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PubMed1996

Infiltrating lobular carcinoma of the breast. Clinicopathologic analysis of 975 cases with reference to data on conservative therapy and metastatic patterns.

BACKGROUND: The clinicopathologic features of infiltrating lobular carcinoma (ILC), which represents 5% to 15% of all breast cancers, are still controversial. In particular, the high frequency of multicentric lesions has led to questioning of the effectiveness of conservative treatment for this type of cancer. By studying a large number of cases, we aimed to compare the clinicopathological features of ILC with those of nonlobular infiltrating carcinoma (NLIC) and to assess the advisability of conservative therapy in the management of ILC. METHODS: The population analyzed included 726 cases of ILC, 249 cases of mixed ILC/invasive ductal carcinoma (ILC/IDC), and 10,061 cases of NLIC. The age of patients, TNM status, estrogen- and progesterone-receptor status (ER, PR), and histologic grades of the 3 groups were compared. The follow-up was carried out on a subgroup of 5846 cases. RESULTS: At diagnosis, ILC tumors were found to be larger on average and were detected in patients older than those with NLIC, but the degree of lymph node involvement was lower in patients with ILC than in NLIC. In ILC, tumors are more frequently grade I and ER-positive than in NLIC. Multicentric lesions were not significantly more frequent in ILC than in NLIC. The overall survival, locoregional control, disease free interval, and metastatic spread rates were not different among the three groups neither by univariate nor multivariate analysis, but the pattern of metastatic dissemination was different. In 480 cases of ILC considered for conservation therapy, the local recurrence and overall survival rates were similar to those observed for IDC. CONCLUSIONS: Our analysis specifies the clinicopathological features of ILC and confirms that conservation therapy may be an appropriate treatment for this type of cancer.

Breast Neoplasms↗
PubMed2006

Prioritization for conservation of northern European cattle breeds based on analysis of microsatellite data.

Northern European indigenous cattle breeds are currently endangered and at a risk of becoming extinct. We analyzed variation at 20 microsatellite loci in 23 indigenous, 3 old imported, and 9 modern commercial cattle breeds that are presently distributed in northern Europe. We measured the breeds' allelic richness and heterozygosity, and studied their genetic relationships with a neighbor-joining tree based on the Chord genetic distance matrix. We used the Weitzman approach and the core set diversity measure of Eding et al. (2002) to quantify the contribution of each breed to the maximum amount of genetic diversity and to identify breeds important for the conservation of genetic diversity. We defined 11 breeds as a "safe set" of breeds (not endangered) and estimated a reduction in genetic diversity if all nonsafe (endangered) breeds were lost. We then calculated the increase in genetic diversity by adding one by one each of the nonsafe breeds to the safe set (the safe-set-plus-one approach). The neighbor-joining tree grouped the northern European cattle breeds into Black-and-White type, Baltic Red, and Nordic cattle groups. Väne cattle, Bohus Poll, and Danish Jersey had the highest relative contribution to the maximum amount of genetic diversity when the diversity was quantified by the Weitzman diversity measure. These breeds not only showed phylogenetic distinctiveness but also low within-population variation. When the Eding et al. method was applied, Eastern Finncattle and Lithuanian White Backed cattle contributed most of the genetic variation. If the loss of the nonsafe set of breeds happens, the reduction in genetic diversity would be substantial (72%) based on the Weitzman approach, but relatively small (1.81%) based on the Eding et al. method. The safe set contained only 66% of the observed microsatellite alleles. The safe-set-plus-one approach indicated that Bohus Poll and Väne cattle contributed most to the Weitzman diversity, whereas the Eastern Finncattle contribution was the highest according to the Eding et al. method. Our results indicate that both methods of Weitzman and Eding et al. recognize the importance of local populations as a valuable resource of genetic variation.

Animals↗
PubMed2001

Pseudoknots in prion protein mRNAs confirmed by comparative sequence analysis and pattern searching.

The human prion gene contains five copies of a 24 nt repeat that is highly conserved among species. An analysis of folding free energies of the human prion mRNA, in particular in the repeat region, suggested biased codon selection and the presence of RNA patterns. In particular, pseudoknots, similar to the one predicted by Wills in the human prion mRNA, were identified in the repeat region of all available prion mRNAs available in GenBank, but not those of birds and the red slider turtle. An alignment of these mRNAs, which share low sequence homology, shows several co-variations that maintain the pseudoknot pattern. The presence of pseudoknots in yeast Sup35p and Rnq1 suggests acquisition in the prokaryotic era. Computer generated three-dimensional structures of the human prion pseudoknot highlight protein and RNA interaction domains, which suggest a possible effect in prion protein translation. The role of pseudoknots in prion diseases is discussed as individuals with extra copies of the 24 nt repeat develop the familial form of Creutzfeldt-Jakob disease.

Base Sequence↗
PubMed1996

Mutational analysis of the human nucleotide excision repair gene ERCC1.

The human DNA repair protein ERCC1 resides in a complex together with the ERCC4, ERCC11 and XP-F correcting activities, thought to perform the 5' strand incision during nucleotide excision repair (NER). Its yeast counterpart, RAD1-RAD10, has an additional engagement in a mitotic recombination pathway, probably required for repair of DNA cross-links. Mutational analysis revealed that the poorly conserved N-terminal 91 amino acids of ERCC1 are dispensable for both repair functions, in contrast to a deletion of only four residues from the C-terminus. A database search revealed a strongly conserved motif in this C-terminus sharing sequence homology with many DNA break processing proteins, indicating that this part is primarily required for the presumed structure-specific endonuclease activity of ERCC1. Most missense mutations in the central region give rise to an unstable protein (complex). Accordingly, we found that free ERCC1 is very rapidly degraded, suggesting that protein-protein interactions provide stability. Survival experiments show that the removal of cross-links requires less ERCC1 than UV repair. This suggests that the ERCC1-dependent step in cross-link repair occurs outside the context of NER and provides an explanation for the phenotype of the human repair syndrome xeroderma pigmentosum group F.

Amino Acid Sequence↗
PubMed1999

Characterization of the gene encoding a 26-kilodalton protein (OMP26) from nontypeable Haemophilus influenzae and immune responses to the recombinant protein.

A 26-kDa protein (OMP26) isolated and purified from nontypeable Haemophilus influenzae (NTHI) strain 289 has been shown to enhance clearance of infection following pulmonary challenge with NTHI in rats. DNA sequence analysis revealed that it was 99% identical to a gene encoding a cell envelope protein of the H. influenzae Rd strain (TIGR accession no. HI0916). The deduced amino acid sequence revealed a hydrophilic polypeptide rich in basic amino acids. Restriction fragment length polymorphism analysis suggested that the OMP26 gene was relatively conserved among isolates of NTHI. Analysis of the deduced amino acid sequence of the OMP26 gene from 20 different isolates showed that similarity with NTHI-289 ranged from 96.5% (1 isolate) to 99.5% (14 isolates). Two recombinant forms of OMP26, a full length 28-kDa protein (equivalent to preprotein) and a 26-kDa protein lacking a 23-amino-acid leader peptide (equivalent to processed protein), were assessed in immunization studies for the ability to induce an immune response that would be as effective as the native protein in enhancing the clearance of NTHI following pulmonary challenge in rats. Immunization with the recombinant protein that included the leader peptide was more effective in enhancing pulmonary clearance, and it induced a better cell-mediated response and higher titers of systemic and mucosal antibody. This study has characterized a 26-kDa protein from NTHI that shows significant potential as a vaccine candidate.

Amino Acid Sequence↗
PubMed2001

Analysis of Schizosaccharomyces pombe mediator reveals a set of essential subunits conserved between yeast and metazoan cells.

With the identification of eight new polypeptides, we here complete the subunit characterization of the Schizosaccharomyces pombe RNA polymerase II holoenzyme. The complex contains homologs to all 10 essential gene products present in the Saccharomyces cerevisiae Mediator, but lacks clear homologs to any of the 10 S. cerevisiae components encoded by nonessential genes. S. pombe Mediator instead contains three unique components (Pmc2, -3, and -6), which lack homologs in other cell types. Presently, pmc2(+) and pmc3(+) have been shown to be nonessential genes. The data suggest that S. pombe and S. cerevisiae share an essential protein module, which associates with nonessential speciesspecific subunits. In support of this view, sequence analysis of the conserved yeast Mediator components Med4 and Med8 reveals sequence homology to the metazoan Mediator components Trap36 and Arc32. Therefore, 8 of 10 essential genes conserved between S. pombe and S. cerevisiae also have a metazoan homolog, indicating that an evolutionary conserved Mediator core is present in all eukaryotic cells. Our data suggest a closer functional relationship between yeast and metazoan Mediator than previously anticipated.

Amino Acid Sequence↗
PubMed2005

Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.

Semaphorins are a large family of transmembrane proteins. The gene for SEMA4A encodes a transmembrane protein comprising 760 amino acids. To investigate its association with human retinal degeneration, mutation screening of the SEMA4A gene was carried out on 190 unrelated patients suffering from a variety of eye diseases. We report the first observation of the involvement of SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD). We screened the DNA of 135 patients with RP, 25 patients with CRD, and 30 with LCA using SSCP and direct DNA sequencing for mutations in the SEMA4A gene. Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects. Both mutations identified occur in the conserved semaphorin domain. Multiple sequence alignments using Clustal analysis showed that R713Q is a conserved substitution and D345H is a semi-conserved substitution. We conclude that these mutations are a cause of various retinal degenerations.

Blindness↗
PubMed2002

Phylogenetic analysis of Hoxa 11 sequences reveals absence of transposable elements, conservation of transcription factor binding sites, and suggests antisense coding function.

Nine thousand and eighty-eight base pairs of the chicken Hoxa 11 gene, including 8470 bases 5' of the translation start site were sequenced, and the characteristics of the upstream sequence investigated. Consistent with previous findings that middle repetitive elements are rare in the HoxA cluster, no repetitive elements were found other than simple oligonucleotide repeats. Multiple and pairwise alignments of the chicken upstream sequence with its human and mouse orthologs revealed multiple regions of 80% or higher homology across species. For the chicken, these regions were separated by sequences with no significant homology to human, mouse, or in most cases any other Genbank sequences. Selective clustering of transcription factor binding motifs was found to occur within the conserved homologous regions, suggesting evolutionary conservation of critical regulatory sequences. Of particular interest, seven conserved Cdx binding sites were found in the Hoxa 11 promoter, suggesting regulation by a non-clustered Caudal homeobox gene. Previous analysis of the mouse and human Hoxa 11 genes found a conserved antisense transcript, of unknown function. The chicken Hoxa 11 antisense strand included a conserved open reading frame capable of encoding 168 amino acids. Comparison of this region in mouse and chicken showed seven insertion/deletions, with each a multiple of three bases, thereby preserving open reading frame.

Animals↗
PubMed1992

Structural and putative regulatory sequences of Kluyveromyces ribosomal protein genes.

The transcription of the majority of the ribosomal protein (rp) genes of Saccharomyces cerevisiae is activated by cis-acting elements, designated RPG boxes, which specifically bind the multifunctional protein RAP1 in vitro. To investigate to what extent this global system of transcription regulation has been conserved, we have isolated a number of rp genes of the related yeast species Kluyveromyces lactis and Kluyveromyces marxianus, whose counterparts in Saccharomyces are controlled by RAP1. The coding regions of these genes showed a sequence similarity of about 90% when compared to their Saccharomyces counterparts. In contrast, little or no sequence similarity was found between the upstream regions and the intervening sequences of Kluyveromyces and Saccharomyces homologs. However, the occurrence and the position of the introns is conserved. The sequence data also show that the physical linkage that exists in S. cerevisiae between the rp genes encoding RP59 (CRY1), S24 and L46 is conserved in Kluyveromyces. Northern analysis demonstrated that each of the isolated Kluyveromyces genes is transcriptionally active. By sequence comparison we identified a number of conserved sequences in the upstream region of each of the Kluyveromyces rp genes, which we designated the X, Z and RPGK boxes. The last one is highly similar, though not identical, to the S. cerevisiae RPG box. Functional analysis of the intergenic region between the genes encoding Kluyveromyces ribosomal proteins S24 and L46 showed that the RPGK box (+Z box) functions as a transcriptional activator, while the X box acts as a transcriptional repressor. Band-shift assays confirmed the existence of a RAP1-like protein in Kluyveromyces that binds to the RPGK box but not to the S. cerevisiae RPG box. In contrast, S. cerevisiae RAP1 did recognize the RPGK box.

Amino Acid Sequence↗
PubMed2000

Characterization of an overexpressed spindle protein during a baculovirus infection.

The nucleopolyhedrovirus CfDEFNPV contains a gene encoding a viral protein, which accumulates as bipyramidal inclusion bodies (spindles) in the cytoplasm of infected cells. The spindles appear as early as 24 h postinfection, approximately 1 day earlier than viral occlusion bodies (OBs). Purification and characterization of the spindle protein was complicated by the fact that the OBs copurified with the spindles. We therefore modified CfDEFNPV by replacing the polyhedrin gene (plh) with a cassette containing the green fluorescent protein (GFP) gene. The recombinant virus did not produce OBs; however, the synthesis and morphogenesis of the spindles were not altered. When analyzed by SDS-PAGE, the spindles produced a 50-kDa protein, which was termed spindlin. Tunicamycin inhibition and endoglycosidase studies showed that spindlin was glycosylated. The N-terminus of spindlin was sequenced and its gene (gp50) was located on the viral genome. The gene was cloned and sequenced. Homologs of gp50 were found in several baculoviruses as well as in entomopoxviruses (EPV). In the latter virus, the homologous gene is that of fusolin, which also encodes a protein that forms spindle-shaped inclusion bodies in the cytoplasm of infected cells. Immunoblot analysis indicated that spindlin and fusolin were not serologically related, even though they share conserved polypeptide domains. Sequence analysis showed that gp50 of CfDEFNPV contains two late promoter motifs (TTAAG) in its 5' flanking region. Both were used, but the proximal motif (-14 to -18 nt relative to the ATG) was the primary sequence from which most of the mRNA was initiated. When gp50 was cloned in a heterologous baculovirus expression system, spindlin was synthesized, although the spindles were irregular in shape. This suggested that the spindle structure may be species-specific or it may require more than one gene product for its morphogenesis.

Amino Acid Sequence↗
PubMed1985

Promoter specificity of a sporulation-induced form of RNA polymerase from Bacillus subtilis.

The program of gene expression that underlies endospore formation by Bacillus subtilis may be controlled in part by a sporulation-induced form of RNA polymerase, E sigma 29. The nucleotide sequences of four promoters, which are known to be recognized by E sigma 29, are highly conserved at two regions, 10 bp and 35 bp upstream from the start point of transcription. We have used oligonucleotide-directed mutagenesis to construct several base substitutions in the ctc promoter from B. subtilis to test the role of the highly conserved sequences in utilization of the promoter by E sigma 29. In vitro transcription analysis demonstrated that the conserved nucleotides at positions -15, -14 and -12 affect the utilization of the promoter by E sigma 29. These and previous results support a model in which E sigma 29 recognizes its cognate promoters by interacting with nucleotides near the -10 and -35 regions. We also examined the effects of these base substitutions on utilization of the promoter by two other forms of RNA polymerase from B. subtilis, E sigma 37 and E sigma 32.

Bacillus subtilis↗
PubMed2005

Highly conserved regulatory elements around the SHH gene may contribute to the maintenance of conserved synteny across human chromosome 7q36.3.

Comparative genomic analysis reveals an exceptionally large section of conserved shared synteny between the human 7q36 chromosomal region and the pufferfish (Fugu rubripes) genome. Remarkably, this conservation extends not only to gene order across 16 genes, but also to the position and orientation of a number of prominent conserved noncoding elements (CNEs). A functional assay using zebrafish has shown that most of the CNEs have reproducible and specific enhancer activity. This enhancer activity is often detected in a subset of tissues which reflect the endogenous expression pattern of a proximal gene, though some CNEs may act over a long range. We propose that the distribution of CNEs, and their probable association with a number of genes throughout the region, imposes a critical constraint on genome architecture, resulting in the maintenance of such a large section of conserved synteny across the vertebrate lineage.

Animals↗
PubMed2005

Intercomparison of the community multiscale air quality model and CALGRID using process analysis.

This study was designed to examine the similarities and differences between two advanced photochemical air quality modeling systems: EPA Models-3/CMAQ and CALGRID/CALMET. Both modeling systems were applied to an ozone episode that occurred along the I-5 urban corridor in western Washington and Oregon during July 11-14, 1996. Both models employed the same modeling domain and used the same detailed gridded emission inventory. The CMAQ model was run using both the CB-IV and RADM2 chemical mechanisms, while CALGRID was used with the SAPRC-97 chemical mechanism. Outputfrom the Mesoscale Meteorological Model (MM5) employed with observational nudging was used in both models. The two modeling systems, representing three chemical mechanisms and two sets of meteorological inputs, were evaluated in terms of statistical performance measures for both 1- and 8-h average observed ozone concentrations. The results showed that the different versions of the systems were more similar than different, and all versions performed well in the Portland region and downwind of Seattle but performed poorly in the more rural region north of Seattle. Improving the meteorological input into the CALGRID/CALMET system with planetary boundary layer (PBL) parameters from the Models-3/CMAQ meteorology preprocessor (MCIP) improved the performance of the CALGRID/CALMET system. The 8-h ensemble case was often the best performer of all the cases indicating that the models perform better over longer analysis periods. The 1-h ensemble case, derived from all runs, was not necessarily an improvement over the five individual cases, but the standard deviation about the mean provided a measure of overall modeling uncertainty. Process analysis was applied to examine the contribution of the individual processes to the species conservation equation. The process analysis results indicated that the two modeling systems arrive at similar solutions by very different means. Transport rates are faster and exhibit greater fluctuations in the CMAQ cases than in the CALGRID cases, which lead to different placement of the urban ozone plumes. The CALGRID cases, which rely on the SAPRC97 chemical mechanism, exhibited a greater diurnal production/loss cycle of ozone concentrations per hour compared to either the RADM2 or CBIV chemical mechanisms in the CMAQ cases. These results demonstrate the need for specialized process field measurements to confirm whether we are modeling ozone with valid processes.

Aerosols↗
PubMed2003

The role of the conserved Trp330 in Flp-mediated recombination. Functional and structural analysis.

The active site of Flp contains, in addition to a transdonated nucleophilic tyrosine, five other residues that are highly conserved within the lambda-integrase family of site-specific recombinases and the type IB topoisomerases. We have used site-directed mutagenesis and x-ray crystallography to investigate the roles of two such residues, Lys223 and Trp330. Our findings agree with studies on related enzymes showing the importance of Lys223 in catalysis but demonstrate that in Flp-mediated recombination the primary role of Trp330 is architectural rather than catalytic. Eliminating the hydrogen bonding potential of Trp330 by phenylalanine substitution results in surprisingly small changes in reaction rates, compared with dramatic decreases in the activities of W330A, W330H, and W330Q. The structure of a W330F mutant-DNA complex reveals an active site nearly identical to that of the wild type. The phenylalanine side chain preserves most of the van der Waals interactions Trp330 forms with the Tyr343-containing trans helix, which may be particularly important for the docking of this helix. Our studies of Trp330 provide the first detailed examination of this conserved residue in the lambda-integrase family, suggesting that the relative importance of active site residues may differ among Flp and related enzymes.

Bacterial Proteins↗
PubMed1999

A highly conserved sequence in the 3'-untranslated region of the drosophila Adh gene plays a functional role in Adh expression.

Phylogenetic analysis identified a highly conserved eight-base sequence (AAGGCTGA) within the 3'-untranslated region (UTR) of the Drosophila alcohol dehydrogenase gene, Adh. To examine the functional significance of this conserved motif, we performed in vitro deletion mutagenesis on the D. melanogaster Adh gene followed by P-element-mediated germline transformation. Deletion of all or part of the eight-base sequence leads to a twofold increase in in vivo ADH enzymatic activity. The increase in activity is temporally and spatially general and is the result of an underlying increase in Adh transcript. These results indicate that the conserved 3'-UTR motif plays a functional role in the negative regulation of Adh gene expression. The evolutionary significance of our results may be understood in the context of the amino acid change that produces the ADH-F allele and also leads to a twofold increase in ADH activity. While there is compelling evidence that the amino acid replacement has been a target of positive selection, the conservation of the 3'-UTR sequence suggests that it is under strong purifying selection. The selective difference between these two sequence changes, which have similar effects on ADH activity, may be explained by different metabolic costs associated with the increase in activity.

Alcohol Dehydrogenase↗
PubMedDate not supplied

Breast-conserving therapy vs mastectomy in early-stage breast cancer: a meta-analysis of 10-year survival.

BACKGROUND: The randomized trials comparing breast-conserving therapy (BCT), i.e., surgery and radiation to the breast, with mastectomy in early-stage breast cancer use a variety of protocols. Meta-analysis may assist in understanding the impact of these differences on survival. PURPOSE: To evaluate the possible variations of the relative efficacy of BCT and mastectomy in terms of overall survival according to tumor size, nodal status, and use of adjuvant radiation therapy. METHODS: The most recent published results and, where available, updated patient-level data from randomized controlled trials of BCT and mastectomy for early-stage breast cancer were combined in a meta-analysis using a random effects model. Pooled survival rates and odds ratios were generated according to subgroups of nodal status and tumor size. Five- and 10-year odds ratios were also determined according to adjuvant radiation protocol. RESULTS: The pooled odds ratio comparing 10-year survival for BCT and mastectomy was 0.91. The odds ratios comparing the two treatment regimens were not significant after grouping according to tumor size and nodal status. When more than 50% of node-positive patients in both the mastectomy and BCT arms received adjuvant radiation, both arms had similar survival rates. When less than 50% of node-positive patients in both arms received adjuvant nodal radiation, the odds ratio was 0.69, and patients receiving BCT had a survival advantage. CONCLUSIONS: Patients allocated to BCT have survival rates at least as high as patients allocated to mastectomy. When all protocols were combined, nodal status and tumor size did not significantly alter the relative survival rates. However, under some conditions, particularly for node-positive patients, BCT may confer a relative survival advantage over mastectomy. In particular, mastectomy without adjuvant radiation appears to be inferior to BCT for node-positive patients.

Breast Neoplasms↗
PubMed2003

[Modalities and limits of conservative treatment of adenocarcinoma in situ of the uterine cervix: analysis of nine cases and review of the literature].

OBJECTIVE: The aim of this study is to assess the results of conservative management of adenocarcinoma in situ (AIS) of the uterine cervix in young patients. PATIENTS AND METHODS: Data of 16 patients treated for AIS were reviewed: 10 were treated initially conservatively (cold knife conization in five patients, loop excision in three patients and cervical amputation in two patients) and six radically. One patient treated initially conservatively with loop excision and positive margins underwent a completion surgery (hysterectomy). RESULTS: None patient had recurrence whatever the type of surgery (radical or conservative) with a mean follow-up of 74 months. Two pregnancies were observed. DISCUSSION AND CONCLUSIONS: Conservative surgery for patients with AIS could be considered in young patients. But [for] reviewing literature several conditions should be respected: careful follow-up after conservative treatment; cold knife conization; length of cone specimen >25 mm and free margins. If those criteria are respected the risk of recurrent disease under the form of invasive carcinoma is low.

Adenocarcinoma↗