hairless mouse skin induced by chemical permeation enhancers.

Previous permeant partitioning studies with hairless mouse skin (HMS) in the presence of several chemical skin permeation enhancers have revealed that, when such enhancers induce significant skin permeability coefficient enhancement, it is accompanied by significant enhancement in the equilibrium uptake (partitioning) of the permeant into the intercellular lipid component of the stratum corneum (SC). Particularly, it was found that the 1-alkyl-2-pyrrolidones and the 1-alkyl-2-azacycloheptanones, at aqueous solution concentrations that gave skin permeation enhancement (E) of 10 for corticosterone (CS, the permeant), enhanced the equilibrium uptake of beta-estradiol (E2beta, a surrogate permeant) from the aqueous phase into the intercellular lipids of HMS SC by a factor of 5-7. This finding raised the question of whether this uptake enhancement induced by the permeation enhancer under equilibrium conditions would be essentially the same as that determined kinetically from time-dependent permeation experiments utilizing appropriate SC membrane models and Fick's laws of diffusion to treat the data. HMS transport experiments were conducted with CS as the permeant and 1-octyl-2-pyrrolidone (OP) and 1-hexyl-2-azacyloheptanone (HAZ) as the enhancers. In treating the experimental data, a one-layer skin transport model (SC only) and a two-layer model (SC layer and the epidermis/dermis layer) were both investigated. Both the partition coefficient enhancement (E(K)) and the diffusion coefficient enhancement (E(D)) were deduced from the data treatment. The results showed that when the total transport enhancement of CS was around 11, E(K) was in the range of 6-8 and E(D) was in the range of 1.5-1.9 using both the one-layer and the two-layer models. This E(K) value was found to be in good agreement with the E2beta partition enhancement obtained directly under equilibrium conditions in previous studies. This indicates that (a) the rate-limiting domain for the transport of the lipophilic permeants across HMS and the HMS SC intercellular lipid domain probed in the equilibrium partitioning experiments are essentially the same, and (b) the total flux enhancement (E) of lipophilic permeants across HMS was driven mainly by enhancing the partitioning of the permeant into the rate-limiting domain (E(K)) and secondarily by enhancing the diffusion coefficients (E(D)) of the permeant in the domain. Comparison of the one-layer and two-layer skin model results revealed that non-steady-state transport of lipophilic compounds across HMS was better described by the two-layer model because the dermis/viable epidermis played a significant role in lipophilic permeant binding.

Algorithms↗
PubMed2004

Nodule-in-nodule appearance of hepatocellular carcinomas: comparison of gadolinium-enhanced and ferumoxides-enhanced magnetic resonance imaging.

PURPOSE: To perform comparison of gadolinium-enhanced and ferumoxides-enhanced magnetic resonance imaging (MRI) in the detection of nodule-in-nodule appearance of hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: During a recent 45-month period, we had eight patients (five men and three women; age range, 63-84 years; mean, 71 years) with HCCs with nodule-in-nodule appearance who underwent gadolinium-enhanced MRI, ferumoxides-enhanced MRI, and computed tomography during arterial portography (CTAP) and computed tomography during hepatic arteriography (CTHA), combined and separately, within an interval of two weeks. Two blinded radiologists in consensus retrospectively evaluated three sets of sequences: unenhanced T1- and T2-weighted MR, gadolinium-enhanced MR, and ferumoxides-enhanced MR images in random order of patients and imaging sequences. The depiction degree of nodule-in-nodule appearance of HCC was evaluated in a semiquantitative fashion. The sensitivities of unenhanced T1- and T2-weighted, gadolinium-enhanced, and ferumoxides-enhanced MR images were compared with McNemar's test. RESULTS: The eight HCCs with nodule-in-nodule appearance ranged in size from 16-26 mm (mean, 20.0 +/- 4.0 mm), and there existed nine internal HCC foci ranging in size from 5-14 mm (mean, 7.9 +/- 3.5 mm). On gadolinium-enhanced MR images, the nodule-in-nodule appearance of HCC was typically seen as hypervascular foci in an iso- or hypovascular area: the depiction degree of nodule-in-nodule appearance was distinct in two lesions, equivocal in three, and absent in three. On ferumoxides-enhanced MR images, it was typically seen as hyperintense foci in a hypointense area: the depiction degree was distinct in four, moderate in one, and absent in three. The sensitivities for detection of nodule-in-nodule appearance were 25%, 25%, and 63% on T1- and T2-weighted, gadolinium-enhanced, and ferumoxides-enhanced MR images, respectively, but there was no significant difference in sensitivity. CONCLUSION: Nodule-in-nodule appearance of HCCs can be seen on ferumoxides-enhanced MR images, in some cases more clearly than on gadolinium-enhanced MR images, particularly when the background nodule shows hyperintensity on precontrast T1-weighted images. Ferumoxides-enhanced MRI may be considered when development of malignant foci is suspected during routine examinations.

Aged↗
PubMed2005

Role of cytosolic phospholipase A2 in the enhancement of alpha2-adrenoceptor-mediated vasoconstriction by the thromboxane-mimetic U46619 in the porcine isolated ear artery: comparison with vasopressin-enhanced responses.

Pre-contraction with the thromboxane-mimetic U46619 enhances the subsequent alpha(2)-adrenoceptor-mediated vasoconstriction in the porcine ear artery through an enhanced activation of ERK-MAP kinase. In this study we determined the role of cPLA(2) in this enhanced response, and determined whether vasopressin is also able to enhance alpha(2)-adrenoceptor-mediated vasoconstriction through the same pathway. The cPLA(2) inhibitors AACOCF3 (50 microM) and MAFP (50 microM) both inhibited the U46619-enhanced alpha(2)-adrenoceptor response, but had no effect on the direct alpha(2)-adrenoceptor response. AACOCF3 also inhibited the enhanced ERK activation associated with the enhanced alpha(2)-adrenoceptor-mediated vasoconstriction. Pre-contraction with arachidonic acid mimicked the effect of U46619 by enhancing the contractile response to the alpha(2)-adrenoceptor agonist UK14304 (1 microM) and enhancing the alpha(2)-adrenoceptor-mediated ERK activation. Pre-contraction with vasopressin also enhanced the contractile response to UK14304, but neither PD98059 (50 microM) nor AACOCF3 (50 microM) had any effect this vasopressin-enhanced response, indicating that neither the ERK pathway, nor cPLA(2) are involved in vasopressin-enhanced responses. The alpha(2)-adrenceptor-stimulated activation of ERK was also unaffected by pre-contraction with vasopressin. On the other hand, inhibition of PKCzeta inhibited the enhanced alpha(2)-adrenoceptor contraction after pre-contraction with both U46619 and vasopressin. This study demonstrates that alpha(2)-adrenoceptor-mediated vasoconstriction can be enhanced through two different pathways-one dependent upon the enhanced activation of ERK-MAP kinase through activation of cPLA(2), and the other through a different, ERK/cPLA(2)-independent pathway.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Correlation between enhancing lesion number and volume on standard and triple dose gadolinium-enhanced brain MRI scans from patients with multiple sclerosis.

We investigated the correlations between numbers and volumes of multiple sclerosis (MS) lesions enhancing on standard dose (SD) and triple dose (TD) gadolinium (Gd)-enhanced brain magnetic resonance imaging (MRI) scans, to clarify whether the measurement of enhancing lesion volumes or the use of TD MRI give additional information which can not be obtained by counting enhancing lesions on SD scans. SD and TD Gd-enhanced brain MRI scans were obtained every month for three months from 40 MS patients. The numbers of total and new enhancing lesions were counted, and the total volumes of enhancing lesions were measured from each of the four scans obtained with the two techniques. Univariate correlations between enhancing lesion numbers and volumes were assessed. The numbers of total and new enhancing lesions seen either on SD or TD scans were significantly correlated (r = 0.91 and 0.93, respectively). The numbers and volumes of total enhancing lesions were significantly correlated on both SD (r = 0.90), and TD (r = 0.89) scans. Moderate correlations were found between the total number of enhancing lesions on SD scans and the average difference between TD and SD scans for total enhancing lesion number (r = 0.66), and between the number of new enhancing lesions on SD scans and the average difference between TD and SD scans for new enhancing lesion number (r = 0.50). Our findings indicate that, both on SD and TD MRI, the counts and the volumes of total and new enhancing lesions are highly correlated, and that lesion counting may suffice to monitor MS activity. On the contrary, this study confirms the usefulness of TD MRI for a more complete assessment of the acute changes occurring in MS patients.

Brain↗
PubMed2003

Outcome analysis and rational management of enhancing lesions incidentally detected on contrast-enhanced MRI of the breast.

OBJECTIVE: The purpose of our study was to assess the prevalence, characteristics, and clinical consequence of incidentally detected enhancing lesions on MRI of the breast. SUBJECTS AND METHODS. MRI of the breast (1.0-T scanner, dynamic gadolinium-enhanced T1-weighted three-dimensional gradient-echo sequence, double breast coil) was performed on 1273 women for different indications. Enhancing incidental lesions were defined as enhancing lesions on MRIs that were not expected from findings on the previous conventional imaging. They were classified in five assessment categories using a scoring system based on morphologic and kinetic enhancement characteristics. Detection of enhancing incidental lesions resulted in a review of mammograms and sonograms with the aim of also localizing these lesions on conventional imaging. The lesions were either biopsied or followed up. RESULTS: Twenty-five percent (274/1086) of all enhancing lesions detected in the study population were enhancing incidental lesions. Enhancing incidental lesions were found in 16% (210/1273) of all study patients. Forty-one percent (113/274) of the enhancing incidental lesions were histologically confirmed. Forty-eight percent (54/113) of the biopsied and 20% (54/274) of all enhancing incidental lesions were malignant. Eleven percent (54/508) of all malignant lesions occurring in the 1273 women were detected solely through additional MRI. Fifty-seven percent (31/54) of these MRI-detected malignant lesions could be identified on a reevaluation of sonograms and mammograms. CONCLUSION: Detection of enhancing incidental lesions should lead to a thorough reevaluation of mammograms and sonograms. If not reidentified, suspicious enhancing incidental lesions should be biopsied, and enhancing incidental lesions that are probably benign should be carefully followed up. Indeterminate enhancing incidental lesions should be histologically examined by minimally invasive techniques or, if they are small, followed up by another MRI 6 months later.

Adolescent↗
PubMed1990

Regulation of the human T-cell receptor alpha gene enhancer: multiple ubiquitous and T-cell-specific nuclear proteins interact with four hypomethylated enhancer elements.

Transcription of human T-cell receptor (TCR) alpha genes is regulated by a T-cell-specific transcriptional enhancer that is located 4.5 kilobases 3' of the C alpha gene segment. Previous studies have demonstrated that this enhancer contains at least five nuclear protein-binding sites called T alpha 1 to T alpha 5. In the studies described in this report, we have determined the molecular requirements for human TCR alpha enhancer function. In vitro mutagenesis and deletion analyses demonstrated that full enhancer activity is retained in a 116-base-pair fragment containing the T alpha 1 and T alpha 2 nuclear protein-binding sites and that both of these sites are required for full enhancer function. Functional enhancer activity requires that the T alpha 1 and T alpha 2 binding sites be separated by more than 15 and fewer than 85 base pairs. However, the sequence of this spacer region and the relative phase of the two binding sites on the DNA helix do not affect enhancer function. Deletion and mutation analyses demonstrated that the T alpha 3 and T alpha 4 nuclear protein-binding sites are not necessary or sufficient for TCR alpha enhancer activity. However, a fragment containing these two sites was able to compensate for T alpha 1 and T alpha 2 mutations that otherwise abolished enhancer activity. Electrophoretic mobility shift analyses of the TCR alpha enhancer binding proteins revealed that the T alpha 1, T alpha 3, and T alpha 4 binding proteins are expressed in a variety of T-cell and non-T-cell tumor cell lines. In contrast, one of the two T alpha 2 binding activities was detected only in T-cell nuclear extracts. The activity of the TCR alpha enhancer does not appear to be regulated solely at the level of DNA methylation on that the enhancer sequences were found to be identically hypomethylated in B and T cells as compared with fibroblasts. Taken together, these results suggest that TCR alpha enhancer activity is regulated by the interaction of multiple T-cell-specific and ubiquitous nuclear proteins with partially redundant cis-acting enhancer elements that are hypomethylated in cells of the lymphoid lineage.

Base Sequence↗
PubMed1994

[Usefulness of superparamagnetic iron oxide particle (AMI-25) enhanced MR imaging for the diagnosis of liver tumors: comparison with contrast enhanced CT].

The purpose of this study was to clarify the usefulness of SPIO-enhanced MRI in the diagnosis of liver tumors in comparison with contrast-enhanced CT. The subjects were forty patients with 154 nodules in the liver. We compared SPIO-enhanced MRI with contrast-enhanced CT in terms of tumor-liver contrast and detectability of liver tumors. In terms of tumor liver contrast, SPIO-enhanced MRI was equal or superior to contrast-enhanced CT in 82% of cases. In the detectability of liver tumor, SPIO-enhanced MRI detected more tumors than contrast-enhanced CT, especially small tumors. Tumors undetected by SPIO-enhanced MRI that were detected by contrast-enhanced CT and/or plain MRI were adenomatous hyperplasia and inflammatory pseudotumor according to fine needle biopsy. There were no severe complications of SPIO-enhanced MRI. In conclusion, SPIO-enhanced MRI will be more useful than contrast-enhanced CT in the diagnosis of liver tumors. SPIO-enhanced MRI may be a promising diagnostic method for the detection of hepatic tumors, especially small ones.

Adult↗
PubMed1996

Somatic hypermutation of a lambda 2 transgene under the control of the lambda enhancer or the heavy chain intron enhancer.

Previous experiments have suggested an important role for the Ig enhancers and transcription in targeting somatic hypermutation. To determine whether the requirement of the enhancers is Ig chain specific, we analyzed two lambda 2 light chain transgenes under the control of different enhancers, either the lambda 2-4 enhancer or the heavy chain intron enhancer. The transgenes were amplified and cloned from B220+PNAhigh B cells from either Peyer's patches (PP) or SRBC-immunized spleen. The lambda 2 transgene under the control of the lambda 2-4 enhancer underwent mutation in both the PP and splenic B cell populations, but at a frequency lower than endogenous light chain genes. This requirement for the lambda 2-4 enhancer could be replaced by the heavy chain intron enhancer. Interestingly, the heavy chain intron enhancer-driven lambda 2 construct showed evidence of statistically significant mutation in the PP B cell population, but not the spleen-derived population. This difference in somatic hypermutation suggests that a lower mutation frequency can be more readily detected in B220+PNAhigh B cells isolated from the PP. The ability of the heavy chain intron enhancer to replace the lambda 2-4 enhancer shows that the requirement for the Ig enhancers in somatic hypermutation is not Ig locus specific. Given that these Ig enhancers have very few elements in common, our results further suggest that the Ig enhancers are primarily important in the timing of transcription in the mutating B cell population.

Animals↗
PubMed1993

Transcription enhancer factor-1 (TEF-1) DNA binding sites can specifically enhance gene expression at the beginning of mouse development.

In an effort to identify transcriptional elements that are recognized at different stages of early mouse development, polyomavirus (PyV) enhancer mutations were selected for their ability to support PyV transcription and replication in various mouse undifferentiated embryonal carcinoma (EC) and embryonic stem (ES) cell lines. Several of these enhancer mutations were then isolated, sequenced and tested for their ability to stimulate the PyV early gene promoter in plasmid DNA that was either transfected into EC, ES and fibroblast cell lines, or injected into the nuclei of mouse 1-cell and 2-cell embryos. EC, ES and fibroblast cell lines showed clear preferences for different enhancer configurations, and cleavage-stage embryos (2- to 8-cell stage) strongly preferred the same enhancer configuration favored by ES cells. This 'embryo responsive' (ER) enhancer configuration was characterized by a tandem duplication of the region containing a single point mutation that created a DNA binding site for Transcription Enhancer Factor-1 (TEF-1). ER enhancers stimulated the PyV promoter up to 350-fold in embryos, and were up to 74-fold more active than the wild-type PyV enhancer. Most of the activity from PyER enhancers could be duplicated in 2-cell embryos by synthesizing only the tandemly repeated sequence. Comparison of these synthetic enhancers with ER enhancers confirmed that TEF-1 DNA binding sites were highly preferred in ES cells and cleavage-stage embryos, and suggested that ER enhancer activity resulted primarily from cooperative interaction between either two closely spaced TEF-1 DNA binding sites or two TEF-1 DNA binding sites separated by a third, as yet unidentified, transcription factor binding site. These results provide a prototype of a mammalian embryo responsive enhancer, and suggest that TEF-1 plays an important role in activation of gene expression at the beginning of mammalian development.

Animals↗
PubMed2001

Chronic hepatitis: correlation of early patchy and late linear enhancement patterns on gadolinium-enhanced MR images with histopathology initial experience.

The purposes of our study were to describe the early and late enhancement patterns of the liver on gadolinium-enhanced dynamic magnetic resonance (MR) images in patients with chronic hepatitis and to correlate these findings with histopathology. Patients were entered into the study based on the presence of chronic hepatitis, imaging evaluation with MR imaging (MRI), including early and late postgadolinium images, and histopathologic correlation. Early and late dynamic postgadolinium MR images of 29 consecutive patients with a pathologically proven diagnosis of chronic hepatitis were retrospectively evaluated for the presence of three types of enhancement, i.e., homogeneous, linear, and patchy. Correlation was made between the enhancement patterns on MR images and blinded retrospective interpretation of the histopathologic specimens, which were obtained within 3 months of the MR examination. Of the 29 patients, 16 (55.2%) patients showed patchy enhancement on the early gadolinium-enhanced MR images. In 11 (68.8%) of these 16 patients, histopathology demonstrated numerous macrophages, variable hepatocyte necrosis, and increased steatosis. The remaining 13 (44.8%) patients showed homogeneous enhancement on the early gadolinium-enhanced MR images. In 11 (84.6%) of these 13 patients, histopathology demonstrated few or no macrophages, little or no hepatocellular necrosis, and little or no steatosis. The correlation between patchy enhancement and acute liver inflammation was significant (P = 0.005). On the late gadolinium-enhanced MR images, 20 (69.0%) of 29 patients showed prominent linear enhancement. In 19 (95.0%) of these 20 patients, histopathology revealed hepatic fibrosis. We concluded that in patients with chronic hepatitis, the presence of early patchy enhancement indicates either concurrent or recent hepatocellular damage, whereas the presence of late linear enhancement indicates the presence of fibrosis, with a high degree of correlation with histopathologic findings.

Adolescent↗
PubMed2005

Evolution of transcriptional enhancers in the immunoglobulin heavy-chain gene: functional characteristics of the zebrafish Emu3' enhancer.

Past studies of the channel catfish immunoglobulin heavy-chain (IgH) locus indicates that it lacks an Emu enhancer in the J(H)-Cmu1 intron but does have an enhancer, termed Emu3', in the mu-delta intergenic region. The positioning of the catfish enhancer downstream of the mu-chain exons is predicted to be unfavorable for antibody-affinity maturation in catfish, and would also have been an impediment to the evolution of class switch recombination, had it existed in early tetrapods. To determine if this downstream enhancer is a general feature of teleost fish, we have identified the location of the transcriptional enhancer in the zebrafish IgH locus. We find that zebrafish, like catfish, only have an Emu3'-like enhancer that has cross-species activity, but which is B-cell-specific in its activity. A 300-bp region of the zebrafish enhancer shares sequence homology with the core of the catfish Emu3', although there has been loss and gain of specific octamer enhancer motifs. Mutagenesis studies demonstrate that the zebrafish IgH enhancer depends on a pair of E-box motifs that are found in the enhancer core. Similarly spaced E-box motifs appear to exist in the Emu3' enhancer regions of other teleost fish, suggesting this is a common feature among fish IgH enhancers. We discuss how this distal positioning of the enhancer may influence affinity maturation in extant teleosts as well as the evolution of this process in the early tetrapods.

Amino Acid Motifs↗
PubMed2005

Importance of extracolonic findings at IV contrast medium-enhanced CT colonography versus those at non-enhanced CT colonography.

To compare the clinical importance of extracolonic findings at intravenous (IV) contrast-enhanced CT colonography versus those at non-enhanced CT colonography. IV contrast medium-enhanced (n=72) and non-enhanced (n=30) multidetector CT colonography was performed in 102 symptomatic patients followed by conventional colonoscopy on the same day. The impact of extracolonic findings on further work up and treatment was assessed by a review of patient records. Extracolonic findings were divided into two groups: either leading to further work up respectively having an impact on therapy or not. A total of 303 extracolonic findings were detected. Of those, 71% (215/303) were found on IV contrast-enhanced CT, and 29% (88/303) were found on non-enhanced CT colonography. The extracolonic findings in 25% (26/102) of all patients led to further work up or had an impact on therapy. Twenty-two of these patients underwent CT colonography with IV contrast enhancement, and four without. The percentage of extracolonic findings leading to further work up or having an impact on therapy was higher for IV contrast-enhanced (31%; 22/72) than for non-enhanced (13%; 4/30) CT scans (P=0.12). IV contrast-enhanced CT colonography produced more extracolonic findings than non-enhanced CT colonography. A substantially greater proportion of findings on IV contrast-enhanced CT colonography led to further work up and treatment than did non-enhanced CT colonography.

Adenocarcinoma↗
PubMed1987

Adenovirus transforming 19-kD T antigen has an enhancer-dependent trans-activation function and relieves enhancer repression mediated by viral and cellular genes.

The adenovirus E1b region codes for two major tumor antigens of 19 kD and 55 kD, which are important for cell transformation. Our results indicate that the 19-kD T antigen possesses two enhancer-regulatory functions. It can trans-activate enhancer-linked promoters and relieve enhancer repression mediated by viral and cellular repressors. The 19-kD activation function enhances expression from different promoters linked to SV40, Py, Ela, and immunoglobulin heavy-chain enhancers. Enhancer activation by the 19-kD protein appears to be cell type-specific, since the heavy-chain and SV40 enhancers were not trans-activated in myeloma cells whereas the same enhancers were trans-activated in fibroblasts. The 19-kD enhancer activation function appears to be dominant over the enhancer repression function of E1a, since in cells expressing the 19-kD protein there is no significant repression despite a large increase in E1a expression. The 19-kD T antigen activates the Py enhancer in undifferentiated F9 cells indicating that the activation function of E1b masks enhancer repression by an "E1a-like" cellular gene product. The enhancer activation function of the 19-kD T antigen may be important for cell transformation and cell differentiation.

Adenovirus Early Proteins↗
PubMed1990

The genome of hepatitis B virus contains a second enhancer: cooperation of two elements within this enhancer is required for its function.

Previous studies have identified an enhancer (enhancer I) at nucleotides (nt) 1074 to 1234 in the genome of the human hepatitis B virus (HBV), which locates immediately upstream from the X gene. By analysis of the expression of the chloramphenicol acetyltransferase gene driven by a heterologous simian virus 40 early promoter, we describe the identification of a second enhancer (enhancer II) at nt 1636 to 1741, which locates downstream of enhancer I and immediately upstream of the core gene. With various deletions at the 5' end of enhancer II, a positive regulatory element was identified at nt 1636 to 1690 (the II-A element), with the 5' boundary between nt 1636 and 1671. The II-A element alone did not have an enhancer function, but the enhancer activity was achieved by the concomitant presence of the sequence from nt 1704 to 1741 (the II-B element). The II-B element alone did not have enhancer activity. These results indicate that cooperation between the II-A and II-B elements is required to exhibit the enhancer activity of enhancer II. We also show that enhancer II stimulates the transcriptional activity of both the SPI and SPII promoters of the surface gene. Therefore, the SPI promoter activity is regulated by the proximal HNF-1 binding element and the distal enhancers I and II. These results indicate that multiple regulatory elements scattered over the whole viral genome are involved in the regulation of expression of each individual HBV gene and that the same regulatory element controls the expression of different HBV genes. The relative positions of these regulatory elements in the HBV genome suggest that they may control the expression of HBV genes in a coordinate and cooperative manner.

Carcinoma, Hepatocellular↗
PubMed1999

Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein-specific enhancer sequences.

Splicing enhancers are RNA sequences required for accurate splice site recognition and the control of alternative splicing. In this study, we used an in vitro selection procedure to identify and characterize novel RNA sequences capable of functioning as pre-mRNA splicing enhancers. Randomized 18-nucleotide RNA sequences were inserted downstream from a Drosophila doublesex pre-mRNA enhancer-dependent splicing substrate. Functional splicing enhancers were then selected by multiple rounds of in vitro splicing in nuclear extracts, reverse transcription, and selective PCR amplification of the spliced products. Characterization of the selected splicing enhancers revealed a highly heterogeneous population of sequences, but we identified six classes of recurring degenerate sequence motifs five to seven nucleotides in length including novel splicing enhancer sequence motifs. Analysis of selected splicing enhancer elements and other enhancers in S100 complementation assays led to the identification of individual enhancers capable of being activated by specific serine/arginine (SR)-rich splicing factors (SC35, 9G8, and SF2/ASF). In addition, a potent splicing enhancer sequence isolated in the selection specifically binds a 20-kDa SR protein. This enhancer sequence has a high level of sequence homology with a recently identified RNA-protein adduct that can be immunoprecipitated with an SRp20-specific antibody. We conclude that distinct classes of selected enhancers are activated by specific SR proteins, but there is considerable sequence degeneracy within each class. The results presented here, in conjunction with previous studies, reveal a remarkably broad spectrum of RNA sequences capable of binding specific SR proteins and/or functioning as SR-specific splicing enhancers.

Alternative Splicing↗
PubMed2003

Value of contrast-enhanced power Doppler sonography using a microbubble echo-enhancing agent in evaluation of small breast lesions.

PURPOSE: The purpose of this study was to prospectively evaluate the usefulness of contrast-enhanced power Doppler sonography (PDUS) using a microbubble echo-enhancing agent in differentiating between malignant and benign small breast lesions. PATIENTS AND METHODS: Between July 1, 2000, and September 30, 2001, we performed gray-scale sonographic examination of patients in whom diagnostic sonography or screening mammography had revealed solid breast lesions measuring less than 2 cm in the largest dimension. The patients were then examined on PDUS before and after injection of a microbubble contrast agent. The sonographic findings for all 3 techniques, as well as the morphologic features of the Doppler signals for each patient before and after injection of the contrast agent on PDUS, were independently assessed. Each lesion was classified as "benign" or "malignant" on the basis of specific criteria for sonographic interpretation. A hemodynamic study was performed in which time-transit profiles of the Doppler signals on contrast-enhanced PDUS were generated using a computer-assisted program, and the results for each patient were compared with the findings of a histopathologic examination of surgical specimens. RESULTS: Thirty-six patients (35 women and 1 man) with a mean age of 43.5 years (range, 18-69 years) were evaluated. The tumors ranged from 4 to 19 mm in the largest dimension. Histopathologic examination revealed that 19 tumors were benign and 17 were malignant. For morphologic diagnosis of the malignant lesions, the sensitivity of gray-scale sonography was 100%, compared with 29% for PDUS without contrast enhancement. The specificity of gray-scale sonography was 47%, compared with 74% for PDUS without contrast enhancement. Contrast-enhanced PDUS had a sensitivity of 71% and a specificity of 58%. The diagnostic accuracy was 72% for gray-scale sonography, 53% for PDUS without contrast enhancement, and 64% for contrast-enhanced PDUS. The time-transit profiles of the hemodynamic study did not reveal a statistically significant difference in the accuracy rates of contrast-enhanced PDUS between benign and malignant breast lesions. CONCLUSIONS: Compared with PDUS without contrast enhancement, contrast-enhanced PDUS provides better visualization of the morphology of vascular Doppler signals that is characteristic of malignancy and therefore has a higher sensitivity and diagnostic accuracy, albeit a lower specificity. In differentiating between benign and malignant small breast lesions, contrast-enhanced PDUS can be helpful when used with gray-scale sonography and PDUS without contrast enhancement.

Adolescent↗
PubMedDate not supplied

Segmental enhancement of the cochlea on contrast-enhanced MR: correlation with the frequency of hearing loss and possible sign of perilymphatic fistula and autoimmune labyrinthitis.

PURPOSE: To relate the finding of selective enhancement of different turns of the cochlea to the frequency range of the hearing loss measured by audiogram. METHODS: Six patients aged 23 to 53 years, four men and two women, who presented with sudden hearing loss and had segmental enhancement of different turns of the cochlea on contrast-enhanced MR imaging were included in this retrospective study. The patients were imaged on a 1.5 T MR imaging system using pre- and postcontrast axial T1-weighted images and postcontrast coronal T1-weighted images through the temporal bone. RESULTS: The basal turn of the cochlea enhanced selectively in five of the six patients and the apical turn enhanced in the sixth patient. All patients had sensorineural hearing loss. Three of the patients with basal turn enhancement had predominantly high-frequency hearing loss, whereas the patient with apical turn enhancement had predominantly low-frequency hearing loss. The two other patients with basal turn enhancement had complete hearing loss. Three patients had presumed autoimmune labyrinthitis. The other three patients had strong clinical and surgical evidence of a perilymphatic fistula. CONCLUSION: Contrast-enhanced MR imaging may demonstrate selective enhancement of different turns of the cochlea. In certain patients, the areas of enhancement may correlate with specific hearing loss in the frequencies mapped by the enhancing segment. Enhancement of the cochlea may represent radiologic evidence of cochlear inflammation secondary to a perilymphatic fistula.

Adult↗