Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often described as a model of passively acquired autoimmunity. The signature histologic lesion of autoimmune congenital heart block (CHB) is fibrosis of the conducting tissue and, in some cases, the surrounding myocardium. Although anti-SSA/Ro-SSB/La antibodies are detected in > 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, the risk for a woman with the candidate antibodies to have a child with CHB is 2%. The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and finally eventuate in atrioventricular nodal scarring is not yet defined, but it is clear that the antibodies alone are insufficient to cause disease and fetal factors are likely contributory. Previous in vitro and in vivo studies suggest that the pathologic cascade is initiated via apoptosis, resulting in translocation of SSA/Ro-SSB/La antigens to the cell surface where they are bound by maternal autoantibodies. Subsequently, the Fc portion of the bound immunoglobulin engages Fcgamma receptors on tissue macrophages, resulting in release of TGF-beta at a threshold favoring a profibrotic milieu and irreversible scarring. This cascade also involves tissue-specific activation of TGF-beta, which promotes the modulation of fibroblasts into myofibroblasts, a scarring phenotype. Recent findings point to genetic polymorphisms that promote high production of TGF-beta as possible fetal risk factors for CHB. Further elucidation of maternal and fetal contributory factors should provide insight into the pathogenesis of CHB and the rarity of irreversible injury.
Anat Rec A Discov Mol Cell Evol Biol 2004 Oct
PMID:Autoimmune-associated congenital heart block: dissecting the cascade from immunologic insult to relentless fibrosis. 1536 47

Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRalpha have not been well defined. To identify ERRalpha-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRalpha. ERRalpha upregulated a subset of PGC-1alpha target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRalpha-/- mice. Consistent with the gene expression results, ERRalpha increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRalpha are known targets for the nuclear receptor PPARalpha, and therefore, the interaction between these regulatory pathways was explored. ERRalpha activated PPARalpha gene expression via direct binding of ERRalpha to the PPARalpha gene promoter. Furthermore, in fibroblasts null for PPARalpha and ERRalpha, the ability of ERRalpha to activate several PPARalpha targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1alpha was also shown to activate ERRalpha gene expression. We conclude that ERRalpha serves as a critical nodal point in the regulatory circuitry downstream of PGC-1alpha to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.
Mol Cell Biol 2004 Oct
PMID:Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. 1545 81

This study has been performed to test the hypothesis that different oestrogen receptor beta (ERbeta) splice variants may be important determinants of clinical parameters, including outcome, in post-menopausal women with breast cancer receiving adjuvant endocrine treatment but no chemotherapy. Splice variants ERbeta1, ERbeta2 and ERbeta5 have been analysed by semi-quantitative RT-PCR in a cohort of 105 patients with primary breast cancer. Clinical correlates included age, grade, size, nodal status, ERalpha, progesterone receptor, Ki67, relapse-free survival (RFS) and overall survival (OS). Seventy per cent of cases were ERbeta1 positive, 69% ERbeta2 positive and 70% ERbeta5 positive. Within the cohort, 47% were positive for all three variants while 10% were negative for all three. ERbeta1 exhibited no discernible relationship with disease outcome. ERbeta2 and ERbeta5 expression was significantly associated with better RFS (P<0.005), and ERbeta2 with better OS (P=0.0002). In multivariate analysis, ERbeta2 (P=0.006), nodal status and the level of Ki67 expression were independent predictors for RFS while ERbeta2 (P=0.0008) and Ki67 status were independent predictors for OS. In the ERalpha-positive cases, or in the subset of those receiving adjuvant tamoxifen, ERbeta2 was significantly associated with good RFS (P<0.0005) and was the only independent marker of OS. We conclude that precise identification of splice variants of ERbeta are more important assessors than is ERbeta1 alone of the biological status of individual breast cancers, and hence in predicting their response to endocrine therapy.
J Mol Endocrinol 2004 Dec
PMID:Correlation of mRNA for oestrogen receptor beta splice variants ERbeta1, ERbeta2/ERbetacx and ERbeta5 with outcome in endocrine-treated breast cancer. 1559 Oct 34

Kaposi's sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus type 8, is consistently identified in Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Here we report four cases of KSHV-bearing solid lymphomas that occurred in AIDS patients (cases 1 to 3) and in a human immunodeficiency virus (HIV)-seronegative person (case 4). The patients presented extranodal masses in the abdomen (cases 1, 3, and 4) or skin (case 2), and nodal involvement, together with Kaposi's sarcoma (case 3). The gastrointestinal tract was involved in two patients (cases 1 and 3). The patients did not develop a lymphomatous effusion. KSHV was detected in the tumor cells of all cases by immunohistochemistry and by polymerase chain reaction. Epstein-Barr virus was detected in two of the HIV-related cases. All KSHV-positive solid lymphomas exhibited PEL-like cell morphology. To investigate the relationship of these disorders to PEL and to other AIDS-associated diffuse large cell lymphomas, KSHV-positive solid lymphomas were tested for the expression of a set of genes that were previously shown by gene profiling analysis to define PEL tumor cells. The results showed that expression of this set of genes in KSHV-positive lymphomas is similar to that of PEL but distinct from KSHV-negative AIDS-associated diffuse large cell lymphomas. Because pathobiological features of KSHV-positive solid lymphomas closely mimic those of PEL, our results suggest that KSHV-positive solid lymphomas should be considered as a tissue-based variant of classical PEL, irrespective of HIV status.
J Mol Diagn 2005 Feb
PMID:Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: a tissue-based variant of primary effusion lymphoma. 1568 70

Finite-element modeling provides a full-field method for describing the stress environment of the skull. The utility of finite-element models, however, remains uncertain given our ignorance of whether such models validly portray states of stress and strain. For example, the effects of boundary conditions that are chosen to represent the mechanical environment in vivo are largely unknown. We conducted an in vitro strain gauge experiment on a fresh, fully dentate adult mandible of Macaca fascicularis to model a simplified loading regime by finite-element analysis for purposes of model validation. Under various conditions of material and structural complexity, we constructed dentate and edentulous models to measure the effects of changing boundary conditions (force orientation and nodal constraints) on strain values predicted at the gauge location. Our results offer a prospective assessment of the difficulties encountered when attempting to validate finite-element models from in vivo strain data. Small errors in the direction of load application produce significant changes in predicted strains. An isotropic model, although convenient, shows poor agreement with experimental strains, while a heterogeneous orthotropic model predicts strains that are more congruent with these data. Most significantly, we find that an edentulous model performs better than a dentate one in recreating the experimental strains. While this result is undoubtedly tied to our failure to model the periodontal ligament, we interpret the finding to mean that in the absence of occlusal loads, teeth within alveoli do not contribute significantly to the structural stiffness of the mandible.
Anat Rec A Discov Mol Cell Evol Biol 2005 Apr
PMID:Finite-element modeling of the anthropoid mandible: the effects of altered boundary conditions. 1574 52

The clinical and biologic relevance of the t(14;18) and features of germinal center (GC) differentiation in diffuse large B-cell lymphoma (DLBCL) remain controversial. The authors examined the association of t(14;18) with GC-associated markers and clinical features in 44 de novo DLBCLs (22 nodal and 22 primary extranodal). CD10, bcl-2, and bcl-6 were expressed in 50%, 62%, and 54% of cases respectively. There were no significant differences in expression of these markers between nodal and extranodal cases. Coexpression of CD10 and bcl-6 was seen in 12 of 41 cases, and was more frequent in nodal than extranodal DLBCL (9 of 21 vs. 3 of 20; P = 0.05). A CD10+/bcl-6+ phenotype was not significantly associated with bcl-2 expression, stage, complete remission rate, or survival. The t(14;18) was found in 7 of 44 (16%) cases (6 nodal, 1 extranodal; P = 0.09). It was associated with a CD10+/bcl-6+ phenotype (5 of 7 vs. 7 of 27; P = 0.015) and a trend toward more frequent bcl-6 expression (6 of 7 vs. 15 of 34; P = 0.09), but no association with bcl-2 expression, CD10, clinical stage, complete remission, or survival. Among nodal or high-stage (III-IV) DLBCL, cases with the t(14;18) showed a trend toward decreased survival (P = 0.12).
Appl Immunohistochem Mol Morphol 2005 Jun
PMID:The t(14;18) in diffuse large B-cell lymphoma: correlation with germinal center-associated markers and clinical features. 1589 22

Neoadjuvant chemotherapy (NACT) has become the standard of care for patients with locally advanced breast cancer (LABC). This was a retrospective review of 21 consecutive women who received NACT as initial treatment of LABC, followed by surgical excision. The pre- and post-treatment breast specimens and post-treatment axillary lymph nodes with metastases were immunostained to evaluate for proliferative index (PI) (MIB-1 Immunotech) and vascular endothelial growth factor (VEGF) expression (Santa Cruz, CA, clone A-20). Thirteen of the 21 patients (62%) had more than 50% tumor shrinkage following NACT. The breast's mean PI decreased from 47.86% to 23.95% after treatment (P = 0.005). The mean PI in the post-treatment lymph nodes was 24.47%. A nodal post-NACT PI of less than 10% and progesterone receptor-positive tumor status were associated with better survival, as all such patients are alive. A high PI after NACT was associated with recurrence or death. All of the patients who showed an excellent clinical response had either a decrease in the PI or an absence of a high level of VEGF after NACT. Most patients exhibited persistent expression of VEGF after NACT. Pathologic response in the primary tumor did not correlate with the response in the lymph nodes or with overall survival. NACT reduces the size and PI of the primary breast tumor independent of the patient's node status. The PI may be an early means by which to identify tumors most likely to reduce in size with chemotherapy. A low PI after NACT is associated with better survival. There is persistent expression of VEGF in post-NACT residual breast carcinoma. Thus, anti-VEGF drugs after conventional chemotherapy may benefit patients with residual carcinoma.
Appl Immunohistochem Mol Morphol 2005 Jun
PMID:Expression of vascular endothelial growth factor and proliferation marker MIB1 are influenced by neoadjuvant chemotherapy in locally advanced breast cancer. 1589 27

The oceanic squid family Gonatidae (Mollusca: Cephalopoda) is widely distributed in subpolar and temperate waters, exhibiting behavioral and physiological specializations associated with reproduction. Females of several species undergo muscular degeneration upon maturation; origins of this complex morphogenic change are unknown, hindering our understanding of ecological and morpho-physiological adaptations within the family. To provide further information regarding the evolutionary relationships within Gonatidae, three mitochondrial loci (12S rRNA, 16S rRNA, and cytochrome c oxidase subunit I) were analyzed for 39 individuals representing fourteen gonatid and six outgroup cephalopod species. In addition to elucidating relationships among gonatids, molecular data provided more information than morphological data for problematic specimens. Although some data sets are incongruent or have low nodal support values, combined molecular analysis confirms the presence of gonatid groups previously established by morphological characteristics (i.e., possessing radular teeth in seven longitudinal rows and muscular mantle tissue). These characteristics are basal to taxa possessing radular teeth in five longitudinal rows and less muscular mantle tissue, indicating that the derived forms are those species exhibiting physiological adaptation such as tissue degeneration upon maturation and egg brooding.
Mol Phylogenet Evol 2005 Jul
PMID:Evolutionary relationships among squids of the family Gonatidae (Mollusca: Cephalopoda) inferred from three mitochondrial loci. 1590 60

VEGF signaling inhibition decreases alveolar and vessel growth in the developing lung, suggesting that impaired VEGF signaling may contribute to decreased lung growth in bronchopulmonary dysplasia (BPD). Whether VEGF treatment improves lung structure in experimental models of BPD is unknown. The objective was to determine whether VEGF treatment enhances alveolarization in infant rats after hyperoxia. Two-day-old Sprague-Dawley rats were placed into hyperoxia or room air (RA) for 12 days. At 14 days, rats received daily treatment with rhVEGF-165 or saline. On day 22, rats were killed. Tissue was collected. Morphometrics was assessed by radial alveolar counts (RAC), mean linear intercepts (MLI), and skeletonization. Compared with RA controls, hyperoxia decreased RAC (6.1 +/- 0.4 vs. 11.3 +/- 0.4, P < 0.0001), increased MLI (59.2 +/- 1.8 vs. 44.0 +/- 0.8, P < 0.0001), decreased nodal point density (447 +/- 14 vs. 503 +/- 12, P < 0.0004), and decreased vessel density (11.7 +/- 0.3 vs. 18.9 +/- 0.3, P < 0.001), which persisted despite RA recovery. Compared with hyperoxic controls, rhVEGF treatment after hyperoxia increased RAC (11.8 +/- 0.5, P < 0.0001), decreased MLI (42.2 +/- 1.2, P < 0.0001), increased nodal point density (502 +/- 7, P < 0.0005), and increased vessel density (23.2 +/- 0.4, P < 0.001). Exposure of neonatal rats to hyperoxia impairs alveolarization and vessel density, which persists despite RA recovery. rhVEGF treatment during recovery enhanced vessel growth and alveolarization. We speculate that lung structure abnormalities after hyperoxia may be partly due to impaired VEGF signaling.
Am J Physiol Lung Cell Mol Physiol 2005 Oct
PMID:Recombinant human VEGF treatment enhances alveolarization after hyperoxic lung injury in neonatal rats. 1590 74

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are enzymes involved in the metabolism of 5-fluorouracil (FU). To investigate the relationship of these activities with clinicopathological factors and survival, we measured TS (88 patients) and DPD (122 patients) activities in resected specimens of breast cancer by enzyme assay. Significant difference was found only in TS activity between tumors > or = 20 mm in diameter and those < 20 mm (p = 0.015). There were no significant differences in TS or DPD activity among any other factors. When patients were grouped based on the cut-off levels of TS and DPD activities, 5-year recurrence-free survival rate was 68.8% in the low TS group and 39.7% in the high TS group (p = 0.0081), and 50.8% in the low DPD group and 66.5% in the high DPD group (p = 0.1627). The Cox proportional hazard model demonstrated that in patients in whom we measured TS activity, significant prognostic factors were nodal status and estrogen receptor (ER) status by univariate analysis, and ER status was also significant by multivariate analysis. In patients in whom DPD activity was measured, the significant prognostic factor was ER status by univariate analysis, and ER and Progesterone receptor (PgR) status by multivariate analysis. These results suggested that TS activity, nodal status and hormone receptors may be possible predictors of clinical outcome in breast cancer, but further investigation on prognostic predictors in 5-FU-based chemotherapy is required.
Int J Mol Med 2005 Aug
PMID:Prognostic predictors in breast cancer patients with postoperative 5-fluorouracil-based chemotherapy. 1601 67


<< Previous 1 2 3 4 5 6 7 8 9 10