Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is evident that there is not a single uteroplacental or villous lesion that results in fetal growth restriction. It is more likely that it is the accumulation (or total burden) of placental injury that, when present for a sufficient time interval, leads to FGR. Future studies that focus on patterns of lesions, rather than on individual lesions, may prove to be more rewarding in elucidating the causal pathways by which placental histopathology is translated into FGR and its attendant neonatal and pediatric sequelae.
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PMID:Placental pathology of fetal growth restriction. 942 88

Recent genetic studies have shown that Apert's syndrome results from mutations of the fibroblast growth factor (FGF) receptor 2 gene. We were interested in investigating the expression of FGF receptor 2 at the tissue level in children with Apert's syndrome. We studied FGF receptor activity in cranial sutures of children with Apert's syndrome and nonsyndromic, isolated craniosynostosis. Fourteen children between the ages of 6 months and 12 months were studied. Five of these children had Apert's syndrome with coronal suture stenosis. Nine children had an isolated, nonsyndromic coronal stenosis. Stenosed and nonstenosed cranial sutures were removed at the time of cranioplasty, fixed, decalcified, and paraffinized. Immunohistochemistry was performed with labeled, specific anti-FGR receptor 2 antibodies. We found lower levels of FGF receptor 2 staining in both stenosed and unstenosed sutures of children with Apert's syndrome compared with those from children with a nonsyndromic suture stenosis. Furthermore, fused sutures from children with Apert's syndrome demonstrated lower levels of FGF receptor 2 staining than unfused sutures from the same sample. The findings suggest that Apert's syndrome correlates with low FGF receptor 2 activity in cranial sutures. These results are consistent with and similar to our findings in Crouzon's syndrome, and support genetic studies showing localized mutational changes occurring at the FGF receptor 2 gene for both Apert's and Crouzon's syndromes. Furthermore, the findings suggest the possibility that variable expression of FGF receptor 2 occurs at the tissue level in patients with Apert's syndrome.
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PMID:Apert's syndrome correlates with low fibroblast growth factor receptor activity in stenosed cranial sutures. 955 76

Two obstacles limiting the efficacy of nearly all cancer gene therapy trials are low gene transduction efficiencies and the lack of tumor specificity. Recently, a replication-competent, E1B-attenuated adenovirus (ONYX-015) was developed that could overcome these limitations, because it was capable of efficiently and selectively destroying tumor cells lacking functional p53. In an attempt to improve both the efficacy and safety of this approach, we constructed a similar adenovirus (FGR) containing a cytosine deaminase (CD)/herpes simplex virus type-1 thymidine kinase (HSV-1 TK) fusion gene, thereby allowing for the utilization of double-suicide gene therapy, which has previously been demonstrated to produce significant antitumor effects and potentiate the therapeutic effects of radiation. The FGR virus exhibited the same tumor cell specificity and replication kinetics as the ONYX-015 virus in vitro. Importantly, both the CD/5-FC and HSV-1 TK/GCV suicide gene systems markedly enhanced the tumor cell-specific cytopathic effect of the virus, and, as expected, sensitized tumor cells to radiation. By contrast, neither the FGR virus nor either suicide gene system showed significant toxicity to normal human cells. Both suicide gene systems could be used to suppress viral replication effectively, thereby providing a means to control viral spread. The results support the thesis that the three-pronged approach of viral therapy, suicide gene therapy, and radiotherapy may represent a powerful and safe means of selectively destroying tumor cells in vivo.
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PMID:A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. 965 Jun 10

Several loci on the short arm of chromosome 1 (1p) have been reported as the consensus deleted regions for the putative suppressor genes of neuroblastoma by deletion mapping. The significance of deletion in 1p on the clinical features of neuroblastoma remains controversial. To clarify the relationship between the clinical features of neuroblastoma cases and genetic status of 1p, we performed deletion mapping on 1p on samples obtained from 58 cases with neuroblastoma using 12 highly polymorphic microsatellite or minisatellite loci. Loss of heterozygosity of 1p was detected in 19 cases (33%) of primary tumors and in 21 cases (36%) when metastatic and recurrent sites were included. They were classified into two groups according to the 1p deletion pattern: interstitial deletion (group I, n = 11) and terminal deletion (group T, n = 10). The shortest region of overlap in group I ranged between FGR and D1S170 (1p36.1-2). Clinically, all group I cases survived disease free, and none of these cases showed MYCN amplification. However, in group T, eight (80%) cases showed a large terminal deletion from D1S162 (1p32-pter), including the shortest region of overlap of group I, and two (20%) showed a very terminal deletion from D1S160 (1p 36.3). Of the group T cases, only two survived disease free, and seven (70%) showed MYCN amplification. Thus, the candidates for the locations of neuroblastoma suppressor genes on 1p may involve at least two regions, which demonstrate different clinical features.
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PMID:Clinical investigation of neuroblastoma with partial deletion in the short arm of chromosome 1. 981 3

Insulin-like growth factors (IGFs) and their receptors in the fetus are essential for growth and postnatal survival but the role of maternal IGFs is less well understood. Animal and in vitro evidence suggests that maternal IGF-I may have important effects on placental function. Recent work in humans suggests that although there is no relationship between maternal serum IGF-I and normal fetal growth, levels are low in pregnancies complicated by fetal growth restriction due to placental dysfunction. A prospective and observational study was undertaken of the distribution and concentration of placental type I IGF receptors (IGF-IR) in women with small for gestational age (n=26) or appropriately grown (n=14) fetuses. Women were scanned biweekly from 24 weeks to delivery and cases (birthweight <5th centile) were assigned to two groups: 'fetal growth restriction' (FGR; umbilical artery pulsatility index [UAPI] > +2 s.d.; n=16) and 'normal small for gestational age' (SGA; normal UAPI, growth velocity and amniotic fluid; n=10). Immunohistochemistry of the IGF-IR was performed on formol saline-fixed placental biopsies obtained at delivery. In control pregnancies IGF-IR were present in villous endothelium and stroma, trophoblast and decidua and their distribution and density were unchanged in both SGA and FGR pregnancies. We hypothesize that a therapeutic elevation of maternal IGF-I in FGR pregnancy might lead to enhanced placental function and so fetal growth. Our findings of normal localization and density of placental IGF-IR in FGR encourage us to extend our work to look at the effects of maternal IGF-I on the transport of glucose and amino acids.
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PMID:An immunohistochemical study of type I insulin-like growth factor receptors in the placentae of pregnancies with appropriately grown or growth restricted fetuses. 1032 54

Distal alterations of the short arm of chromosome 1 are among the most frequent cytogenetic abnormalities in human breast carcinoma. We studied 96 primary human breast carcinomas for allelic imbalance using a panel of 31 polymorphic microsatellite, restriction fragment length polymorphism, and variable number of tandem repeat markers located mainly in the 1p32-pter region. Allelic imbalance at one or more loci was observed on the short arm of chromosome 1 in 56 (58.3%) of the 96 tumors. The 56 1p-altered tumor DNAs showed loss of heterozygosity (LOH), 12 (21.4%) at all informative loci tested and 44 (78.6%) at some loci. The LOH pattern of these 44 partially deleted tumors identified two distinct consensus regions of deletion on 1p32-pter (1p36.3 and 1p32). These regions match those described by other investigators but are considerably smaller. The 1p32 band is located within one of the two 1p regions of LOH in neuroblastoma, suggesting the involvement of the same unidentified tumor suppressor gene in both human breast cancer and neuroblastoma. The candidate tumor suppressor genes TNFR2, RIZ, DAN, RAP1GA1, FGR, MDGI, EXTL, and hRAD54 were excluded from the two consensus regions of deletion identified at 1p32-pter. Analysis of six polymorphic markers chosen to map within the other deleted regions described in breast tumors confirmed that two additional breast tumor suppressor genes are located in the proximal part (1p22 and 1p13) of chromosome arm 1p. Taken together, these results suggest that several unknown suppressor genes on 1p might be involved in the development of breast cancer. The refinement of the regions of LOH to within a few cM, and the recent publication of transcript maps of the human genome, mean that candidate genes and expressed sequence tags mapping to these deleted regions can now be investigated.
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PMID:Deletion mapping of chromosomal region 1p32-pter in primary breast cancer. 1045 6

Common genetic aberrations of neuroblastoma are deletions of the short arm of chromosome 1 (1p36) and MYCN amplification. Our deletion analysis of 25 tumor cell lines and 171 tumors strongly suggests that 1p harbors several tumor suppressor loci. Distinct loci are involved in MYCN single-copy versus MYCN-amplified neuroblastoma. Deletions in MYCN single-copy tumors have a shortest region of overlap (SRO) of 20 cM at 1p36.3. MYCN-amplified tumors have large deletions with an SRO of about 60 cM, from 1p36.1 to the telomere. This SRO is defined by D1S7 (1p36.1), which was the most distal locus retained. Therefore, a suppressor gene associated with MYCN-amplified tumors probably maps within a few megabases distal of D1S7. In order to map this locus, we further refined this SRO. We mapped the breakpoint of the MYCN-amplified neuroblastoma with the smallest 1p deletion between 56.6 and 57.2 cM from 1pter. Pulsed-field gel electrophoresis and radiation hybrid mapping were used to construct a 5-Mb physical map of this region. The map includes the region from 82.73 till 92.89 cR from 1pter. About half of it was isolated in P1 and PAC clones. The region harbors the genes FGR, SLC9A1, HMG17, EXTL1, AML2, RH, OP18, four ESTs, and a newly identified gene with a transcript size of approximately 7 Kb. Several of the mapped genes have a putative role in cell growth, differentiation, and morphogenesis. Genes Chromosomes Cancer 27:143-152, 2000.
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PMID:An integrated 5-Mb physical, genetic, and radiation hybrid map of a 1p36.1 region implicated in neuroblastoma pathogenesis. 1061 2

Leptin expression in third trimester placenta (p) and leptin concentrations in umbilical cord blood (cb) were investigated in normal pregnancies [n = 10 (p), 31 (cb)] and abnormal pregnancies complicated with (i) maternal insulin-dependent diabetes [IDDM: n = 3 (p), 13 (cb)], (ii) gestational diabetes [GD: n = 2 (p), 10 (cb)] and (iii) fetal growth retardation [FGR: n = 5 (p), 5 (cb)]. By in-situ hybridization and immunohistochemistry, placental leptin mRNA and protein were co-localized to the syncytiotrophoblast and villous vascular endothelial cells. Leptin receptor was immunolocalized to the syncytiotrophoblast. Relative to controls, the FGR group was characterized by low concentrations of placental and cord blood leptin. In a twin pregnancy, the normal-sized infant exhibited more placental and cord blood leptin than its growth-retarded twin. In contrast, both diabetic groups exhibited high concentrations of placental leptin mRNA and protein. The IDDM group exhibited the highest concentrations of leptin in cord blood. No change was observed in the expression of the leptin receptor in either the growth-retarded or diabetic pregnancies. In conclusion, the localization of placental leptin suggests that it may be released into both maternal and fetal blood. Furthermore, in fetal growth-retarded and diabetic pregnancies, the changes in leptin expression in the placenta and in leptin concentrations in umbilical cord blood appear to be related.
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PMID:Placental leptin in normal, diabetic and fetal growth-retarded pregnancies. 1090 88

We have used a new method of genomic microarray to investigate amplification of oncogenes throughout the genome of glioblastoma multiforme (GBM). Array-based comparative genomic hybridization (array CGH) allows for simultaneous examination of 58 oncogenes/amplicons that are commonly amplified in various human cancers. Amplification of multiple oncogenes in human cancers can be rapidly determined in a single experiment. Tumor DNA and normal control DNA were labeled by nick translation with green- and red-tagged nucleotides, respectively. Instead of hybridizing to normal metaphase chromosomes in conventional comparative genomic hybridization (CGH), the probes of the mixed fluorescent labeled DNA were applied to genomic array templates comprised of P1, PAC, and BAC clones of 58 target oncogenes. The baseline for measuring deviations was established by performing a series of independent array CGH using test and reference DNA made from normal individuals. In the present study, we examined fourteen GBMs (seven cell lines and seven tumours) with CGH and array CGH to reveal the particular oncogenes associated with this cancer. High-level amplifications were identified on the oncogenes/amplicons CDK4, GLI, MYCN, MYC, MDM2, and PDGFRA. The highest frequencies of gains were detected on PIK3CA (64.3%), EGFR (57.1%), CSE1L (57.1%), NRAS (50%), MYCN (42.9%), FGR (35.7%), ESR (35.7%), PGY1 (35.7%), and D17S167 (35.7%). These genes are suggested to be involved in the GBM tumorigenesis.
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PMID:Detection of multiple gene amplifications in glioblastoma multiforme using array-based comparative genomic hybridization. 1135 Oct 43

Identification of newborn babies with fetal growth restriction remains a problem both from the multi-factorial aspect of fetal growth and from statistical definition. Besides the usual terms: "Small for gestational age" (SGA) and intrauterine growth retardation (IUGR), often used synonymously, the term "fetal growth retardation" was recently introduced in reference to the genetic growth potential of infants. From a sample of 72,000 births, we have designed a statistical model in order to estimate the expected birth weight taking into account gestational age, sex, birth rank, maternal age, height and pregravid weight, we then calculated an individual limit of birth weight under that a newborn must be considered as having a "fetal growth restriction" quoted FwGR. This new approach allowed us to identify 2 groups of newborns with FGR, one classically identified as SGA (noted FwGR(I)) (3.9%), and the other newly identified as FGR (noted FwGR(II)) (1.4%). In contrast, this approach allowed us to identify a group of "constitutionally small" infants according to their constitutional growth potential (1.1%). In other words, among infants usually defined as SGA (5%), 22% appeared in fact to be "constitutionally small" and therefore misclassified. As an initial validation, we observed that the proportion of maternal hypertension during pregnancy was low in the "constitutionally small" infants (close to that of the normal group), and three times higher in the newly identified group FwGR(II) than in the normal group. Following these results, it seems to be meaningful to follow-up this new group of FwGR(II) infants, in terms of catch-up growth and neurodevelopmental outcome.
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PMID:Definition of fetal growth restriction according to constitutional growth potential. 1164 51


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